PDZRN3 destabilizes endothelial cell-cell junctions through a PKCζ-containing polarity complex to increase vascular permeability

2017 ◽  
Vol 10 (464) ◽  
pp. eaag3209 ◽  
Author(s):  
Raj N. Sewduth ◽  
Héléna Kovacic ◽  
Béatrice Jaspard-Vinassa ◽  
Vincent Jecko ◽  
Thomas Wavasseur ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Vascular Permeability ◽  
Cell Junctions ◽  
Cell Cell

scholarly journals RAF dimers control vascular permeability and cytoskeletal rearrangements at endothelial cell‐cell junctions

FEBS Journal ◽  
2019 ◽  
Vol 286 (12) ◽  
pp. 2277-2294 ◽  
Author(s):  
Coralie Dorard ◽  
Botond Cseh ◽  
Karin Ehrenreiter ◽  
Reiner Wimmer ◽  
Andrea Varga ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Vascular Permeability ◽  
Cell Junctions ◽  
Cytoskeletal Rearrangements ◽  
Cell Cell

scholarly journals Phosphorylation of VE-cadherin controls endothelial phenotypes via p120-catenin coupling and Rac1 activation

2011 ◽  
Vol 300 (1) ◽  
pp. H162-H172 ◽  
Author(s):  
Kunihiko Hatanaka ◽  
Michael Simons ◽  
Masahiro Murakami
Keyword(s):  
Cell Migration ◽  
Endothelial Cell ◽  
Vascular Permeability ◽  
Cell Junctions ◽  
Endothelial Cell Migration ◽  
Wild Type ◽  
P120 Catenin ◽  
Cell Functions ◽  
Preferential Binding ◽  
Cell Cell

To establish the role of vascular endothelial (VE)-cadherin in the regulation of endothelial cell functions, we investigated the effect of phosphorylation of a VE-cadherin site sought to be involved in p120-catenin binding on vascular permeability and endothelial cell migration. To this end, we introduced either wild-type VE-cadherin or Y658 phosphomimetic (Y658E) or dephosphomimetic (Y658F) VE-cadherin mutant constructs into an endothelial cell line (rat fat pad endothelial cells) lacking endogenous VE-cadherin. Remarkably, neither wild-type- nor Y658E VE-cadherin was retained at cell-cell contacts because of p120-catenin preferential binding to N-cadherin, resulting in the targeting of N-cadherin to cell-cell junctions and the exclusion of VE-cadherin. However, Y658F VE-cadherin was able to bind p120-catenin and to localize at adherence junctions displacing N-cadherin. This resulted in an enhanced barrier function and a complete abrogation of Rac1 activation and lamellipodia formation, thereby inhibiting cell migration. These findings demonstrate that VE-cadherin, through the regulation of Y658 phosphorylation, competes for junctional localization with N-cadherin and controls vascular permeability and endothelial cell migration.

scholarly journals Angiomotin Regulates Endothelial Cell-Cell Junctions and Cell Motility

2005 ◽  
Vol 280 (41) ◽  
pp. 34859-34869 ◽  
Author(s):  
Anders Bratt ◽  
Olivier Birot ◽  
Indranil Sinha ◽  
Niina Veitonmäki ◽  
Karin Aase ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Motility ◽  
Cell Junctions ◽  
Cell Cell

scholarly journals Brain Endothelial Cell-Cell Junctions: How to “Open” the Blood Brain Barrier

2008 ◽  
Vol 6 (3) ◽  
pp. 179-192 ◽  
Author(s):  
Svetlana Stamatovic ◽  
Richard Keep ◽  
Anuska Andjelkovic
Keyword(s):  
Endothelial Cell ◽  
Blood Brain Barrier ◽  
Cell Junctions ◽  
Brain Barrier ◽  
Brain Endothelial Cell ◽  
Blood Brain ◽  
Cell Cell

Endothelial Cell-Cell Junctions in Tumor Angiogenesis

2019 ◽  
pp. 91-119
Author(s):  
Quentin Roux ◽  
Julie Gavard
Keyword(s):  
Endothelial Cell ◽  
Tumor Angiogenesis ◽  
Cell Junctions ◽  
Cell Cell

scholarly journals A mechanism of Rap1-induced stabilization of endothelial cell–cell junctions

2011 ◽  
Vol 22 (14) ◽  
pp. 2509-2519 ◽  
Author(s):  
Jian J. Liu ◽  
Rebecca A. Stockton ◽  
Alexandre R. Gingras ◽  
Ararat J. Ablooglu ◽  
Jaewon Han ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Small Gtpases ◽  
Cell Junctions ◽  
Physical Interaction ◽  
Dependent Manner ◽  
Cardiovascular Development ◽  
Cavernous Malformations ◽  
Cell Cell

Activation of Rap1 small GTPases stabilizes cell–cell junctions, and this activity requires Krev Interaction Trapped gene 1 (KRIT1). Loss of KRIT1 disrupts cardiovascular development and causes autosomal dominant familial cerebral cavernous malformations. Here we report that native KRIT1 protein binds the effector loop of Rap1A but not H-Ras in a GTP-dependent manner, establishing that it is an authentic Rap1-specific effector. By modeling the KRIT1–Rap1 interface we designed a well-folded KRIT1 mutant that exhibited a ∼40-fold-reduced affinity for Rap1A and maintained other KRIT1-binding functions. Direct binding of KRIT1 to Rap1 stabilized endothelial cell–cell junctions in vitro and was required for cardiovascular development in vivo. Mechanistically, Rap1 binding released KRIT1 from microtubules, enabling it to locate to cell–cell junctions, where it suppressed Rho kinase signaling and stabilized the junctions. These studies establish that the direct physical interaction of Rap1 with KRIT1 enables the translocation of microtubule-sequestered KRIT1 to junctions, thereby supporting junctional integrity and cardiovascular development.

scholarly journals PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jesús Gómez-Escudero ◽  
Cristina Clemente ◽  
Diego García-Weber ◽  
Rebeca Acín-Pérez ◽  
Jaime Millán ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Inflammatory Disease ◽  
Chronic Inflammatory Disease ◽  
Cell Junctions ◽  
Cell Junction ◽  
Collective Migration ◽  
Sprouting Angiogenesis ◽  
Cell Cell

Abstract Angiogenesis, the formation of new blood vessels from pre-existing ones, occurs in pathophysiological contexts such as wound healing, cancer, and chronic inflammatory disease. During sprouting angiogenesis, endothelial tip and stalk cells coordinately remodel their cell-cell junctions to allow collective migration and extension of the sprout while maintaining barrier integrity. All these processes require energy, and the predominant ATP generation route in endothelial cells is glycolysis. However, it remains unclear how ATP reaches the plasma membrane and intercellular junctions. In this study, we demonstrate that the glycolytic enzyme pyruvate kinase 2 (PKM2) is required for sprouting angiogenesis in vitro and in vivo through the regulation of endothelial cell-junction dynamics and collective migration. We show that PKM2-silencing decreases ATP required for proper VE-cadherin internalization/traffic at endothelial cell-cell junctions. Our study provides fresh insight into the role of ATP subcellular compartmentalization in endothelial cells during angiogenesis. Since manipulation of EC glycolysis constitutes a potential therapeutic intervention route, particularly in tumors and chronic inflammatory disease, these findings may help to refine the targeting of endothelial glycolytic activity in disease.

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