PT  - JOURNAL ARTICLE
AU  - Le Guelte, Armelle
AU  - Galan-Moya, Eva-Maria
AU  - Dwyer, Julie
AU  - Treps, Lucas
AU  - Kettler, Garance
AU  - Hebda, Jagoda K.
AU  - Dubois, Sonia
AU  - Auffray, Cedric
AU  - Chneiweiss, Herve
AU  - Bidere, Nicolas
AU  - Gavard, Julie
TI  - Semaphorin 3A elevates endothelial cell permeability through PP2A inactivation
AID  - 10.1242/jcs.108282
DP  - 2012 Sep 01
TA  - Journal of Cell Science
PG  - 4137--4146
VI  - 125
IP  - 17
4099  - http://jcs.biologists.org/content/125/17/4137.short
4100  - http://jcs.biologists.org/content/125/17/4137.full
SO  - J. Cell Sci.2012 Sep 01; 125
AB  - VE-cadherin-mediated cell–cell junction weakening increases paracellular permeability in response to both angiogenic and inflammatory stimuli. Although Semaphorin 3A has emerged as one of the few known anti-angiogenic factors to exhibit pro-permeability activity, little is known about how it triggers vascular leakage. Here we report that Semaphorin 3A induced VE-cadherin serine phosphorylation and internalisation, cell–cell junction destabilisation, and loss of barrier integrity in brain endothelial cells. In addition, high-grade glioma-isolated tumour-initiating cells were found to secrete Semaphorin 3A, which promoted brain endothelial monolayer permeability. From a mechanistic standpoint, Semaphorin 3A impinged upon the basal activity of the serine phosphatase PP2A and disrupted PP2A interaction with VE-cadherin, leading to cell–cell junction disorganization and increased permeability. Accordingly, both pharmacological inhibition and siRNA-based knockdown of PP2A mimicked Semaphorin 3A effects on VE-cadherin. Hence, local Semaphorin 3A production impacts on the PP2A/VE-cadherin equilibrium and contributes to elevated vascular permeability.