Interactions between Eph kinases and ephrins provide a mechanism to support platelet aggregation once cell-to-cell contact has occurred

Prévost, Nicolas; Woulfe, Donna S.; Tanaka, Takako; Brass, Lawrence F.

doi:10.1073/pnas.142053899

Cited by 118 publications

(133 citation statements)

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“…The contacts that develop allow interactions to occur among molecules on the surface of adjacent platelets. A well described example involves the integrin ␣ IIb ␤ 3 , but contact-dependent events can also occur when a ligand on the surface of one platelet binds to a receptor on another, as when ephrinB1 binds to EphA4 and EphB1 (30,31). The present studies evolved from an ongoing effort to identify additional molecules on the platelet surface that can participate in communication between platelets once platelet activation has begun.…”

Section: Discussionmentioning

confidence: 99%

“…Human blood obtained from healthy donors was anticoagulated 1:5 with ACD (65 mM Na 3 citrate/70 mM citric acid/100 mM dextrose, pH 4.4) and centrifuged at 129 ϫ g for 20 min to obtain platelet-rich plasma (PRP). Gel-filtered platelets were prepared as described (31). Washed platelets were prepared by centrifuging PRP that had been diluted with HEN (150 mM NaCl/1 mM Na 2 EDTA/10 mM Hepes, pH 6.5) containing 1 M PGI 2 and 0.5 units/ml apyrase at 341 ϫ g for 15 min.…”

Section: Methodsmentioning

confidence: 99%

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Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury

Zhu¹,

Bergmeier

Wu³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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176

221

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Semaphorin 4D (sema4D; CD100) is an integral membrane protein and the ligand for two receptors, CD72 and plexin-B1. Soluble sema4D has been shown to evoke angiogenic responses from endothelial cells and impair monocyte migration, but the origin of soluble sema4D, particularly at sites of vascular injury, has been unclear. Here we show that platelets express sema4D and both of its receptors and provide evidence that these molecules promote thrombus formation. We also show that the surface expression of sema4D and CD72 increases during platelet activation, followed by the gradual shedding of the sema4D extracellular domain. Shedding is blocked by metalloprotease inhibitors and abolished in mouse platelets that lack the metalloprotease ADAM17 (TACE). Mice that lack sema4D exhibit delayed arterial occlusion after vascular injury in vivo, and their platelets show impaired collagen responses in vitro. In resting platelets, as in B lymphocytes, CD72 is associated with the protein tyrosine phosphatase SHP-1. Platelet activation causes dissociation of the complex, as does the addition of soluble sema4D. These findings suggest a dual role for sema4D in vascular responses to injury. As thrombus formation begins, platelet-associated sema4D can bind to its receptors on nearby platelets, promoting thrombus formation. As thrombus formation continues, sema4D is shed from the platelet surface and becomes available to interact with receptors on endothelial cells and monocytes, as well as continuing to interact with platelets.signaling ͉ thrombosis ͉ metalloprotease ͉ CD72 ͉ plexin-B1 P latelet activation typically begins with the exposure of collagen within a damaged vessel wall or the local generation of thrombin, but the establishment of a stable thrombus requires the recruitment of additional platelets and the development of stable contacts between platelets (1). Platelet activation also results in the release from platelets of molecules that can affect nearby cells, including endothelial cells and leukocytes as well as other platelets. In a continuing search for molecules that might contribute to contact-dependent events during thrombus formation, we screened human platelets for members of the semaphorin family. Although sempahorins are best known as regulators of neurite outgrowth and vascular development, individual family members have been shown to participate in a variety of events. Class IV semaphorin [semaphorin 4D (sema4D; CD100)] is a type I integral membrane protein first reported on T cells where it supports B cell development by binding to CD72 (2-4). However, sema4D receptors are not limited to B cells. Prior work has shown that a soluble sema4D extracellular domain fragment can activate endothelial cells by its other known receptor, plexin-B1. This causes endothelial migration, actin rearrangement, and the formation of tube-like structures in vitro, responses that are relevant for wound healing and angiogenesis (5-11). Soluble sema4D has also been shown to inhibit monocyte (12) and dendritic cell (13) migration. ...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury

Zhu¹,

Bergmeier

Wu³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

176

221

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“…Gel-filtered human platelets were prepared as described by Yi et al and Prevost et al [31,32] with some modifications. Human blood was collected from antecubital veins of healthy volunteers who were not taking medication during the 2 weeks preceding venipuncture.…”

Section: Preparation Of Gel-filtered Human Plateletsmentioning

confidence: 99%

The pyrrolidinoindoline alkaloid Psm2 inhibits platelet aggregation and thrombus formation by affecting PI3K/Akt signaling

Wang

et al. 2016

Acta Pharmacol Sin

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Aim: Psm2, one of the pyrrolidinoindoline alkaloids isolated from whole Selaginella moellendorffii plants, has shown a potent antiplatelet activity. In this study, we further evaluated the antiplatelet effects of Psm2, and elucidated the underlying mechanisms. Methods: Human platelet aggregation in vitro and rat platelet aggregation ex vivo were investigated. Agonist-induced platelet aggregation was measured using a light transmission aggregometer. The antithrombotic effects of Psm2 were evaluated in arteriovenous shunt thrombosis model in rats. To elucidate the mechanisms underlying the antiplatelet activity of Psm2, ELISAs, Western blotting and molecular docking were performed. The bleeding risk of Psm2 administration was assessed in a mouse tail cutting model, and the cytotoxicity of Psm2 was measured with MTT assay in EA.hy926 cells. Results: Psm2 dose-dependently inhibited human platelet aggregation induced by ADP, U4619, thrombin and collagen with IC 50 values of 0.64, 0.37, 0.35 and 0.87 mg/mL, respectively. Psm2 (1, 3, 10 mg/kg) administered to rats significantly inhibited platelet aggregation ex vivo induced by ADP. Psm2 (1, 3, 10 mg/mL, iv) administered to rats with the A-V shunt dose-dependently decreased the thrombus formation. Psm2 inhibited platelet adhesion to fibrinogen and collagen with IC 50 values of 84.5 and 96.5 mg/mL, respectively, but did not affect the binding of fibrinogen to GPIIb/IIIa. Furthermore, Psm2 inhibited AktSer473 phosphorylation, but did not affect MAPK signaling and Src kinase activation. Molecular docking showed that Psm2 bound to phosphatidylinositol 3-kinase β (PI3Kβ) with a binding free energy of -13.265 kcal/mol. In addition, Psm2 did not cause toxicity in EA.hy926 cells and produced only slight bleeding in a mouse tail cutting model. Conclusion: Psm2 inhibits platelet aggregation and thrombus formation by affecting PI3K/Akt signaling. Psm2 may be a lead compound or drug candidate that could be developed for the prevention or treatment of thrombotic diseases.

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“…One involves Eph kinases and ephrins, specifically EphA4 and ephrinB1, which through receptor ligand interactions on the platelet surface enhance the binding of GP IIb-IIIa to immobilized fibrinogen in the presence of physiological agonists [66]. Recent work from our laboratory using both oligonucleotide-based microarray analyses and mass spectrometric proteomics techniques has identified two additional receptor families that are involved.…”

Section: Secondary Aggregation Receptorsmentioning

confidence: 99%

Therapeutic approaches in arterial thrombosis

Phillips

Conley

Sinha

et al. 2005

Journal of Thrombosis and Haemostasis

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Summary. The current standard of care for the treatment of arterial thrombosis includes anticoagulants and three classes of antiplatelet agents -aspirin, thienopyridines and glycoprotein IIb-IIIa antagonists. Although these drugs have had a significant impact on morbidity and mortality in several patient populations, up to 15% of the high risk patients with acute coronary syndrome continue to suffer from ischemic events. This problem may occur, in part, because the platelets in many patients are non-responsive to aspirin and clopidogrel. Murine models now indicate that platelets are not only responsible for arterial occlusion, they are also involved in the progression of atherosclerotic disease. New opportunities have emerged identifying potential targets and strategies for drug discovery suited to address these deficiencies by more effectively modulating platelet adhesion, thrombus growth, thrombus stability and the pro-inflammatory activity of platelets. In addition, a growing need has emerged for the development of bedside devices capable of bringing personalized medicine to patients being treated with antithrombotic drugs in order to measure the pharmacodynamic activities of new therapies, to assess the activities achieved by combined antithrombotic therapy, and to identify patients that fail to respond.

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Interactions between Eph kinases and ephrins provide a mechanism to support platelet aggregation once cell-to-cell contact has occurred

Cited by 118 publications

References 55 publications

Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury

Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury

The pyrrolidinoindoline alkaloid Psm2 inhibits platelet aggregation and thrombus formation by affecting PI3K/Akt signaling

Therapeutic approaches in arterial thrombosis

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