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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4243-4252. Prepublished online as a Blood First Edition Paper on September 7, 2007; DOI 10.1182/blood-2006-10-050633. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-10-050633v1 110/13/4243    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 Hers, I. Search for Related Content PubMed PubMed Citation Articles by Hers, I. Related Collections Hemostasis, Thrombosis, and Vascular Biology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Insulin-like growth factor-1 potentiates platelet activation via the IRS/PI3K pathway Ingeborg Hers1 1 Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, United Kingdom As insulin-like growth factor-1 (IGF-1) is present in the granules of platelets and its receptor is expressed on the platelet surface, it may contribute to the amplification of platelet responses and pathogenesis of cardiovascular disease. The functional and signaling pathways that are involved in IGF-1 modulation of platelet function, however, are presently unknown. Here, I report that IGF-1 stimulation of platelets results in dose-dependent phosphorylation of the IGF receptor in the range of 1 to 100 nM. Phosphorylation of the IGF receptor is rapid and sustained, with maximal phosphorylation reached within 1 minute. Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). IGF-1–stimulated tyrosine phosphorylation of IRS-1 and IRS-2 and subsequent p85 binding is transient and precedes phosphorylation of protein kinase B (PKB) on Ser473. PAR-1–mediated platelet aggregation is potentiated by IGF-1 and this potentiation, together with PKB phosphorylation, is abolished by the PI3K inhibitors PI-103 and PIK-75. Importantly, the IGF receptor inhibitor NVP-AEW541 and the neutralization antibody IR3 inhibit SFLLRN-stimulated aggregation, implicating IGF-1 in autocrine regulation of platelet function. These results demonstrate that IGF-1 activates the IGF receptor/IRS/PI3K/PKB pathway, and that PI3K is essential for the potentiatory effect of IGF-1 on platelet responses. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. W. Hunter, C. MacKintosh, and I. Hers Protein Kinase C-mediated Phosphorylation and Activation of PDE3A Regulate cAMP Levels in Human Platelets J. Biol. Chem., May 1, 2009; 284(18): 12339 - 12348. [Abstract] [Full Text] [PDF] V. Randriamboavonjy and I. Fleming Insulin, Insulin Resistance, and Platelet Signaling in Diabetes Diabetes Care, April 1, 2009; 32(4): 528 - 530. [Full Text] [PDF]

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