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Blood, 9 April 2009, Vol. 113, No. 15, pp. 3585-3592. Prepublished online as a Blood First Edition Paper on November 12, 2008; DOI 10.1182/blood-2008-09-180687. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-09-180687v1 113/15/3585    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 Ablooglu, A. J. Articles by Shattil, S. J. Search for Related Content PubMed PubMed Citation Articles by Ablooglu, A. J. Articles by Shattil, S. J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 22, 2008 Accepted October 31, 2008 Anti-thrombotic effects of targeting IIb3 signaling in platelets Ararat J. Ablooglu*, Jian Kang, Brian G. Petrich, Mark H. Ginsberg, and Sanford J. Shattil Department of Medicine, University of California San Diego, La Jolla, CA, United States * Corresponding author; email: aablooglu{at}ucsd.edu. IIb3 interaction with fibrinogen promotes Src-dependent platelet spreading in vitro. To determine the consequences of this outside-in signaling pathway in vivo, a "3(760-762)" knock-in mouse was generated that lacked the three C-terminal 3 residues (RGT) necessary for IIb3 interaction with c-Src, but retained 3 residues necessary for talin-dependent fibrinogen binding. 3(760-762) mice were compared with wild-type 3+/+ littermates, 3+/- heterozygotes, and knock-in mice where 3 RGT was replaced by 1 C-terminal EGK to potentially enable signaling by Src kinases other than c-Src. Whereas 3+/+, 3+/- and 3/1(EGK) platelets spread and underwent tyrosine phosphorylation normally on fibrinogen, 3(760-762) platelets spread poorly and exhibited reduced tyrosine phosphorylation of c-Src substrates, including 3 (Tyr747). Unlike control mice, 3(760-762) mice were protected from carotid artery thrombosis following vessel injury with FeCl3. Some 3(760-762) mice exhibited prolonged tail bleeding times; however, none demonstrated spontaneous bleeding, excess bleeding after surgery, fecal blood loss or anemia. Fibrinogen binding to 3(760-762) platelets was normal in response to saturating concentrations of PAR4 or GP VI agonists, but responses to ADP were impaired. Thus, deletion of 3 RGT disrupts c-Src-mediated IIb3 signaling and confers protection from arterial thrombosis. Consequently, targeting IIb3 signaling may represent a feasible anti-thrombotic strategy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Pinning a tail on platelet thrombi Joel S. Bennett Blood 2009 113: 3395. [Full Text] [PDF] This article has been cited by other articles: J. S. Bennett Pinning a tail on platelet thrombi Blood, April 9, 2009; 113(15): 3395 - 3395. [Full Text] [PDF]

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