Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy.
Arterial thrombosis is the primary cause of most cases of myocardial infarction and stroke, the leading causes of death in the developed world. Platelets, highly specialized cells of the circulatory system, are key contributors to thrombotic events. Antiplatelet drugs, which prevent platelets from aggregating, have been very effective in reducing the mortality and morbidity of these conditions. However, approved antiplatelet therapies have adverse side effects, most notably the increased risk of bleeding. Moreover, there remains a considerable incidence of arterial thrombosis in a subset of patients receiving currently available drugs. Thus, there is a pressing medical need for novel antiplatelet agents with a more favorable safety profile and less patient resistance. The discovery of novel antiplatelet targets is the matter of intense ongoing research. Recent findings demonstrate the potential of targeting key signaling molecules, including kinases and phosphatases, to prevent platelet activation and aggregation. Here, we offer perspectives to targeting members of the protein tyrosine phosphatase (PTP) superfamily, a major class of enzymes in signal transduction. We give an overview of previously identified PTPs in platelet signaling, and discuss their potential as antiplatelet drug targets. We also introduce VHR (DUSP3), a PTP that we recently identified as a major player in platelet biology and thrombosis. We review our data on genetic deletion as well as pharmacological inhibition of VHR, providing proof-of-principle for a novel and potentially safer VHR-based antiplatelet therapy.
NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA. Electronic address: tautz@sanfordburnham.org.
Lutz
L
Tautz
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.
Yotis A
YA
Senis
Laboratory of Thrombosis and Haemostasis, GIGA-Cardiovascular Sciences, University of Liège, Liège, Belgium.
Cécile
C
Oury
Immunology and Infectious Diseases Unit, GIGA-Signal Transduction, University of Liège, Liège, Belgium.
Souad
S
Rahmouni
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology*; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013927:Thrombosis / Q000188:drug therapy / Q000201:enzymology
D010975:Platelet Aggregation Inhibitors; D017027:Protein Tyrosine Phosphatases
Antiplatelet; Antithrombotic; CD148; CLEC-2; DUSP3; Drug; GPVI; Inhibitor; PTP; PTP1B; Platelets; Protein tyrosine phosphatases; SHP1; SHP2; Therapy; Thrombosis; VHR