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Sci. Signal., 26 October 2010
Vol. 3, Issue 145, p. ra76
[DOI: 10.1126/scisignal.2001026]

RESEARCH ARTICLES

PI3K Signaling Through the Dual GTPase–Activating Protein ARAP3 Is Essential for Developmental Angiogenesis

Laure Gambardella1, Myriam Hemberger2,3, Bethany Hughes1, Enrique Zudaire4, Simon Andrews5, and Sonja Vermeren1*{dagger}

1 Inositide Laboratory, The Babraham Institute, Cambridge CB22 3AT, UK.
2 Epigenetics and Development Laboratory, The Babraham Institute, Cambridge CB22 3AT, UK.
3 Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
4 Angiogenesis Core Facility, National Cancer Institute, National Institutes of Health, Gaithersburg, MD 20892–4605, USA.
5 Bioinformatics, The Babraham Institute, Cambridge CB22 3AT, UK.

* Née Krugmann.

Abstract: One function of phosphoinositide 3-kinase {alpha} (PI3K{alpha}), which generates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3], is its regulation of angiogenesis in the developing embryo and in pathological situations. ARAP3 is a PtdIns(3,4,5)P3- and Rap-activated guanosine triphosphatase (GTPase)–activating protein (GAP) for the small GTPases RhoA and Arf6. Here, we show that deleting Arap3 in the mouse caused embryonic death in mid-gestation due to an endothelial cell–autonomous defect in sprouting angiogenesis. Explants taken at a developmental stage at which no defect was yet present reproduced this phenotype ex vivo, demonstrating that the defect was not secondary to hypoxia, placental defects, or organ failure. In addition, knock-in mice expressing an ARAP3 point mutant that cannot be activated by PtdIns(3,4,5)P3 had angiogenesis defects similar to those of Arap3–/– embryos. Our work delineates a previously unknown signaling pathway that controls angiogenesis immediately downstream of PI3K{alpha} through ARAP3 to the Rho and Arf family of small GTPases.

{dagger} To whom correspondence should be addressed. E-mail: sonja.vermeren{at}bbsrc.ac.uk

Citation: L. Gambardella, M. Hemberger, B. Hughes, E. Zudaire, S. Andrews, S. Vermeren, PI3K Signaling Through the Dual GTPase–Activating Protein ARAP3 Is Essential for Developmental Angiogenesis. Sci. Signal. 3, ra76 (2010).

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