Journal
JOURNAL OF CELL SCIENCE
Volume 125, Issue 17, Pages 4137-4146Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.108282
Keywords
VE-cadherin; Cell-cell junction; Internalisation; Plexin; Glioma stem cell
Categories
Funding
- Ligue Nationale contre le Cancer [RS12/7595-8]
- Fondation ARC pour la Recherche sur le Cancer [SFI20101201140, JR/AD/MDV-A09/4]
- Association des NeuroOncologues d'Expression Francaise [074391]
- Fondation pour la Recherche Medicale [DPC20111122987]
- Agence Nationale pour la Recherche sur le SIDA et les hepatites virales [NM/no1380/CSS3/AO 2011-2]
- Agence Nationale pour la Recherche [ANRJCJC2010/130601]
- Marie Curie International Reintegration Grant [239126]
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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.
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