Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration.
Phosphoinositide 3-kinases (PI3Ks) signal downstream of multiple cell-surface receptor types. Class IA PI3K isoforms couple to tyrosine kinases and consist of a p110 catalytic subunit (p110alpha, p110beta or p110delta), constitutively bound to one of five distinct p85 regulatory subunits. PI3Ks have been implicated in angiogenesis, 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 p110alpha activity is essential for vascular development. Ubiquitous or endothelial cell-specific inactivation of p110alpha led to embryonic lethality at mid-gestation because of severe defects in angiogenic sprouting and vascular remodelling. p110alpha exerts this critical endothelial cell-autonomous function by regulating endothelial cell migration through the small GTPase RhoA. p110alpha activity is particularly high in endothelial cells and preferentially induced by tyrosine kinase ligands (such as vascular endothelial growth factor (VEGF)-A). In contrast, p110beta in endothelial cells signals downstream of G-protein-coupled receptor (GPCR) ligands such as SDF-1alpha, whereas p110delta 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.
Graupera
Mariona
M
Centre for Cell Signalling, Institute of Cancer, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK.
Guillermet-Guibert
Julie
J
Foukas
Lazaros C
LC
Phng
Li-Kun
LK
Cain
Robert J
RJ
Salpekar
Ashreena
A
Pearce
Wayne
W
Meek
Stephen
S
Millan
Jaime
J
Cutillas
Pedro R
PR
Smith
Andrew J H
AJ
Ridley
Anne J
AJ
Ruhrberg
Christiana
C
Gerhardt
Holger
H
Vanhaesebroeck
Bart
B
D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D042783:Endothelial Cells / Q000166:cytology* / Q000201:enzymology*; D005260:Female; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D014947:Wounds and Injuries; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D042461:Vascular Endothelial Growth Factor A; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; C497132:PIK3CB protein, human; C526380:RhoA protein, mouse