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Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration

Item Type:Article
Title:Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration
Creators Name:Graupera, M., Guillermet-Guibert, J., Foukas, L.C., Phng, L.K., Cain, R.J., Salpekar, A., Pearce, W., Meek, S., Millan, J., Cutillas, P.R., Smith, A.J.H., Ridley, A.J., Ruhrberg, C., Gerhardt, H. and Vanhaesebroeck, B.
Abstract:Phosphoinositide 3-kinases (PI3Ks) signal downstream of multiple cell-surface receptor types. Class IA PI3K isoforms1 couple to tyrosine kinases and consist of a p110 catalytic subunit (p110α, p110β or p110δ), constitutively bound to one of five distinct p85 regulatory subunits. PI3Ks have been implicated in angiogenesis(2,3,4,5), but little is known about potential selectivity among the PI3K isoforms and their mechanism of action in endothelial cells during angiogenesis in vivo. Here we show that only p110α activity is essential for vascular development. Ubiquitous or endothelial cell-specific inactivation of p110α led to embryonic lethality at mid-gestation because of severe defects in angiogenic sprouting and vascular remodelling. p110α exerts this critical endothelial cell-autonomous function by regulating endothelial cell migration through the small GTPase RhoA. p110α activity is particularly high in endothelial cells and preferentially induced by tyrosine kinase ligands (such as vascular endothelial growth factor (VEGF)-A). In contrast, p110β in endothelial cells signals downstream of G-protein-coupled receptor (GPCR) ligands such as SDF-1α, whereas p110δ is expressed at low level and contributes only minimally to PI3K activity in endothelial cells. These results provide the first in vivo evidence for p110-isoform selectivity in endothelial PI3K signalling during angiogenesis.
Keywords:Cell Movement, Class I Phosphatidylinositol 3-Kinases, Cultured Cells, Endothelial Cells, Phosphatidylinositol 3-Kinases, Physiologic Neovascularization, RNA Interference, Signal Transduction, Vascular Endothelial Growth Factor A, Wounds and Injuries, rho GTP-Binding Proteins, Animals, Mice, Rats
Publisher:Nature Publishing Group
Page Range:662-666
Date:29 May 2008
Official Publication:https://doi.org/10.1038/nature06892
PubMed:View item in PubMed

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