Essential in Vivo Roles of the C-type Lectin Receptor CLEC-2

Suzuki‐Inoue, Katsue; Ito, Osamu; Ding, Guohua; Nishimura, Satoshi; Hokamura, Kazuya; Eto, Koji; Kashiwagi, Hirokazu; Tomiyama, Yoshiaki; Yatomi, Yutaka; Umemura, Kazuo; Shin, Yonchol; Hirashima, Masanori; Ozaki, Yukio

doi:10.1074/jbc.m110.130575

Cited by 235 publications

(117 citation statements)

References 34 publications

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“…25-27 DUSP3 was dispensable for integrin α IIb β 3 outside-in signaling, as indicated by unaltered fibrin clot retraction (data not shown). Dusp3 -KO mice exhibited levels of thrombus formation comparable to the previously reported GPVI-KO/FcRγ-KO 28-30 CLEC-2-KO, 31 CLEC-2-depleted, 26 GPVI-depleted, 32 and CLEC-2/GPVI-depleted mice. 27 Similar to our findings in DUSP3-deficient mice, GPVI-KO and CLEC-2-KO mice do not exhibit prolonged bleeding time.…”

Section: Discussionsupporting

confidence: 84%

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Dual-Specificity Phosphatase 3 Deficiency or Inhibition Limits Platelet Activation and Arterial Thrombosis

Musumeci¹,

Kuijpers²,

Gilio³

et al. 2015

Circulation

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Background A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. Better understanding of the molecular mechanisms leading to platelet activation is of importance for the development of improved therapies. Recently, protein tyrosine phosphatases (PTPs) 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 through the collagen receptor glycoprotein VI (GPVI) and the C-type lectin-like receptor 2 (CLEC-2). DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism, compared to wild-type mice, and showed severely impaired thrombus formation upon 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 PLCγ2 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 CLEC-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 CLEC-2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a PTP, implicated in platelet signaling, has been targeted with a small-molecule drug.

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Section: Discussionsupporting

confidence: 84%

“…27 Similar to our findings in DUSP3-deficient mice, GPVI-KO and CLEC-2-KO mice do not exhibit prolonged bleeding time. 28, 31, 33 DUSP3-deficient mice were also protected against pulmonary thromboembolism induced by a mixture of collagen and epinephrine, similar to GPVI-KO mice. 33 …”

Section: Discussionmentioning

confidence: 76%

Dual-Specificity Phosphatase 3 Deficiency or Inhibition Limits Platelet Activation and Arterial Thrombosis

Musumeci¹,

Kuijpers²,

Gilio³

et al. 2015

Circulation

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“…This also phenocopies the effects observed upon genetic deletion of Prospero homeobox 1 ( prox-1 ) [36], Src homology domain-containing leukocyte protein-76 ( slp-76) [37] or C-type lectin-like receptor 2 ( clec-2 ) [38]. All show impaired lymphatic vessel development and die in utero with severe edema and hemorrhages.…”

Section: Resultsmentioning

confidence: 72%

The role of RNA interference in the developmental separation of blood and lymphatic vasculature

et al. 2014

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BackgroundDicer is an RNase III enzyme that cleaves double stranded RNA and generates functional interfering RNAs that act as important regulators of gene and protein expression. Dicer plays an essential role during mouse development because the deletion of the dicer gene leads to embryonic death. In addition, dicer-dependent interfering RNAs regulate postnatal angiogenesis. However, the role of dicer is not yet fully elucidated during vascular development.MethodsIn order to explore the functional roles of the RNA interference in vascular biology, we developed a new constitutive Cre/loxP-mediated inactivation of dicer in tie2 expressing cells.ResultsWe show that cell-specific inactivation of dicer in Tie2 expressing cells does not perturb early blood vessel development and patterning. Tie2-Cre; dicerfl/fl mutant embryos do not show any blood vascular defects until embryonic day (E)12.5, a time at which hemorrhages and edema appear. Then, midgestational lethality occurs at E14.5 in mutant embryos. The developing lymphatic vessels of dicer-mutant embryos are filled with circulating red blood cells, revealing an impaired separation of blood and lymphatic vasculature.ConclusionThus, these results show that RNA interference perturbs neither vasculogenesis and developmental angiogenesis, nor lymphatic specification from venous endothelial cells but actually provides evidence for an epigenetic control of separation of blood and lymphatic vasculature.

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“…This newly recognized role for platelets in lymphatic development is based on murine models and is important because organization of the lymphatic system, lymphocyte, and other cellular trafficking via lymphatics and immune and inflammatory responses are intimately intertwined [272]. CLEC-2 is also required for stable platelet aggregation and thrombus stabilization in vivo and in vitro based on studies of genetically altered mice [269]. …”

Section: Platelets In Adaptive Immune Responsesmentioning

confidence: 99%

Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum

et al. 2011

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Platelets are chief effector cells in hemostasis. In addition, however, their specializations include activities and intercellular interactions that make them key effectors in inflammation and in the continuum of innate and adaptive immunity. This review focuses on the immune features of human platelets and platelets from experimental animals and on interactions between inflammatory, immune, and hemostatic activities of these anucleate but complex and versatile cells. The experimental findings and evidence for physiologic immune functions include previously unrecognized biologic characteristics of platelets and are paralleled by new evidence for unique roles of platelets in inflammatory, immune, and thrombotic diseases.

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Essential in Vivo Roles of the C-type Lectin Receptor CLEC-2

Cited by 235 publications

References 34 publications

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

The role of RNA interference in the developmental separation of blood and lymphatic vasculature

Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum

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