TY - JOUR
T1 - Dual-Specificity Phosphatase 3 Deficiency or Inhibition Limits Platelet Activation and Arterial Thrombosis
AU - Musumeci, Lucia
AU - Kuijpers, Marijke J.
AU - Gilio, Karen
AU - Hego, Alexandre
AU - Theatre, Emilie
AU - Maurissen, Lisbeth
AU - Vandereyken, Maud
AU - Diogo, Catia V.
AU - Lecut, Christelle
AU - Guilmain, William
AU - Bobkova, Ekaterina V.
AU - Eble, Johannes A.
AU - Dahl, Russell
AU - Drion, Pierre
AU - Rascon, Justin
AU - Mostofi, Yalda
AU - Yuan, Hongbin
AU - Sergienko, Eduard
AU - Chung, Thomas D. Y.
AU - Thiry, Marc
AU - Senis, Yotis
AU - Moutschen, Michel
AU - Mustelin, Tomas
AU - Lancellotti, Patrizio
AU - Heemskerk, Johan W. M.
AU - Tautz, Lutz
AU - Oury, Cecile
AU - Rahmouni, Souad
PY - 2015/2/17
Y1 - 2015/2/17
N2 - Background-A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. A better understanding of the molecular mechanisms leading to platelet activation is important for the development of improved therapies. Recently, protein tyrosine phosphatases 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 by the collagen receptor glycoprotein VI and the C-type lectin-like receptor 2. DUSP3-deficient mice were more resistant to collagen-and epinephrine-induced thromboembolism compared with wild-type mice and showed severely impaired thrombus formation on 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 phospholipase C gamma 2 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 C-type lectin-like receptor 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 C-type lectin-like receptor 2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a protein tyrosine phosphatase, implicated in platelet signaling, has been targeted with a small-molecule drug.
AB - Background-A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. A better understanding of the molecular mechanisms leading to platelet activation is important for the development of improved therapies. Recently, protein tyrosine phosphatases 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 by the collagen receptor glycoprotein VI and the C-type lectin-like receptor 2. DUSP3-deficient mice were more resistant to collagen-and epinephrine-induced thromboembolism compared with wild-type mice and showed severely impaired thrombus formation on 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 phospholipase C gamma 2 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 C-type lectin-like receptor 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 C-type lectin-like receptor 2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a protein tyrosine phosphatase, implicated in platelet signaling, has been targeted with a small-molecule drug.
KW - antagonists and inhibitors
KW - blood platelets
KW - signal transduction
KW - thrombosis
U2 - 10.1161/CIRCULATIONAHA.114.010186
DO - 10.1161/CIRCULATIONAHA.114.010186
M3 - Article
C2 - 25520375
SN - 0009-7322
VL - 131
SP - 656-U194
JO - Circulation
JF - Circulation
IS - 7
ER -