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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3185-3192. Prepublished online as a Blood First Edition Paper on January 4, 2005; DOI 10.1182/blood-2004-09-3605. This Article Full Text (PDF) All Versions of this Article: 2004-09-3605v1 105/8/3185    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 Schultess, J. Articles by Smolenski, A. P Search for Related Content PubMed PubMed Citation Articles by Schultess, J. Articles by Smolenski, A. P Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 16, 2004 Accepted December 27, 2004 Rap1GAP2 is a new GTPase activating protein of Rap1 expressed in human platelets Jan Schultess, Oliver Danielewski, and Albert P Smolenski* Institute for Biochemistry II, University of Frankfurt Medical School, Frankfurt, Germany * Corresponding author; email: smolenski{at}biochem2.de. The Ras-like guanine-nucleotide-binding protein Rap1 controls integrin IIb3 activity and platelet aggregation. Recently, we have found that Rap1 activation can be blocked by the NO/cGMP signaling pathway via type I cGMP-dependent protein kinase (cGKI). In search of possible targets of NO/cGMP/cGKI we studied the expression of Rap1-specific GTPase-activating proteins (GAPs) and guanine nucleotide-exchange factors (GEFs) in platelets. We could detect mRNAs for a new protein most closely related to Rap1GAP as well as for PDZ-GEF1, CalDAG-GEFs I and III. Using 5'-RACE we isolated the complete cDNA of the new GAP encoding a 715 aminoacid protein, which we have termed Rap1GAP2. Rap1GAP2 is expressed in at least three splice variants, two of which are detectable in platelets. Endogenous Rap1GAP2 protein partially colocalizes with Rap1 in human platelets. In transfected cells we show that Rap1GAP2 exhibits strong GTPase-activating activity towards Rap1. Rap1GAP2 is highly phosphorylated and we have identified cGKI as a Rap1GAP2 kinase. cGKI phosphorylates Rap1GAP2 exclusively on serine 7, a residue present only in the platelet splice variants of Rap1GAP2. Phosphorylation of Rap1GAP2 by cGKI might mediate inhibitory effects of NO/cGMP on Rap1. Rap1GAP2 is the first GTPase activating protein of Rap1 found in platelets and is likely to have an important regulatory role in platelet aggregation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. H. Ulfman, V. M. Kamp, C. W. van Aalst, L. P. Verhagen, M. E. Sanders, K. A. Reedquist, M. Buitenhuis, and L. Koenderman Homeostatic Intracellular-Free Ca2+ Is Permissive for Rap1-Mediated Constitutive Activation of {alpha}4 Integrins on Eosinophils J. Immunol., April 15, 2008; 180(8): 5512 - 5519. [Abstract] [Full Text] [PDF] M. Hoffmeister, P. Riha, O. Neumuller, O. Danielewski, J. Schultess, and A. P. Smolenski Cyclic Nucleotide-dependent Protein Kinases Inhibit Binding of 14-3-3 to the GTPase-activating Protein Rap1GAP2 in Platelets J. Biol. Chem., January 25, 2008; 283(4): 2297 - 2306. [Abstract] [Full Text] [PDF] J. S. Isenberg, M. J. Romeo, C. Yu, C. K. Yu, K. Nghiem, J. Monsale, M. E. Rick, D. A. Wink, W. A. Frazier, and D. D. Roberts Thrombospondin-1 stimulates platelet aggregation by blocking the antithrombotic activity of nitric oxide/cGMP signaling Blood, January 15, 2008; 111(2): 613 - 623. [Abstract] [Full Text] [PDF] T. J. Jeon, D.-J. Lee, S. Lee, G. Weeks, and R. A. 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