生物谷报道：磷酯酰肌醇3-激酶的p110 α-异形体被发现在正常及病理性血管形成中扮演一个关键角色。尤其是，它是调控VEGF受体激发下游的内皮细胞迁移所需要的，在RhoA的上游发挥作用。这一发现表明，p110α-选择性抑制因子，除了它们在抑制癌细胞增殖中所起的直接作用外，还能影响肿瘤中病理性的血管形成。
生物谷推荐英文原文：
Nature 453, 662-666 (29 May 2008) | doi:10.1038/nature06892; Received 5 November 2007; Accepted 5 March 2008; Published online 30 April 2008
Angiogenesis selectively requires the p110 isoform of PI3K to control endothelial cell migration
Mariona Graupera1, Julie Guillermet-Guibert1, Lazaros C. Foukas1, Li-Kun Phng2, Robert J. Cain3, Ashreena Salpekar1, Wayne Pearce1, Stephen Meek4, Jaime Millan3, Pedro R. Cutillas1, Andrew J. H. Smith4, Anne J. Ridley3, Christiana Ruhrberg5, Holger Gerhardt2 & Bart Vanhaesebroeck1
Centre for Cell Signalling, Institute of Cancer, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK
Vascular Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
King's College London, Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, London SE1 1UL, UK
Gene Targeting Laboratory, The Institute for Stem Cell Research, University of Edinburgh, West Mains Road, Edinburgh EH9 3JQ, UK
Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, UK
Correspondence to: Holger Gerhardt2Bart Vanhaesebroeck1 Correspondence and requests for materials should be addressed to H.G. (Email: Holger.gerhardt@cancer.org.uk) or B.V. (Email: bart.vanh@qmul.ac.uk).
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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 (p110, p110 or p110), constitutively bound to one of five distinct p85 regulatory subunits. PI3Ks have been implicated in angiogenesis2, 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 p110 activity is essential for vascular development. Ubiquitous or endothelial cell-specific inactivation of p110 led to embryonic lethality at mid-gestation because of severe defects in angiogenic sprouting and vascular remodelling. p110 exerts this critical endothelial cell-autonomous function by regulating endothelial cell migration through the small GTPase RhoA. p110 activity is particularly high in endothelial cells and preferentially induced by tyrosine kinase ligands (such as vascular endothelial growth factor (VEGF)-A). In contrast, p110 in endothelial cells signals downstream of G-protein-coupled receptor (GPCR) ligands such as SDF-1, whereas p110 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.
