Musumeci Lucia, Kuijpers Marijke J, Gilio Karen, Hego Alexandre, Théâtre Emilie, Maurissen Lisbeth, Vandereyken Maud, Diogo Catia V, Lecut Christelle, Guilmain William, Bobkova Ekaterina V, Eble Johannes A, Dahl Russell, Drion Pierre, Rascon Justin, Mostofi Yalda, Yuan Hongbin, Sergienko Eduard, Chung Thomas D Y, Thiry Marc, Senis Yotis, Moutschen Michel, Mustelin Tomas, Lancellotti Patrizio, Heemskerk Johan W M, Tautz Lutz, Oury Cécile, Rahmouni Souad
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.).
Circulation. 2015 Feb 17;131(7):656-68. doi: 10.1161/CIRCULATIONAHA.114.010186. Epub 2014 Dec 17.
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.
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.
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.
当前抗血小板疗法的一个局限性在于它们无法区分血栓形成事件和出血事件。更好地理解导致血小板活化的分子机制对于开发改进疗法至关重要。最近，蛋白酪氨酸磷酸酶已成为血小板功能的关键调节因子。
这是首篇表明双特异性磷酸酶3（DUSP3）参与血小板信号传导和血栓形成的报告。这种磷酸酶在人和小鼠血小板中高度表达。来自DUSP3缺陷小鼠的血小板在由胶原受体糖蛋白VI和C型凝集素样受体2介导的聚集和颗粒分泌方面表现出选择性损伤。与野生型小鼠相比，DUSP3缺陷小鼠对胶原和肾上腺素诱导的血栓栓塞更具抵抗力，并且在氯化铁诱导的颈动脉损伤上血栓形成严重受损。有趣的是，DUSP3缺陷小鼠的出血时间没有改变。在分子水平上，DUSP3缺陷会损害Syk酪氨酸磷酸化，随后降低磷脂酶Cγ2的磷酸化和钙通量。为了研究DUSP3在人血小板中的功能，开发了一种新型的DUSP3小分子抑制剂。该化合物特异性抑制胶原和C型凝集素样受体2诱导的人血小板聚集，从而模拟了DUSP3缺陷在鼠细胞中的作用。
DUSP3在体内胶原和C型凝集素样受体2介导的血小板活化和血栓形成中起选择性和关键作用。抑制DUSP3可能被证明对动脉血栓形成具有治疗作用。这是首次针对参与血小板信号传导的蛋白酪氨酸磷酸酶使用小分子药物进行靶向治疗。
