Intracellular platelet signalling as a target for drug development

Vilahur, Gemma; Gutiérrez, Manuel; Aržanauskaitė, Monika; Mendieta, Guiomar; Ben‐Aicha, Soumaya; Badimon, Lina

doi:10.1016/j.vph.2018.08.007

Cited by 30 publications

(25 citation statements)

References 33 publications

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“…We have identified the inhibitory effects of Fruitflow on the platelet granule secretion, and further investigated the potential intracellular signalling targets in platelets. Src family members, PLCγ2, PKC have been proved to play an important role in platelet granule secretion [15,29]. In our study, we found that Fruitflow (40, 80 mg/L) significantly suppressed thrombin-induced platelet Lyn expression ( Fig.…”

Section: Fruitflow Downregulates Platelet Src/plcγ2/pkc Signallingsupporting

confidence: 54%

Fruitflow attenuates human platelet granule secretion through down-regulating Src/PLCγ2/PKC signaling pathway

Fan¹,

Ma²,

Ya³

et al. 2020

Preprint

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Background : Platelet can release lots of active molecules from granules in active state, which contributes to the progress of atherosclerosis and thrombosis. Fruitflow is a water-soluble tomato extract that has been reported to exert protective cardiovascular effects. The present study aims to investigate whether Fruitflow acts on human platelet granule secretion in vitro and further explore its underlying mechanisms. Methods: Recruit healthy volunteers to collect their peripheral blood and isolate gel-filtered platelets for in vitro experiments. Agonist-induced platelet granule secretion was detected by flow cytometry or ELISA kit. To elucidate the molecular mechanisms, the signaling pathway was tested by western blotting. Results: Fruitflow inhibited platelet surface expression of CD62P, CD40L, and CD63. Moreover, agonist-induced release of platelet factor 4 (PF4), β-thromboglobulin (β-TG), Regulated on Activation Normal T cell Expressed and Secreted (RANTES), transforming growth factor-β1 (TGF-β1), ATP, Ca 2+ , and serotonin were also significantly attenuated by Fruitflow. Furthermore, Fruitflow down-regulated expression of Lyn and phosphorylation of Src, LAT, Syk, PLCγ2 and PKC. However, PKC inhibitor GF109203X did not show additive effects on platelet granule secretion when combined with Fruitflow. Conclusion: Fruitflow effectively inhibited platelet granule secretion via down-regulating platelet Src/PLC-γ2/PKC signaling pathway in vitro , which may provide a novel evidence for the cardioprotective benefits of tomato.

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Section: Fruitflow Downregulates Platelet Src/plcγ2/pkc Signallingsupporting

confidence: 54%

Fruitflow attenuates human platelet granule secretion through down-regulating Src/PLCγ2/PKC signaling pathway

Fan¹,

Ma²,

Ya³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…αIIbβ3 is the most dominant integrin expressed on platelets ( 83 ) and can recognize arginine-glycine-aspartic acid (RGD)-containing ligands such as fibrinogen and fibrin ( 84 ). Ligation of integrins on platelets initiates “inside-out” or “outside-in” signaling pathways to result in functional outcomes such as cell activation, adhesion, or degranulation ( 85 ).…”

Section: Platelet-leukocyte Signaling and Cellular Interactions In Tbmentioning

confidence: 99%

Platelet Activation and the Immune Response to Tuberculosis

2021

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In 2019 10 million people developed symptomatic tuberculosis (TB) disease and 1.2 million died. In active TB the inflammatory response causes tissue destruction, which leads to both acute morbidity and mortality. Tissue destruction in TB is driven by host innate immunity and mediated via enzymes, chiefly matrix metalloproteinases (MMPs) which are secreted by leukocytes and stromal cells and degrade the extracellular matrix. Here we review the growing evidence implicating platelets in TB immunopathology. TB patients typically have high platelet counts, which correlate with disease severity, and a hypercoagulable profile. Platelets are present in human TB granulomas and platelet-associated gene transcripts are increased in TB patients versus healthy controls. Platelets most likely drive TB immunopathology through their effect on other immune cells, particularly monocytes, to lead to upregulation of activation markers, increased MMP secretion, and enhanced phagocytosis. Finally, we consider current evidence supporting use of targeted anti-platelet agents in the treatment of TB due to growing interest in developing host-directed therapies to limit tissue damage and improve treatment outcomes. In summary, platelets are implicated in TB disease and contribute to MMP-mediated tissue damage via their cellular interactions with other leukocytes, and are potential targets for novel host-directed therapies.

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“…PKCs is a family of related serine/threonine kinases, which have been implicated in α IIb β 3 integrin activation and outside-in signaling (Buensuceso et al, 2005;Soriani et al, 2006;Yacoub et al, 2006;Cifuni et al, 2008;Vilahur et al, 2018). It is well established that PKCs can be activated directly by phorbol esters, including PMA (Castagna et al, 1982;Kikkawa et al, 1983).…”

Section: Development Of Kindlin-3 Phosphoantibodiesmentioning

confidence: 99%

Site-specific phosphorylation regulates the functions of kindlin-3 in a variety of cells

et al. 2019

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Studies of isolated cells, mice, and humans have demonstrated the vital role of the FERM domain protein kindlin-3 in integrin activation in certain hematopoietic and non-hematopoietic cells, consequent to binding to integrin β-subunits. To explore regulatory mechanisms, we developed a monoclonal antibody that selectively recognizes the phosphorylated form of Ser484 (pS484) in kindlin-3. Activation of platelets, HEL megakaryocytic-like cells and BT549 breast cancer cells led to enhanced expression of pS484 as assessed by immunofluorescence or Western blotting. In platelets, pS484 rose rapidly and transiently upon stimulation. When a mutant form of kindlin-3, T482S484/AA kindlin-3, was transduced into mouse megakaryocytes, it failed to support activation of integrin αIIbβ3, whereas wild-type kindlin-3 did. In MDA-MB231 breast cancer cells, expression of T482S484/AA kindlin-3 suppressed cell spreading, migration, invasion, and VEGF production. Wild-type kindlin-3 expressing cells markedly increased tumor growth in vivo, whereas T482S484/AA kindlin-3 significantly blunted tumor progression. Thus, our data establish that a unique phosphorylation event in kindlin-3 regulates its cellular functions.

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Intracellular platelet signalling as a target for drug development

Cited by 30 publications

References 33 publications

Fruitflow attenuates human platelet granule secretion through down-regulating Src/PLCγ2/PKC signaling pathway

Fruitflow attenuates human platelet granule secretion through down-regulating Src/PLCγ2/PKC signaling pathway

Platelet Activation and the Immune Response to Tuberculosis

Site-specific phosphorylation regulates the functions of kindlin-3 in a variety of cells

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