Reference : DUSP3 Phosphatase Deficiency or Inhibition Limit Platelet Activation and Arterial Thr...
Scientific journals : Article
Human health sciences : Cardiovascular & respiratory systems
http://hdl.handle.net/2268/175247
DUSP3 Phosphatase Deficiency or Inhibition Limit Platelet Activation and Arterial Thrombosis
English
Musumeci, Lucia mailto [Université de Liège - ULiège > > GIGA-Research >]
Kuijpers, Marijke [> >]
Gilio, Karen [> >]
Hego, Alexandre mailto [Université de Liège - ULiège > > GIGA-R : Virologie - Immunologie >]
Theatre, Emilie [Université de Liège - ULiège > Département de productions animales > GIGA-R : Génomique animale >]
Maurissen, Lisbeth [> >]
Vandereyken, Maud [Université de Liège - ULiège > Département des sciences cliniques > GIGA-R:Immunopath. - Maladies infect. et médec. inter. gén. >]
Diogo, Catia [> >]
LECUT, Christelle mailto [Centre Hospitalier Universitaire de Liège - CHU > > Hématologie biologique et immuno hématologie >]
Guilmain, William [> >]
Bobkova, Ekaterina [> >]
Eble, Johannes [> >]
Dahl, Russell [> >]
Drion, Pierre mailto [Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R:Méth. expér.des anim. de labo et éth. en expér. anim. >]
Rascon, Justin [> >]
Mostofi, Yalda [> >]
Yuan, Hongbin [> >]
Sergienko, Eduard [> >]
Chung, Thomas [> >]
Thiry, Marc mailto [Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie cellulaire >]
Senis, Yotis [> >]
MOUTSCHEN, Michel [Centre Hospitalier Universitaire de Liège - CHU > > Maladies infectieuses et médecine interne générale >]
Mustelin, Tomas [> >]
Lancellotti, Patrizio mailto [Université de Liège - ULiège > Département des sciences cliniques > Imagerie cardiaque fonctionnelle par échographie >]
Heemskerk, Johan [> >]
Tautz, Lutz* [> >]
Oury, Cécile* mailto [Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Génétique humaine >]
Rahmouni, Souad* mailto [Université de Liège - ULiège > Département des sciences cliniques > GIGA-R:Immunopath. - Maladies infect. et médec. inter. gén. >]
* These authors have contributed equally to this work.
17-Feb-2015
Circulation
Lippincott Williams & Wilkins
131
7
656-68
Yes (verified by ORBi)
International
0009-7322
1524-4539
Hagerstown
MD
[en] Platelets ; Arterial Thrombosis ; Animal model for human disease ; Inhibitors ; CLEC-2 ; Collagen
[en] Background
A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. Better understanding of the molecular mechanisms leading to platelet activation is of importance for the development of improved therapies. Recently, protein tyrosine phosphatases (PTPs) have emerged as critical regulators of platelet function.
Methods and Results
This is the first report implicating the dual-specificity phosphatase 3 (DUSP3) in platelet signaling and thrombosis. This phosphatase is highly expressed in human and mouse platelets. Platelets from DUSP3-deficient mice displayed a selective impairment of aggregation and granule secretion mediated through the collagen receptor glycoprotein VI (GPVI) and the C-type lectin-like receptor 2 (CLEC-2). DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism, compared to wild-type mice, and showed severely impaired thrombus formation upon ferric chloride-induced carotid artery injury. Intriguingly, bleeding times were not altered in DUSP3-deficient mice. At the molecular level, DUSP3 deficiency impaired Syk tyrosine phosphorylation, subsequently reducing phosphorylation of PLCγ2 and calcium fluxes. To investigate DUSP3 function in human platelets, a novel small-molecule inhibitor of DUSP3 was developed. This compound specifically inhibited collagen and CLEC-2-induced human platelet aggregation, thereby phenocopying the effect of DUSP3 deficiency in murine cells.
Conclusions
DUSP3 plays a selective and essential role in collagen- and CLEC-2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a PTP, implicated in platelet signaling, has been targeted with a small-molecule drug.
Researchers ; Professionals ; Students
http://hdl.handle.net/2268/175247
10.1161/CIRCULATIONAHA.114.010186
http://reflexions.ulg.ac.be/en/ArterialThrombosis

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