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

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, Andrew M Hanby, Peter J Selby, Mihaela Lorger, T Neil Dear, Tony Pawson, Christopher J Marshall, Georgia Mavria

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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.

Original languageEnglish
Article number7286
Number of pages14
JournalNature Communications
Publication statusPublished - 1 Jul 2015
Externally publishedYes

Bibliographical note

We thank Hironori Katoh for EGFP DOCK4; Vijay Yajnik for flag-tagged DOCK4 and deletion mutants; Martin Schwartz for the DOCK9 expression construct; Len Stephens for RhoG expression construct; Jean-François Côté for GST–ELMO. We thank Janine Erler for advice on CA-IX staining and Kiran Kulkarni for discussions on DOCK9; Demelza Bird and Kris Wronski for the tumour experiments; Ben Woodman and staff at St James’ Biological Services for ES microinjections and animal husbandry; Biological Services Unit, ICR, for animal husbandry; Mike Shires for optimization of DOCK4 IHC; Anne Sanford and Rebecca Horsfall for technical assistance; Sean Lawler and other colleagues for commenting on the manuscript. The work was funded through project grant from Cancer Research UK (C107/A7631) awarded to C.J.M. and G.M.; project grant from Yorkshire Cancer Research (L357) and pilot grant from Breast Cancer Campaign (2012MaySP047) awarded to G.M. T.P. was supported by grants from the Ontario Research Fund GL2 program and CIHR (MOP-6849); and R.D.B. was supported by a CIHR fellowship. C.J.M. is a Gibb Life Fellow of Cancer Research UK.


  • Animals
  • Cytoskeleton
  • GTPase-Activating Proteins
  • Guanine Nucleotide Exchange Factors
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Pathologic
  • Neovascularization, Physiologic
  • Pseudopodia
  • Vascular Endothelial Growth Factor A
  • cdc42 GTP-Binding Protein
  • rho GTP-Binding Proteins
  • Journal Article
  • Research Support, Non-U.S. Gov't


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