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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 (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 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 Su, X. Articles by Xi, X. Search for Related Content PubMed PubMed Citation Articles by Su, X. Articles by Xi, X. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 7, 2007 Accepted March 20, 2008 RGT, a synthetic peptide corresponding to the integrin 3 cytoplasmic C-terminal sequence, selectively inhibits outside-in signaling in human platelets by disrupting the interaction of integrin IIb3 with Src kinase Xiaoyu Su, Jianqing Mi, Jingsong Yan, Panagiotis Flevaris, Yuanjing Lu, Hongchen Liu, Zheng Ruan, Xuefeng Wang, Nelly Kieffer, Saijuan Chen, Xiaoping Du, and Xiaodong Xi* State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China Department of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, United States CNRS LIA 124, Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China * Corresponding author; email: xixiaodong{at}shsmu.edu.cn. Mutational analysis has established that the cytoplasmic tail of the integrin 3 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 3 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 ADP, ristocetin or thrombin. Thus, myr-RGT inhibited integrin outside-in signaling. In contrast, myr-RGT had no inhibitory effect on ADP-induced soluble fibrinogen binding to platelets that is dependent on integrin inside-out signaling. Furthermore, the RGT peptide induced dissociation of Src from integrin 3 and dose-dependently inhibited the purified recombinant 3 cytoplasmic domain binding to Src-SH3. In addition, phosphorylation of the 3 cytoplasmic tyrosines, Y747 and Y759, was inhibited by myr-RGT. These data indicate an important role for 3-Src interaction in outside-in signaling. Thus, in intact human platelets, disruption of the association of Src with 3 and selective blockade of integrin IIb3 outside-in signaling by myr-RGT suggest a potential new anti-thrombotic 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] This article has been cited by other articles: P. Fogelstrand, C. C. Feral, R. Zargham, and M. H. Ginsberg Dependence of proliferative vascular smooth muscle cells on CD98hc (4F2hc, SLC3A2) J. Exp. Med., October 26, 2009; 206(11): 2397 - 2406. [Abstract] [Full Text] [PDF] M.-P. Gratacap, V. Martin, M.-C. Valera, S. Allart, C. Garcia, P. Sie, C. Recher, and B. Payrastre The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo Blood, August 27, 2009; 114(9): 1884 - 1892. [Abstract] [Full Text] [PDF] A. J. Ablooglu, J. Kang, B. G. Petrich, M. H. Ginsberg, and S. J. Shattil Antithrombotic effects of targeting {alpha}IIb{beta}3 signaling in platelets Blood, April 9, 2009; 113(15): 3585 - 3592. [Abstract] [Full Text] [PDF] D. H. Craig, C. P. Gayer, K. L. Schaubert, Y. Wei, J. Li, Y. Laouar, and M. D. Basson Increased extracellular pressure enhances cancer cell integrin-binding affinity through phosphorylation of {beta}1-integrin at threonine 788/789 Am J Physiol Cell Physiol, January 1, 2009; 296(1): C193 - C204. [Abstract] [Full Text] [PDF]

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