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Blood, 1 August 2008, Vol. 112, No. 3, pp. 592-602. Prepublished online as a Blood First Edition Paper on April 8, 2008; DOI 10.1182/blood-2007-09-110437. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-09-110437v1 112/3/592    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 Google Scholar Articles by Su, X. Articles by Xi, X. PubMed PubMed Citation Articles by Su, X. Articles by Xi, X. Related Collections Hemostasis, Thrombosis, and Vascular Biology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY RGT, a synthetic peptide corresponding to the integrin β3 cytoplasmic C-terminal sequence, selectively inhibits outside-in signaling in human platelets by disrupting the interaction of integrin IIbβ3 with Src kinase Xiaoyu Su1,2,*, Jianqing Mi2,3,*, Jinsong Yan1,2, Panagiotis Flevaris4, Yuanjing Lu1,2, Hongchen Liu1,2, Zheng Ruan1,2, Xuefeng Wang1,2, Nelly Kieffer5, Saijuan Chen1,2, Xiaoping Du4, and Xiaodong Xi1,2,5 1 State Key Laboratory of Medical Genomics, 2 Shanghai Institute of Hematology, 3 Department of Hematology, all at Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; 4 Department of Pharmacology, University of Illinois at Chicago; and 5 Centre National de la Recherche Scientifique LIA 142, Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China Mutational analysis has established that the cytoplasmic tail of the integrin β3 subunit binds c-Src (termed as Src in this study) and is critical for bidirectional integrin signaling. Here we show in washed human platelets that a cell-permeable, myristoylated RGT peptide (myr-RGT) corresponding to the integrin β3 C-terminal sequence dose-dependently inhibited stable platelet adhesion and spreading on immobilized fibrinogen, and fibrin clot retraction as well. Myr-RGT also inhibited the aggregation-dependent platelet secretion and secretion-dependent second wave of platelet aggregation induced by adenosine diphosphate, ristocetin, or thrombin. Thus, myr-RGT inhibited integrin outside-in signaling. In contrast, myr-RGT had no inhibitory effect on adenosine diphosphate-induced soluble fibrinogen binding to platelets that is dependent on integrin inside-out signaling. Furthermore, the RGT peptide induced dissociation of Src from integrin β3 and dose-dependently inhibited the purified recombinant β3 cytoplasmic domain binding to Src-SH3. In addition, phosphorylation of the β3 cytoplasmic tyrosines, Y747 and Y759, was inhibited by myr-RGT. These data indicate an important role for β3-Src interaction in outside-in signaling. Thus, in intact human platelets, disruption of the association of Src with β3 and selective blockade of integrin IIbβ3 outside-in signaling by myr-RGT suggest a potential new antithrombotic strategy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Outside-in: peptide versus integrin Joel S. Bennett Blood 2008 112: 453-454. [Full Text] [PDF]

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