| First Author | Ablooglu AJ | Year | 2009 |
| Journal | Blood | Volume | 113 |
| Issue | 15 | Pages | 3585-92 |
| PubMed ID | 19005179 | Mgi Jnum | J:148306 |
| Mgi Id | MGI:3844207 | Doi | 10.1182/blood-2008-09-180687 |
| Citation | Ablooglu AJ, et al. (2009) Antithrombotic effects of targeting alphaIIbbeta3 signaling in platelets. Blood 113(15):3585-92 |
| abstractText | alphaIIbbeta3 interaction with fibrinogen promotes Src-dependent platelet spreading in vitro. To determine the consequences of this outside-in signaling pathway in vivo, a 'beta3(Delta760-762)' knockin mouse was generated that lacked the 3 C-terminal beta3 residues (arginine-glycine-threonine [RGT]) necessary for alphaIIbbeta3 interaction with c-Src, but retained beta3 residues necessary for talin-dependent fibrinogen binding. beta3(Delta760-762) mice were compared with wild-type beta3(+/+) littermates, beta3(+/-) heterozygotes, and knockin mice where beta3 RGT was replaced by beta1 C-terminal cysteine-glycine-lysine (EGK) to potentially enable signaling by Src kinases other than c-Src. Whereas beta3(+/+), beta3(+/-) and beta3/beta1(EGK) platelets spread and underwent tyrosine phosphorylation normally on fibrinogen, beta3(Delta760-762) platelets spread poorly and exhibited reduced tyrosine phosphorylation of c-Src substrates, including beta3 (Tyr(747)). Unlike control mice, beta3(Delta760-762) mice were protected from carotid artery thrombosis after vessel injury with FeCl(3). Some beta3(Delta760-762) mice exhibited prolonged tail bleeding times; however, none demonstrated spontaneous bleeding, excess bleeding after surgery, fecal blood loss, or anemia. Fibrinogen binding to beta3(Delta760-762) 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 beta3 RGT disrupts c-Src-mediated alphaIIbbeta3 signaling and confers protection from arterial thrombosis. Consequently, targeting alphaIIbbeta3 signaling may represent a feasible antithrombotic strategy. |
