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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 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 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 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. Related Collections Cytoskeleton Signal Transduction Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Rap1GAP2 is a new GTPase-activating protein of Rap1 expressed in human platelets Jan Schultess, Oliver Danielewski, and Albert P. Smolenski From the Institute for Biochemistry II, University of Frankfurt Medical School, Frankfurt/Main, Germany. 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 nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling pathway by type 1 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 and for postsynaptic density-95 discs-large and zona occludens protein 1 (PDZ)–GEF1 and CalDAG-GEFs I and III. Using 5'–rapid amplification of cDNA ends (RACE), we isolated the complete cDNA of the new GAP encoding a 715-amino acid protein, which we have termed Rap1GAP2. Rap1GAP2 is expressed in at least 3 splice variants, 2 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-stimulating activity toward 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. Firtel Regulation of Rap1 activity by RapGAP1 controls cell adhesion at the front of chemotaxing cells J. Cell Biol., December 3, 2007; 179(5): 833 - 843. [Abstract] [Full Text] [PDF] S. K. de Oliveira, M. Hoffmeister, S. Gambaryan, W. Muller-Esterl, J. A. Guimaraes, and A. P. Smolenski Phosphodiesterase 2A Forms a Complex with the Co-chaperone XAP2 and Regulates Nuclear Translocation of the Aryl Hydrocarbon Receptor J. Biol. Chem., May 4, 2007; 282(18): 13656 - 13663. [Abstract] [Full Text] [PDF] M. Antl, M.-L. von Bruhl, C. Eiglsperger, M. Werner, I. Konrad, T. Kocher, M. Wilm, F. Hofmann, S. Massberg, and J. Schlossmann IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation Blood, January 15, 2007; 109(2): 552 - 559. [Abstract] [Full Text] [PDF] M. Holinstat, B. Voss, M. L. Bilodeau, J. N. McLaughlin, J. Cleator, and H. E. Hamm PAR4, but Not PAR1, Signals Human Platelet Aggregation via Ca2+ Mobilization and Synergistic P2Y12 Receptor Activation J. Biol. Chem., September 8, 2006; 281(36): 26665 - 26674. [Abstract] [Full Text] [PDF] F. Hofmann, R. Feil, T. Kleppisch, and J. Schlossmann Function of cGMP-Dependent Protein Kinases as Revealed by Gene Deletion Physiol Rev, January 1, 2006; 86(1): 1 - 23. [Abstract] [Full Text] [PDF] P. J. S. Stork and T. J. Dillon Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functions Blood, November 1, 2005; 106(9): 2952 - 2961. [Abstract] [Full Text] [PDF]

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