A Rac/Cdc42 Exchange Factor Complex Promotes Formation of Lateral Filopodia and Blood Vessel Lumen Morphogenesis

Overview

Journal Nat Commun

Specialty Biology

Date 2015 Jul 2

PMID 26129894

Citations 54

Authors

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

Affiliations

Soon will be listed here.

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.

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