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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 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 Citation Map 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 CrossRef Google Scholar Articles by Rondaij, M. G. Articles by Voorberg, J. PubMed PubMed Citation Articles by Rondaij, M. G. Articles by Voorberg, J. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Guanine exchange factor RalGDS mediates exocytosis of Weibel-Palade bodies from endothelial cells Mariska G. Rondaij1,*, Ruben Bierings1,2,*, Ellen L. van Agtmaal1, Karina A. Gijzen1, Erica Sellink1, Astrid Kragt1, Stephen S. G. Ferguson3, Koen Mertens1,4, Matthew J. Hannah2, Jan A. van Mourik1,5, Mar Fernandez-Borja6, and Jan Voorberg1 1 Department of Plasma Proteins, Sanquin Research and Landsteiner Laboratory Academic Medical Centre (AMC), University of Amsterdam, Amsterdam, The Netherlands; 2 Division of Molecular Neuroendocrinology, Medical Research Council (MRC) National Institute for Medical Research, London, United Kingdom; 3 Cell Biology Research Group, Robarts Research Institute, Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON; 4 Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; 5 Department of Vascular Medicine AMC, University of Amsterdam, Amsterdam, The Netherlands; and 6 Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory AMC, University of Amsterdam, Amsterdam, The Netherlands 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 knockdown 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 because 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 after stimulation with Ca2+- or cAMP-raising agonists. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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