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A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis

Author

Listed:
  • Sabu Abraham

    (Institute of Cancer Research
    Present address: Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, UK.)

  • Margherita Scarcia

    (Leeds Institute of Cancer and Pathology, University of Leeds, St James’ University Hospital, Beckett Street, Leeds LS9 7TF, UK
    Present address: Faculty of Life Sciences, University of Manchester, Manchester M13 9NT, UK.)

  • Richard D. Bagshaw

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital
    Present address: Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay St., Toronto, M5G0A4, Canada.)

  • Kathryn McMahon

    (Leeds Institute of Cancer and Pathology, University of Leeds, St James’ University Hospital, Beckett Street, Leeds LS9 7TF, UK
    Present address: Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds LS2 9JT, UK.)

  • Gary Grant

    (Leeds Institute of Cancer and Pathology, University of Leeds, St James’ University Hospital, Beckett Street, Leeds LS9 7TF, UK)

  • Tracey Harvey

    (Leeds Institute of Cancer and Pathology, University of Leeds, St James’ University Hospital, Beckett Street, Leeds LS9 7TF, UK
    Present address: The School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.)

  • Maggie Yeo

    (Institute of Cancer Research)

  • Filomena O.G. Esteves

    (Leeds Institute of Cancer and Pathology, University of Leeds, St James’ University Hospital, Beckett Street, Leeds LS9 7TF, UK)

  • Helene H. Thygesen

    (Leeds Institute of Cancer and Pathology, University of Leeds, St James’ University Hospital, Beckett Street, Leeds LS9 7TF, UK
    Present address: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands.)

  • Pamela F. Jones

    (Leeds Institutes of Molecular Medicine, University of Leeds, St James’ University Hospital, Beckett Street, Leeds LS9 7TF, UK)

  • Valerie Speirs

    (Leeds Institute of Cancer and Pathology, University of Leeds, St James’ University Hospital, Beckett Street, Leeds LS9 7TF, UK)

  • Andrew M. Hanby

    (Leeds Institute of Cancer and Pathology, University of Leeds, St James’ University Hospital, Beckett Street, Leeds LS9 7TF, UK)

  • Peter J. Selby

    (Leeds Institute of Cancer and Pathology, University of Leeds, St James’ University Hospital, Beckett Street, Leeds LS9 7TF, UK)

  • Mihaela Lorger

    (Leeds Institute of Cancer and Pathology, University of Leeds, St James’ University Hospital, Beckett Street, Leeds LS9 7TF, UK)

  • T. Neil Dear

    (Leeds Institutes of Molecular Medicine, University of Leeds, St James’ University Hospital, Beckett Street, Leeds LS9 7TF, UK
    Present address: South Australian Health and Medical Research Institute, Adelaide, Australia.)

  • Tony Pawson

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital)

  • Christopher J. Marshall

    (Institute of Cancer Research)

  • Georgia Mavria

    (Leeds Institute of Cancer and Pathology, University of Leeds, St James’ University Hospital, Beckett Street, Leeds LS9 7TF, UK)

Abstract

During angiogenesis, Rho-GTPases influence endothelial cell migration and cell–cell adhesion; however it is not known whether they control formation of vessel lumens, which are essential for blood flow. Here, using an organotypic system that recapitulates distinct stages of VEGF-dependent angiogenesis, we show that lumen formation requires early cytoskeletal remodelling and lateral cell–cell contacts, mediated through the RAC1 guanine nucleotide exchange factor (GEF) DOCK4 (dedicator of cytokinesis 4). DOCK4 signalling is necessary for lateral filopodial protrusions and tubule remodelling prior to lumen formation, whereas proximal, tip filopodia persist in the absence of DOCK4. VEGF-dependent Rac activation via DOCK4 is necessary for CDC42 activation to signal filopodia formation and depends on the activation of RHOG through the RHOG GEF, SGEF. VEGF promotes interaction of DOCK4 with the CDC42 GEF DOCK9. These studies identify a novel Rho-family GTPase activation cascade for the formation of endothelial cell filopodial protrusions necessary for tubule remodelling, thereby influencing subsequent stages of lumen morphogenesis.

Suggested Citation

  • Sabu Abraham & Margherita Scarcia & Richard D. Bagshaw & Kathryn McMahon & Gary Grant & Tracey Harvey & Maggie Yeo & Filomena O.G. Esteves & Helene H. Thygesen & Pamela F. Jones & Valerie Speirs & And, 2015. "A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8286
    DOI: 10.1038/ncomms8286
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    Cited by:

    1. Stergios Tsartsalis & Hannah Sleven & Nurun Fancy & Frank Wessely & Amy M. Smith & Nanet Willumsen & To Ka Dorcas Cheung & Michal J. Rokicki & Vicky Chau & Eseoghene Ifie & Combiz Khozoie & Olaf Ansor, 2024. "A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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