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Blood, 15 January 2007, Vol. 109, No. 2, pp. 552-559. Prepublished online as a Blood First Edition Paper on September 21, 2006; DOI 10.1182/blood-2005-10-026294.
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation1 Institut für Pharmakologie und Toxikologie der Technischen Universität München, Munich, Germany; 2 Deutsches Herzzentrum und 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; 3 Biological and Medical Mass Spectrometry, Uppsala Biomedical Centre, Uppsala, Sweden; 4 Protein and Peptide Group, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany; 5 Institute for Biomedical Research (CBR), Harvard Medical School, Boston, MA; 6 Department of Pathology, Harvard Medical School, Boston, MA
Defective regulation of platelet activation/aggregation is a predominant cause for arterial thrombosis, the major complication of atherosclerosis triggering myocardial infarction and stroke. A central regulatory pathway conveying inhibition of platelet activation/aggregation is nitric oxide (NO)/cyclic GMP (cGMP) signaling by cGMP-dependent protein kinase I (cGKI). However, the regulatory cascade downstream of cGKI mediating platelet inhibition is still unclear. Here, we show that the inositol-1,4,5-trisphosphate receptorassociated cGMP kinase substrate (IRAG) is abundantly expressed in platelets and assembled in a macrocomplex together with cGKIß and the inositol-1,4,5-trisphosphate receptor type I (InsP3RI). cGKI phosphorylates IRAG at Ser664 and Ser677 in intact platelets. Targeted deletion of the IRAG-InsP3RI interaction in IRAG
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