Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy

Abstract

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.

Maintenance of murine platelet homeostasis by the kinase Csk and phosphatase CD148

“…72,73 Based on our findings, CD148 is an attractive antithrombotic drug target, and its inhibition should attenuate, but not completely block, the main platelet activation pathways and have minimal bleeding side effects. Tyrosine phosphatases are increasingly considered to be druggable, 74 which is supported by the recent development of the highly specific Shp2 inhibitor SHP099 75 ; thus, targeting CD148 is not inconceivable.…”

Revisiting the roles of VHR/DUSP3 phosphatase in human diseases

“…Another very recent and important report provided mechanistic clues about the roles that VHR plays in platelet aggregation 61 , 62 . This phosphatase seems to be responsible for reducing the levels of tyrosine phosphorylation of the enzymes Syk and PLCγ2, which regulate signaling via collagen receptor glycoprotein VI (GPVI) and C-type lectin-like type II (CLEC-2) receptors to promote aggregation in a MAPK-independent manner.…”

Modulation of VEGF receptor 2 signaling by protein phosphatases

“…In the vascular system, DEP-1 (also called CD148, PTPη, SCC1) is expressed in endothelial cells, smooth muscle cells, leukocytes, and platelets [26, 45-48]. DEP-1 substrates include PDGFRβ [49, 50], VEGFR2 [51], insulin receptor [52-55], p120 [56], β-catenin [57] and Src [58].…”

“…A number of recent reviews have addressed the role of protein phosphatases in animal disease models and human diseases such as cancer [23, 24], diabetes [25], antiplatelet therapy [26], and hereditary disorders [27]. This review will focus on phosphatases known to affect VEGFR2 signaling (and its biological effects) by means of targeting phosphorylation of the receptor itself (Fig.1) or that of its downstream signal transducers (Fig.…”