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Blood, 1 January 2009, Vol. 113, No. 1, pp. 244-253.
Prepublished online as a Blood First Edition Paper on September 29, 2008; DOI 10.1182/blood-2008-04-153874.
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Submitted April 28, 2008
Accepted July 28, 2008
The Amot/Patj/Syx signalling complex spatially controls RhoA GTPase activity in migrating endothelial cells
Mira Ernkvist, Nathalie Luna Persson, Stephane Audebert, Patrick Lecine, Indranil Sinha, Miaoliang Liu, Marc Schlueter, Arie Horowitz, Karin Aase, Thomas Weide, Jean-Paul Borg, Arindam Majumdar, and Lars Holmgren*
Department of Oncology and Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden
INSERM, U599, Centre de Recherche en Cancerologie de Marseille, Department of Molecular Pharmacology, Institut Paoli-Calmettes, Universite de la Mediterranee, Marseille, France
Angiogenesis Research Center and Section of Cardiology, Department of Medicine, Dartmouth Medical School, Lebanon, NH, United States
Division of Molecular Nephrology, Department of Internal Medicine D, University Hospital Muenster, Muenster, Germany
Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
* Corresponding author; email: lars.holmgren{at}ki.se.
Controlled regulation of Rho GTPase activity is an essential component mediating growth factor stimulated migration. We have previously shown that angiomotin (Amot), a membrane associated scaffold protein, plays a critical role during vascular patterning and endothelial migration during embryogenesis. However, the signaling pathways by which Amot controls directional migration are not known. Here we have employed peptide pull-down and yeast two-hybrid (Y2H) screening to identify proteins that interact with the C-terminal PDZ-binding motifs of Amot and its related proteins AmotL1 and 2. We report that Amot and its related proteins bind to the RhoA GTPase Exchange Factor (RhoGEF) protein Syx. We show that Amot forms a ternary complex together with Patj (or its paralogue Mupp1) and Syx. By using FRET analysis we provide evidence that Amot controls targeting of RhoA activity to lamellipodia in vitro. We also report that, similar to Amot, morpholino knock down of Syx in zebrafish results in inhibition of migration of inter-segmental arteries. Taken together, our results indicate that the directional migration of capillaries in the embryo is governed by the Amot:Patj/Mupp1:Syx signaling that control local GTPase activity.
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