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Blood, 1 July 2008, Vol. 112, No. 1, pp. 56-63. Prepublished online as a Blood First Edition Paper on April 16, 2008; DOI 10.1182/blood-2007-07-099309. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-07-099309v1 112/1/56    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Rondaij, M. G Articles by Voorberg, J. Search for Related Content PubMed PubMed Citation Articles by Rondaij, M. G Articles by Voorberg, J. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 10, 2007 Accepted March 19, 2008 Guanine exchange factor RalGDS mediates exocytosis of Weibel-Palade bodies from endothelial cells Mariska G Rondaij, Ruben Bierings, Ellen L van Agtmaal, Karina A Gijzen, Erica Sellink, Astrid Kragt, Stephen S.G. Ferguson, Koen Mertens, Matthew J Hannah, Jan A van Mourik, Mar Fernandez-Borja, and Jan Voorberg* Department of Plasma Proteins, Sanquin Research and Landsteiner Laboratory, Amsterdam, Netherlands Division of Molecular Neuroendocrinology, MRC National Institute for Medical Research, London, United Kingdom Department of Physiology and Pharmacology, Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands Department of Vascular Medicine Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Amsterdam, Netherlands * Corresponding author; email: j.voorberg{at}sanquin.nl. The small GTP binding protein Ral has been implicated in regulated exocytosis via its interaction with the mammalian exocyst complex. We have previously demonstrated that Ral is involved in exocytosis of Weibel-Palade bodies (WPBs). Little is known about intracellular signaling pathways that promote activation of Ral in response to ligand binding of G protein-coupled receptors. Here we show that RNAi-mediated knock-down of RalGDS, an exchange factor for Ral, results in inhibition of thrombin- and epinephrine-induced exocytosis of WPBs, while overexpression of RalGDS promotes exocytosis of WPBs. A RalGDS variant lacking its exchange domain behaves in a dominant negative manner by blocking release of WPBs. We also provide evidence that RalGDS binds calmodulin (CaM) via an amino-terminal CaM-binding domain. RalGDS association to CaM is required for Ral activation since a cell permeable peptide comprising this RalGDS CaM-binding domain inhibits Ral activation and WPB exocytosis. Together our findings suggest that RalGDS plays a vital role in the regulation of Ral-dependent WPB exocytosis following stimulation with Ca2+- or cAMP-raising agonists. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Disse, N. Vitale, M.-F. Bader, and V. Gerke Phospholipase D1 is specifically required for regulated secretion of von Willebrand factor from endothelial cells Blood, January 22, 2009; 113(4): 973 - 980. [Abstract] [Full Text] [PDF]

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