Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/115463
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Type: Journal article
Title: A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis
Author: Abraham, S.
Scarcia, M.
Bagshaw, R.
McMahon, K.
Grant, G.
Harvey, T.
Yeo, M.
Esteves, F.
Thygesen, H.
Jones, P.
Speirs, V.
Hanby, A.
Selby, P.
Lorger, M.
Dear, T.
Pawson, T.
Marshall, C.
Mavria, G.
Citation: Nature Communications, 2015; 6(1):ncomms8286-1-ncomms8286-14
Publisher: Macmillan Publishers
Issue Date: 2015
ISSN: 2041-1723
2041-1723
Statement of
Responsibility: 
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
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.
Keywords: 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
Rights: © 2015 Macmillan Publishers Limited. All rights reserved. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
RMID: 0030050075
DOI: 10.1038/ncomms8286
Appears in Collections:Medicine publications

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