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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.

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PLATELETS AND THROMBOPOIESIS

Antithrombotic effects of targeting {alpha}IIbβ3 signaling in platelets

Ararat J. Ablooglu1, Jian Kang1, Brian G. Petrich1, Mark H. Ginsberg1, and Sanford J. Shattil1

1 Department of Medicine, University of California San Diego, La Jolla

{alpha}IIbβ3 interaction with fibrinogen promotes Src-dependent platelet spreading in vitro. To determine the consequences of this outside-in signaling pathway in vivo, a "β3({Delta}760-762)" knockin mouse was generated that lacked the 3 C-terminal β3 residues (arginine-glycine-threonine [RGT]) necessary for {alpha}IIbβ3 interaction with c-Src, but retained β3 residues necessary for talin-dependent fibrinogen binding. β3({Delta}760-762) mice were compared with wild-type β3+/+ littermates, β3+/– heterozygotes, and knockin mice where β3 RGT was replaced by β1 C-terminal cysteine-glycine-lysine (EGK) to potentially enable signaling by Src kinases other than c-Src. Whereas β3+/+, β3+/– and β3/β1(EGK) platelets spread and underwent tyrosine phosphorylation normally on fibrinogen, β3({Delta}760-762) platelets spread poorly and exhibited reduced tyrosine phosphorylation of c-Src substrates, including β3 (Tyr747). Unlike control mice, β3({Delta}760-762) mice were protected from carotid artery thrombosis after vessel injury with FeCl3. Some β3({Delta}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 β3({Delta}760-762) platelets was normal in response to saturating concentrations of protease-activated receptor 4 or glycoprotein VI agonists, but responses to adenosine diphosphate were impaired. Thus, deletion of β3 RGT disrupts c-Src–mediated {alpha}IIbβ3 signaling and confers protection from arterial thrombosis. Consequently, targeting {alpha}IIbβ3 signaling may represent a feasible antithrombotic strategy.


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