Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration (original) (raw)

Nature volume 453, pages 662–666 (2008)Cite this article

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 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 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.

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Acknowledgements

We thank F. Ramadani and K. Okkenhaug (Babraham Institute, Cambridge), E. Cernuda (Hospital Universitario Central de Asturias), T. Makinen (Cancer Research UK London Research Institute), K. Hodivala-Dilke, A. Reynolds and G. D’Amico (Institute of Cancer, Queen Mary, University of London), P. Villalonga (Universitat de les Illes Balears, Spain) and members of the Vanhaesebroeck laboratory (especially N. Osborne, C. See and M. Whitehead) for help and advice, E. Wagner (Research Institute of Molecular Pathology, Vienna), E. Dejana (Institute of Molecular Oncology, Milan), G. Balconi (Mario Negri Institute for Pharmacological Research, Milan), M. Yanagisawa (University of Texas Southwestern Medical Center, Dallas), D. Vestweber (Max-Planck Institute, Muenster), C. Rommel, M. Camps and T. Ruckle (Merck-Serono, Geneva) and Piramed (Slough, UK) for mice and reagents. Personal support was from EMBO (M.G., J.G.-G.), Cancer Research UK (M.G.) and the Fondation pour la Recherche Médicale and the European Union Marie Curie (J.G.-G.). Work in the Vanhaesebroeck laboratory was supported by the Ludwig Institute for Cancer Research Institute, the Biotechnology and Biological Sciences Research Council (BB/C505659/1), the Association for International Cancer Research, European Union (FP6-502935), Cancer Research UK and Barts and the London Charity. R.J.C. is supported by an Association for International Cancer Research grant to A.J.R. (07-0173). L.-K.P. and H.G. are supported by Cancer Research UK.

Author Contributions All authors designed research and analysed data. M.G., J.G.-G., L.C.F., L.-K.P., R.J.C., A.S., W.P., S.M. and P.R.C. performed research. M.G., H.G. and B.V. wrote the paper.

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Authors and Affiliations

  1. Centre for Cell Signalling, Institute of Cancer, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK,
    Mariona Graupera, Julie Guillermet-Guibert, Lazaros C. Foukas, Ashreena Salpekar, Wayne Pearce, Pedro R. Cutillas & Bart Vanhaesebroeck
  2. Vascular Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK,
    Li-Kun Phng & Holger Gerhardt
  3. Randall Division of Cell and Molecular Biophysics, King’s College London, New Hunt’s House, Guy’s Campus, London SE1 1UL, UK
    Robert J. Cain, Jaime Millan & Anne J. Ridley
  4. Gene Targeting Laboratory, The Institute for Stem Cell Research, University of Edinburgh, West Mains Road, Edinburgh EH9 3JQ, UK,
    Stephen Meek & Andrew J. H. Smith
  5. Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, UK
    Christiana Ruhrberg

Authors

  1. Mariona Graupera
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  2. Julie Guillermet-Guibert
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  3. Lazaros C. Foukas
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  4. Li-Kun Phng
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  5. Robert J. Cain
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  6. Ashreena Salpekar
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  7. Wayne Pearce
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  8. Stephen Meek
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  9. Jaime Millan
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  10. Pedro R. Cutillas
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  11. Andrew J. H. Smith
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  12. Anne J. Ridley
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  13. Christiana Ruhrberg
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  14. Holger Gerhardt
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  15. Bart Vanhaesebroeck
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Corresponding authors

Correspondence toHolger Gerhardt or Bart Vanhaesebroeck.

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B.V. is a consultant for PIramed Pharma.

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The file contains Supplementary Methods with additional references and Supplementary Figures S1-S29 with Legends. (PDF 30710 kb)

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Graupera, M., Guillermet-Guibert, J., Foukas, L. et al. Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration.Nature 453, 662–666 (2008). https://doi.org/10.1038/nature06892

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Editorial Summary

Phosphoinositide 3-kinase: Role of the p110a isoform

The p110α isoform of phosphoinositide 3-kinase is shown to play a critical role in normal and pathological angiogenesis. In particular, it is needed to mediate the migration of endothelial cells downstream of VEGF receptor activation, acting upstream of RhoA. This finding suggests that p110a-selective inhibitors, in addition to their direct effects in inhibiting cancer cell proliferation, will also impact on pathological angiogenesis in tumours.