2. Academic Validation
  3. Dual-specificity phosphatase 3 deficiency or inhibition limits platelet activation and arterial thrombosis

Dual-specificity phosphatase 3 deficiency or inhibition limits platelet activation and arterial thrombosis

  • Circulation. 2015 Feb 17;131(7):656-68. doi: 10.1161/CIRCULATIONAHA.114.010186.
Lucia Musumeci 1,  Marijke J Kuijpers 1,  Karen Gilio 1,  Alexandre Hego 1,  Emilie Théâtre 1,  Lisbeth Maurissen 1,  Maud Vandereyken 1,  Catia V Diogo 1,  Christelle Lecut 1,  William Guilmain 1,  Ekaterina V Bobkova 1,  Johannes A Eble 1,  Russell Dahl 1,  Pierre Drion 1,  Justin Rascon 1,  Yalda Mostofi 1,  Hongbin Yuan 1,  Eduard Sergienko 1,  Thomas D Y Chung 1,  Marc Thiry 1,  Yotis Senis 1,  Michel Moutschen 1,  Tomas Mustelin 1,  Patrizio Lancellotti 1,  Johan W M Heemskerk 1,  Lutz Tautz 2,  Cécile Oury 2,  Souad Rahmouni 2
Affiliations

Affiliations

  • 1 From the Immunology and Infectious Diseases Unit, GIGA-Signal Transduction (L. Musumeci, L. Maurissen, M.V., C.V.D., M.M., S.R.), Laboratory of Thrombosis and Haemostasis, GIGA-Cardiovascular Sciences (A.H., L. Maurissen, C.V.D., C.L., W.G., C.O.), Unit of Animal Genomics, GIGA-Genetics and Faculty of Veterinary Medicine (E.T.), Unit of Hepato-Gastroenterology, CHU de Liège and Faculty of Medicine (E.T.), GIGA-Animal Facility (B23) (P.D.), Laboratory of Cell and Tissue Biology, GIGA-Neurosciences (M.T.), and Department of Cardiology, Heart Valve Clinic, CHU Sart Tilman, GIGA Cardiovascular Sciences (P.L.), University of Liège, Liège, Belgium; Laboratory of Cellular Thrombosis and Haemostasis, Cardiovascular Research Institute Maastricht CARIM, Maastricht University, Maastricht, the Netherlands (M.J.K., K.G., L. Maurissen, J.W.M.H.); Conrad Prebys Center for Chemical Genomics (E.V.B., R.D., J.R., Y.M., H.Y., E.S., T.D.Y.C.) and NCI-Designated Cancer Center (L.T.), Sanford-Burnham Medical Research Institute, La Jolla, CA; Institute for Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany (J.A.E.); and Centre for Cardiovascular Sciences, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK (Y.S.).
  • 2 From the Immunology and Infectious Diseases Unit, GIGA-Signal Transduction (L. Musumeci, L. Maurissen, M.V., C.V.D., M.M., S.R.), Laboratory of Thrombosis and Haemostasis, GIGA-Cardiovascular Sciences (A.H., L. Maurissen, C.V.D., C.L., W.G., C.O.), Unit of Animal Genomics, GIGA-Genetics and Faculty of Veterinary Medicine (E.T.), Unit of Hepato-Gastroenterology, CHU de Liège and Faculty of Medicine (E.T.), GIGA-Animal Facility (B23) (P.D.), Laboratory of Cell and Tissue Biology, GIGA-Neurosciences (M.T.), and Department of Cardiology, Heart Valve Clinic, CHU Sart Tilman, GIGA Cardiovascular Sciences (P.L.), University of Liège, Liège, Belgium; Laboratory of Cellular Thrombosis and Haemostasis, Cardiovascular Research Institute Maastricht CARIM, Maastricht University, Maastricht, the Netherlands (M.J.K., K.G., L. Maurissen, J.W.M.H.); Conrad Prebys Center for Chemical Genomics (E.V.B., R.D., J.R., Y.M., H.Y., E.S., T.D.Y.C.) and NCI-Designated Cancer Center (L.T.), Sanford-Burnham Medical Research Institute, La Jolla, CA; Institute for Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany (J.A.E.); and Centre for Cardiovascular Sciences, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK (Y.S.). [email protected] [email protected] [email protected].
PMID: 25520375 DOI: 10.1161/CIRCULATIONAHA.114.010186
Abstract

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 Cγ2 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.

Keywords

antagonists and inhibitors; blood platelets; signal transduction; thrombosis.

Figures
Products