Semaphorin 3A elevates endothelial cell permeability through PP2A inactivation.
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.
Cnrs, UMR8104, 75014 Paris, France.
Armelle
A
Le Guelte
Eva-Maria
EM
Galan-Moya
Julie
J
Dwyer
Lucas
L
Treps
Garance
G
Kettler
Jagoda K
JK
Hebda
Sonia
S
Dubois
Cedric
C
Auffray
Herve
H
Chneiweiss
Nicolas
N
Bidere
Julie
J
Gavard
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology*; D004789:Enzyme Activation; D005910:Glioma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D040121:Semaphorin-3A / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
D040121:Semaphorin-3A; D019061:src-Family Kinases; D054648:Protein Phosphatase 2