Article (Scientific journals)
DUSP3 Phosphatase Deficiency or Inhibition Limit Platelet Activation and Arterial Thrombosis
Musumeci, Lucia; Kuijpers, Marijke; Gilio, Karen et al.
2015In Circulation, 131 (7), p. 656-68
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Keywords :
Platelets; Arterial Thrombosis; Animal model for human disease; Inhibitors; CLEC-2; Collagen
Abstract :
[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.
Disciplines :
Cardiovascular & respiratory systems
Author, co-author :
Musumeci, Lucia ;  Université de Liège - ULiège > GIGA-Research
Kuijpers, Marijke
Gilio, Karen
Hego, Alexandre ;  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 ;  Centre Hospitalier Universitaire de Liège - CHU > Hématologie biologique et immuno hématologie
Guilmain, William
Bobkova, Ekaterina
Eble, Johannes
Dahl, Russell
Drion, Pierre ;  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  ;  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  ;  Université de Liège - ULiège > Département des sciences cliniques > Imagerie cardiaque fonctionnelle par échographie
Heemskerk, Johan
Tautz, Lutz 
Oury, Cécile   ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Génétique humaine
Rahmouni, Souad   ;  Université de Liège - ULiège > Département des sciences cliniques > GIGA-R:Immunopath. - Maladies infect. et médec. inter. gén.
More authors (18 more) Less
 These authors have contributed equally to this work.
Language :
English
Title :
DUSP3 Phosphatase Deficiency or Inhibition Limit Platelet Activation and Arterial Thrombosis
Publication date :
17 February 2015
Journal title :
Circulation
ISSN :
0009-7322
eISSN :
1524-4539
Publisher :
Lippincott Williams & Wilkins, Hagerstown, United States - Maryland
Volume :
131
Issue :
7
Pages :
656-68
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 17 December 2014

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