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Blood, 22 January 2009, Vol. 113, No. 4, pp. 893-901. Prepublished online as a Blood First Edition Paper on October 28, 2008; DOI 10.1182/blood-2008-05-155978. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-05-155978v1 113/4/893    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Flevaris, P. Articles by Du, X. Search for Related Content PubMed PubMed Citation Articles by Flevaris, P. Articles by Du, X. Related Collections Platelets and Thrombopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLATELETS AND THROMBOPOIESIS Two distinct roles of mitogen-activated protein kinases in platelets and a novel Rac1-MAPK–dependent integrin outside-in retractile signaling pathway Panagiotis Flevaris1,*, Zhenyu Li1,*, Guoying Zhang1, Yi Zheng2, Junling Liu1, and Xiaoping Du1 1 Department of Pharmacology, University of Illinois at Chicago; and 2 Division of Experimental Hematology, Cincinnati Children's Research Foundation, University of Cincinnati, OH Mitogen-activated protein kinases (MAPK), p38, and extracellular stimuli-responsive kinase (ERK), are acutely but transiently activated in platelets by platelet agonists, and the agonist-induced platelet MAPK activation is inhibited by ligand binding to the integrin IIbβ3. Here we show that, although the activation of MAPK, as indicated by MAPK phosphorylation, is initially inhibited after ligand binding to integrin IIbβ3, integrin outside-insignaling results in a late but sustained activation of MAPKs in platelets. Furthermore, we show that the early agonist-induced MAPK activation and the late integrin-mediated MAPK activation play distinct roles in different stages of platelet activation. Agonist-induced MAPK activation primarily plays an important role in stimulating secretion of platelet granules, while integrin-mediated MAPK activation is important in facilitating clot retraction. The stimulatory role of MAPK in clot retraction is mediated by stimulating myosin light chain (MLC) phosphorylation. Importantly, integrin-dependent MAPK activation, MAPK-dependent MLC phosphorylation, and clot retraction are inhibited by a Rac1 inhibitor and in Rac1 knockout platelets, indicating that integrin-induced activation of MAPK and MLC and subsequent clot retraction is Rac1-dependent. Thus, our results reveal 2 different activation mechanisms of MAPKs that are involved in distinct aspects of platelet function and a novel Rac1-MAPK–dependent cell retractile signaling pathway. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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