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Blood, 9 April 2009, Vol. 113, No. 15, pp. 3577-3584. Prepublished online as a Blood First Edition Paper on February 3, 2009; DOI 10.1182/blood-2008-09-178913. This Article Full Text (PDF) All Versions of this Article: blood-2008-09-178913v1 113/15/3577    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lian, L. Articles by Abrams, C. S. Search for Related Content PubMed PubMed Citation Articles by Lian, L. Articles by Abrams, C. S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 12, 2008 Accepted January 26, 2009 Loss of pleckstrin defines a novel pathway for PKC-mediated exocytosis Lurong Lian, Yanfeng Wang, Matthew Flick, John Choi, Edward W. Scott, Jay Degen, Mark A. Lemmon, and Charles S. Abrams* Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, United States University of Cincinnati College of Medicine, Cincinnati, OH, United States Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA, United States University of Florida Health Science Center, Gainesville, FL, United States Department of Biochemistry & Molecular Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA, United States * Corresponding author; email: abrams{at}mail.med.upenn.edu. Pleckstrin, the Platelet and Leukocyte C Kinase Substrate, is a prominent substrate of PKC in platelets, monocytes, macrophages, lymphocytes and granulocytes. Pleckstrin accounts for one percent of the total protein in these cells, but is best known for containing the two prototypic Pleckstrin Homology, or PH, domains. Overexpressed pleckstrin can affect polyphosphoinositide second messenger based signaling events; however, its true in vivo role has been unknown. Here we describe mice containing a null mutation within the pleckstrin gene. Platelets lacking pleckstrin exhibit a marked defect in exocytosis of delta and alpha granules, IIb3 activation, actin assembly, and aggregation following exposure to the PKC stimulant, PMA. Pleckstrin-null platelets aggregate normally in response to thrombin, but fail to aggregate in response to thrombin in the presence of PI3K inhibitors, suggesting that a PI3K-dependent signaling pathway compensates for the loss of pleckstrin. Although pleckstrin-null platelets merged their granules in response to stimulation of PKC, they failed to empty their contents into the open canalicular system. This might be attributable to impaired actin assembly present in cells lacking pleckstrin. These data demonstrate that pleckstrin regulates the fusion of granules to the cell membrane, and is an essential component of PKC-mediated exocytosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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