Highlight Publication November 2010

Gambardella L, Hemberger MC, Hughes B, Zudaire E, Andrews SR, Vermeren S (2010)
PI3K signaling through the dual GTPase-activating protein ARAP3 is essential for developmental angiogenesis.
Science Signaling 3 ra76
http://dx.doi.org/10.1126/scisignal.2001026

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Lay description

This paper reports the discovery of a previously unknown signalling pathway that controls the formation and remodelling of blood vessels – a process called angiogenesis. The research reveals that a signalling protein called ARAP3 is vital for establishing a circulatory system to nourish the developing embryo. Mice lacking ARAP3 die before birth because of the failure to ‘sprout’ new blood vessels during embryonic development, a process orchestrated by a family of proteins called phosphoinositide 3-kinases (PI3Ks) which regulate ARAP3.

While angiogenesis occurs during growth and development, it also serves to repair and rebuild blood vessels after injury and in wound healing. Understanding how these processes normally work opens up the possibility of finding out what is happening when things go wrong. Angiogenesis also occurs in many pathological situations like cancer - tumours need a blood supply to obtain oxygen and nutrients. Age-related macular degeneration (AMD) is another condition involving aberrant growth of blood vessels, which causes irreversible loss of vision in the elderly. The identification of a novel player in these pathways opens up possibilities for novel anti-angiogenic and pro-angiogenic therapies.

PI3Ks are involved in a diverse range of activities inside cells, such as cell proliferation, motility and survival, which are central to angiogenesis. PI3Ks generate a lipid signalling molecule called phosphatidylinositol-(3, 4,5)-trisphosphate, known as PIP3 for short, which localises to the inside of the outer cell membrane and activates PI3K effectors. About 50 PI3K effectors have been identified, which bind to and are regulated by PIP3. ARAP3 is one such effector.

The paper now reports that ARAP3, which was discovered at Babraham, is needed for angiogenesis – embryos of mice lacking ARAP3 died because they did not form blood vessels correctly. Instead of an organised network of capillaries, the circulatory system of these embryos was highly disorganised and remodelling of the primitive vascularisation had not progressed in an orderly fashion. The process of the formation of new ‘sprouts’ during angiogenesis thus goes wrong when ARAP3 is missing, or indeed if it is unable to interact with the PI3K lipid product PIP3, pointing to a previously unknown signalling pathway that controls developmental angiogenesis immediately downstream of the PI3K signalling protein, through ARAP3 to Rho and Arf family small GTPases, which are important for cell motility, a crucial aspect of angiogenesis.

ARAP3’s unique binding specificity to and regulation by PIP3 may make it a suitable drug target for anti-angiogenic therapies. Results from these investigations, supported by both MRC and BBSRC, are thus contributing greater understanding to the processes through which angiogenesis occurs and may provide a rationale for the development of therapies to treat angiogenesis-based diseases.

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About the lead author

Laure Gambardella holds a PhD in Molecular & Cellular Biology of Development from the Pierre et Marie Curie University, Paris, awarded for her work with Yann Barrandon on transcription factors in epidermal stem cells. She obtained a post-doctoral position in the Department of Hematology, University of Cambridge led by Anthony Green, working on hematopoietic stem cells, erythopoiesis and angiogenesis. Back in the laboratory of Yann Barrandon in Paris and then in Lausanne, Laure supervised projects developing in vivo and in vitro models to follow stem cell migration inside hair follicles using retroviral infection and confocal microscopy. She joined Martin Turner’s group at the Babraham Institute in 2004 and applied the technique of retroviral infection to hematopoietic stem cells. Since 2008 Laure has been working with Sonja Vermeren analysing the function of the GTPase activating protein ARAP3 in angiogenesis.