Molecular dissection of the role of ARAP3 in angiogenesis
Lead Research Organisation:
Babraham Institute
Department Name: UNLISTED
Abstract
Consistent delivery of oxygen and nutrients to all cells is vital for multicellular organisms. This need becomes particularly apparent during embryonic development or during growth of tumours. To be successful, in both cases, blood vessels need to be formed, by a specialised process termed angiogenesis. Angiogenesis is a very comlex process which requires the co-ordinated action of multiple cellular factors within specialised cells. When the process fails, the developing embryo (or tumour) dies. ARAP3 is a signalling protein which regulates cross-talk between small GTPase proteins of different subfamilies, and which is regulated itself by phosphoinositide 3OH-kinase (PI3K), a key regulator of many cellular processes. We have very recently derived two ARAP3 models, where we can analyse the results of loss of ARAP3 or a situation where the protein is no longer under the control of PI3K. We find that both loss of ARAP3 and loss of its regulation by PI3K leads to embryonic death due to an angiogenesis defect, indicating that ARAP3 is required for embryonic angiogenesis and that this is regulated by PI3K. This project aims to understand why this happens, and which of the small GTPases that ARAP3 talks to are important for this.
Publications

Gambardella L
(2010)
PI3K signaling through the dual GTPase-activating protein ARAP3 is essential for developmental angiogenesis.
in Science signaling

Kartopawiro J
(2014)
Arap3 is dysregulated in a mouse model of hypotrichosis-lymphedema-telangiectasia and regulates lymphatic vascular development.
in Human molecular genetics

Song Y
(2014)
ARAP3 functions in hematopoietic stem cells.
in PloS one

Zudaire E
(2011)
A computational tool for quantitative analysis of vascular networks.
in PloS one
Description | This work explored the physiological function of ARAP3, a poorly characterised effector of phosphoinositide 3-kinase (PI3K). By analysing a mouse that lacked ARAP3, we were able to show that ARAP3, rather than the much better understood 'canonical' PI3K effector PKB/Akt is absolutely required in physiological angiogenesis. Moreover, we showed that ARAP3 is acting immediately downstream of PI3K to regulate angiogenesis, by developing and analysing a mouse in which ARAP3 carried a point mutation that uncoupled it from activation by PI3K. The point mutation mouse phenocopied the severe angiogenesis defect of ARAP3 deficient mice. We also provided evidence to further signalling events both up- and downstream of ARAP3. |
Exploitation Route | This work identified for the first time a PI3K effector that is absolutely required for physiological (developmental) angiogenesis. PI3K is known to also regulate pathological angiogenesis, where it is particularly important in cancer. Clinical trials are underway to block PI3K in cancer with a view to blocking angiogenesis, however, PI3K regulates a large number of processes unrelated to angiogenesis as well. Our work could be taken forward to characterise the role of ARAP3 in pathological angiogenesis. Inhibiting ARAP3 rather than PI3K might be advantageous since fewer side effects would be expected. |
Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | Our work on ARAP3 has been extended to analysis of angiogenesis in the zebrafish by others. Moreover, many groups have started to use a computational analysis tool of complex images of blood vessels that we developed (Angiotool). |
First Year Of Impact | 2010 |
Sector | Digital/Communication/Information Technologies (including Software),Pharmaceuticals and Medical Biotechnology,Other |
Description | Project Grant |
Amount | £237,663 (GBP) |
Funding ID | PG/17/54/32981 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2017 |
End | 09/2020 |
Title | Angiotool |
Description | AngioTool is a software tool for quantitative analysis of microscopic images depicting complex vascular networks. To our knowledge there was no such tool available before. We published an open access article describing AngioTool to increase awareness in the scientific community (see papers) |
Type Of Material | Data analysis technique |
Year Produced | 2011 |
Provided To Others? | Yes |
Impact | This software tool was made freely available to the public and was published as an open access research paper as well. It appears to be widely used in the research community and has been cited in numerous other research papers that use it for analysis of their vascular networks. |
URL | https://ccrod.cancer.gov/confluence/display/ROB2/Home |
Description | International collaboration with NIH National Cancer Institute |
Organisation | National Institutes of Health (NIH) |
Department | National Cancer Institute (NCI) |
Country | United States |
Sector | Public |
PI Contribution | The research pursued for this fellowship has resulted in an international collaboration which already led to publications in peer-reviewed journals. |
Collaborator Contribution | intellectual input |
Impact | two research papers and a book chapter |
Start Year | 2009 |
Description | Press Release Science Signalling |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Our recent Science Signaling paper was chosen for broadcasting by podcast by the editors of Science Signaling. After recording the interview, we also put together a press release, to co-incide with the paper appearing. We had further enquiries from several journalists. I understand the work was cited in some local papers and in 'Business Weekly'. This has publicised our work more widely than the publication in a scientific journal alone would have. |
Year(s) Of Engagement Activity | 2010 |
URL | http://stke.sciencemag.org/content/suppl/2010/10/22/3.145.pc19.DC1 |
Description | Schools Open Day |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | 10 GSCE / 'A'-level student came to the lab, listened to a short talk and participated in a hands-on practical experience. Some of the students provided positive feed-back on the visit to the lab and said it had helped them with their career choice |
Year(s) Of Engagement Activity | 2008,2009,2010,2011 |