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  • 1
    Electronic Resource
    Electronic Resource
    Dual mechanism of protein-tyrosine phosphorylation in concanavalin A-stimulated platelets (1995)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 57 (1995), S. 30-38 
    Details
    ISSN: 0730-2312
    Keywords: signal transduction ; membrane glycoproteins ; tyrosine kinases ; clustering ; adhensive proteins ; aggregation ; adhesion ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Treatment of human platelets with the lectin Concanavalin A (Con A) resulted in the tyrosine phosphorylation of several proteins with molecular masses 65, 80, 85, 95, 120, 135, and 150 kDa. These proteins were divided in two groups: the first group included the 65-, 85-, 95-, and 120-kDa bands, which were tyrosine phosphorylated also in thrombin-stimulated platelets; the second group (80-, 135-, and 150-kDa bands) included proteins whose tyrosine phosphorylation was exclusively promoted by Con A, but not by thrombin. Members of the second group were rapidly dephosphorylated when the lectin was displaced from the cell surface by methyl α-D-mannopyranoside. Pretreatment of intact platelets with the prostacyclin analog iloprost, inhibited Con A-induced tyrosine phosphorylation of the first group of proteins, but had no effect on the tyrosine phosphorylation of the proteins of the second group. Succinyl-Con A, a dimeric derivative of the lectin, which binds to the platelet surface but does not promote clustering of the receptor, did not induce tyrosine phosphorylation of the second group of proteins, although phosphorylation of some members of the first group was observed. Our results demonstrate the presence of two different mechanisms leading to protein-tyrosine phosphorylation in Con A-stimulated platelets, and identify a new signal transduction pathway, promoted by the clustering of membrane glycoproteins, that produces tyrosine phosphorylation of specific substrates. This new pathway may be activated by platelet interaction with multivalent ligands, such as adhesive proteins, during adhesion, spreading, and aggregation.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcb.240570105
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  • 2
    Electronic Resource
    Electronic Resource
    Intracellular calcium mobilization is triggered by clustering of membrane glycoproteins in concanavalin A-stimulated platelets (1993)
    New York, NY [u.a.] : Wiley-Blackwell
    Cell Biochemistry and Function 11 (1993), S. 241-249 
    Details
    ISSN: 0263-6484
    Keywords: Platelets ; concanavalin A ; membrane glycoproteins ; intracellular calcium ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Stimulation of human platelets with concanavalin A resulted in a significant increase in the concentration of cytoplasmic free Ca2+. This effect was due to two different processes: Ca2+ mobilization from internal stores and Ca2+ influx from the extracellular medium. Kinetic analysis revealed that the release of Ca2+ from internal storage sites occurred sooner than the opening of plasma membrane Ca2+ channels. The ability of concanavalin A to induce a sustained increase in cytoplasmic Ca2+ concentration was antagonized and reversed by methyl ∝-D-mannopyranoside, demonstrating that it was promoted by the interaction of the lectin with cell surface glycoproteins. Succinyl-concanavalin A, a dimeric derivative of the lectin, that does not promote patching/capping of the receptor, was able to bind to the platelet surface, and antagonized the effects of native concanavalin A. In addition, succinyl-concanavalin A, per se, was unable to induce Ca2+ mobilization in human platelets. Therefore, the action of the native concanavalin A was mediated by receptor clustering events. Concanavalin A mobilized Ca2+ from the same internal stores from which Ca2+ was mobilized in response to strong platelet agonists, such as thrombin and arachidonic acid. However, while thrombin was ineffective in inducing Ca2+ release after stimulation of platelets with Con A, Con A was able to cause a full discharge of Ca2+ from internal stores even in platelets previously stimulated with thrombin. These results demonstrate for the first time that the clustering of specific membrane glycoproteins can trigger platelet activation. The physiological implications during platelet aggregation are discussed.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cbf.290110404
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  • 3
    Electronic Resource
    Electronic Resource
    Stimulation of human platelets with concanavalin a involves phospholipase C activation (1992)
    New York, NY [u.a.] : Wiley-Blackwell
    Cell Biochemistry and Function 10 (1992), S. 53-59 
    Details
    ISSN: 0263-6484
    Keywords: Platelets ; concanavalin A ; platelet activation ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: In response to concanavalin A, cytoplasmic calcium movement was observed in human platelets, both in the presence of 1 mM Ca2+ or 1 mM EGTA in the medium. Concanavalin A also caused the activation of inositide turnover and the production of inositol phosphates, suggesting that activation of phospholipase C occurs. The mechanism by which concanavalin A stimulates phospholipase C does not depend on GTP-binding transducers, because it was not inhibited by GDPβS, while experiments performed in the presence of cytochalasin B suggested a role for membrane glycoprotein IIb-IIIa-cytoskeleton interaction in this process. Ca2+-proteases and Na +/H+ antiport also seemed to be related to concanavalin A-induced phospholipase C activation, as suggested by experiments performed in the presence of leupeptin and amiloride.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cbf.290100109
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  • 4
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    The proline-rich tyrosine kinase Pyk2 modulates integrin-mediated neutrophil adhesion and reactive oxygen species generation (2020)
    Elsevier
    Details
    Publication Date: 2020-10-01
    Print ISSN: 0167-4889
    Electronic ISSN: 1879-2596
    Topics: Biology , Chemistry and Pharmacology , Medicine , Physics
    Published by Elsevier
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  • 5
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    Tyrosine Phosphorylation-Independent Activation of PLCγ2 Downstream Integrin α2β1 in Platelets: A Possible Role for the Small GTPase Rac. (2006)
    American Society of Hematology
    Details
    Publication Date: 2006-11-16
    Description: We have recently documented the existence of a cross-talk between platelet integrins α2β1 and αIIbβ3 involving phospholipase C (PLC)-mediated activation of the small GTPase Rap1b (Bernardi B et al, Blood2006; 107:2728–35). Here we report that integrin α2β1-mediated platelet adhesion to monomeric collagen and to other specific ligands, such as decorin and collagen-derived peptides, actually induced a robust activation of PLC, evaluated as phosphorylation of pleckstrin, the main platelet substrate for protein kinase C. This was paralleled by a robust tyrosine phosphorylation of the PLCγ2. We found that inhibition of Src kinases by PP2 completely abolished integrin α2β1-promoted PLCγ2 tyrosine phosphorylation, but did not affect either Rap1b stimulation or integrin αIIbβ3 activation in adherent platelets. Surprisingly, phosphorylation of pleckstrin occurred normally under conditions in which tyrosine phosphorylation of PLCγ2 was totally suppressed. The Src-kinase-independent PLC activity in integrin α2β1-adherent cells was not inhibited by pretreatment of platelets with aspirin and apyrase, excluding any possible contribution of Gq-regulated PLCβ isoforms stimulated by released thromboxane A2 or secreted ADP. In addition, PLC-dependent activation of Rap1b and integrin αIIbβ3 were not affected by aspirin and apyrase. Phosphorylation of pleckstrin induced by adhesion to monomeric collagen was not detected in platelets from PLCγ2 knockout mice, confirming that this was the only isoform activated downstream of integrin α2β1. In addition, mouse platelets lacking PLCγ2 showed impaired integrin α2β1-mediated outside-in signaling, and were unable to promote both GTP binding to Rap1b and integrin αIIbβ3 activation. These results indicate that although PLCγ2 is the only PLC isoform stimulated downstream integrin α2β1 and is responsible for the cross-talk to integrin αIIbβ3 through the small GTPase Rap1b, its activation in adherent platelets can occur independently of Src-mediated tyrosine phosphorylation. A recent work has reported that, in vitro, the activity of PLCγ2, but not that of PLCγ1, can be stimulated by the active, GTP-bound form of the small GTPase Rac, with a mechanism independent of phosphorylation on tyrosine residues (Piechlek T el al, J Biol Chem2005; 208:38923–31). In platelets adherent through integrin α2β1, Rac was found to be activated upstream PLC. Activation of Rac was efficiently prevented by the inhibitor NSC23766, which is able to bind and block Rac-specific GEFs. In integrin α2β1-adherent platelets, inhibition of Rac by NSC23766 did not affect PLCγ2 tyrosine phosphorylation and activation of PLC and Rap1b. However, upon inhibition of Src kinases by PP2 and consequent prevention of PLCγ2 tyrosine phosphorylation, NSC23766 almost completely abolished PLC activation, GTP binding to Rap1b and integrin αIIbβ3 stimulation. These results demonstrate that PLCγ2 is the main PLC isoform involved in integrin α2β1-mediated activation of Rap1b and integrin αIIbβ3, and that its activation can occur through two alternative mechanisms involving either tyrosine phosphorylation or stimulation by Rac GTPase.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 6
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    Possible Role of Rap1B in the Cross-Talk between Integrins α2β1 and αIIbβ3. (2004)
    American Society of Hematology
    Details
    Publication Date: 2004-11-16
    Description: Platelet adhesion to subendothelial collagen plays a key role in cell activation and thrombus formation. Two main receptors promote platelet binding to collagen, GPVI and integrin α2β1. It is now clear that both receptors are involved in signal transduction and platelet activation. Rap1B is a small GTPase highly expressed in platelets, and its activation is mediated by a number of agonists through multiple pathways involving PKC, Ca2+, as well as PI-3K. Although a role for Rap1B in integrin αIIbβ3 regulation has been documented, its involvement in integrin-mediated outside-in signaling and cross-talk between integrins has been poorly investigated. In this work we investigated the possible relationship between Rap1B and integrin αIIbβ3 activation mediated by platelet adhesion via integrin α2β1. Integrin α2β1-mediated adhesion has been investigated under static conditions. Monomeric collagen, decorin, and two different peptides obtained by digestion of collagen type II with CNBr (CB8 and CB11) have been used as integrin ligands. Rap1B activation in adherent cells has been evaluated by pull-down experiments using GST-RalGDS-RBD. Integrin αIIbβ3 activation in collagen adherent platelets has been monitored by measuring binding of biotinylated fibrinogen in a colorimetric assay. Integrin α2β1-mediated adhesion to monomeric collagen, decorin and collagen-derived peptides induced a rapid and sustained activation of Rap1B independently of secretion of ADP, production of thromboxane A2, or integrin αIIbβ3-dependent platelet aggregation. We further analysed the effect of several pharmacological inhibitors on Rap1B activation supported by integrin α2β1. Integrin α2β1-mediated platelet adhesion resulted in the activation of PLC, as revealed by the strong and sustained phosphorylation of pleckstrin. Inhibition of PLC by U73122 completely prevented Rap1B activation. We found that both PKC activation and intracellular calcium increase contributed to Rap1B activation in collagen adherent platelets. Platelet adhesion through integrin α2β1 also caused tyrosine phosphorylation of Src, Syk and PLCγ2. Inhibition of Src kinase by PP2 prevented tyrosine phosphorylation of PLCγ2, but had minimal effect on integrin α2β1-promoted pleckstrin phosphorylation. Moreover, inhibition of Src kinase by PP2 did not affect integrin α2β1-mediated Rap1B activation. Analysis of fibrinogen binding revealed that platelet adhesion via integrin α2β1 induces activation of integrin αIIbβ3 indicating a cross-talk between platelet integrin receptors. Binding of fibrinogen to integrin α2β1-adherent platelets was blocked by the same pharmacological inhibitors able to prevent Rap1B activation. By contrast, Src kinases did not appear to be involved in integrin α2β1-mediated integrin αIIbβ3 activation. These results demonstrated that Rap1B is activated downstream integrin α2β1-mediated platelet adhesion and suggest that it may be involved in the cross-talk between the collagen and the fibrinogen receptors.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 7
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    Role and regulation of phosphatidylinositol 3-kinase β in platelet integrin α2β1 signaling (2012)
    American Society of Hematology
    Details
    Publication Date: 2012-01-19
    Description: Integrin α2β1–mediated adhesion of human platelets to monomeric type I collagen or to the GFOGER peptide caused a time-dependent activation of PI3K and Akt phosphorylation. This process was abrogated by pharmacologic inhibition of PI3Kβ, but not of PI3Kγ or PI3Kα. Moreover, Akt phosphorylation was undetectable in murine platelets expressing a kinase-dead mutant of PI3Kβ (PI3KβKD), but occurred normally in PI3KγKD platelets. Integrin α2β1 failed to stimulate PI3Kβ in platelets from phospholipase Cγ2 (PLCγ2)–knockout mice, and we found that intracellular Ca2+ linked PLCγ2 to PI3Kβ activation. Integrin α2β1 also caused a time-dependent stimulation of the focal kinase Pyk2 downstream of PLCγ2 and intracellular Ca2+. Whereas activation of Pyk2 occurred normally in PI3KβKD platelets, stimulation of PI3Kβ was strongly reduced in Pyk2-knockout mice. Neither Pyk2 nor PI3Kβ was required for α2β1–mediated adhesion and spreading. However, activation of Rap1b and inside-out stimulation of integrin αIIbβ3 were reduced after inhibition of PI3Kβ and were significantly impaired in Pyk2-deficient platelets. Finally, both PI3Kβ and Pyk2 significantly contributed to thrombus formation under flow. These results demonstrate that Pyk2 regulates PI3Kβ downstream of integrin α2β1, and document a novel role for Pyk2 and PI3Kβ in integrin α2β1 promoted inside-out activation of integrin αIIbβ3 and thrombus formation.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 8
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    Platelet amyloid precursor protein is a modulator of venous thromboembolism in mice (2017)
    American Society of Hematology
    Details
    Publication Date: 2017-07-27
    Description: Key Points APP is dispensable for platelet activation and arterial thrombosis. APP is an important novel regulator of vein thrombosis and controls coagulation and neutrophil extracellular traps formation.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 9
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    Genetic evidence for a predominant role of PI3Kβ catalytic activity in ITAM- and integrin-mediated signaling in platelets (2009)
    American Society of Hematology
    Details
    Publication Date: 2009-09-03
    Description: Phosphatidylinositol 3-kinase (PI3K) isoforms PI3Kβ and PI3Kγ are implicated in platelet adhesion, activation, and aggregation, but their relative contribution is still unclear or controversial. Here, we report the first comparative functional analysis of platelets from mice expressing a catalytically inactive form of PI3Kβ or PI3Kγ. We demonstrate that both isoforms were similarly required for maximal activation of the small GTPase Rap1b and for complete platelet aggregation upon stimulation of G protein–coupled receptors for adenosine 5′-diphosphate (ADP) or U46619. Their contribution to these events, however, was largely redundant and dispensable. However, PI3Kβ, but not PI3Kγ, enzymatic activity was absolutely required for Akt phosphorylation, Rap1 activation, and platelet aggregation downstream of the immunoreceptor tyrosine-based activation motif (ITAM)–bearing receptor glycoprotein VI (GPVI). Moreover, PI3Kβ was a major essential regulator of platelet adhesion to fibrinogen and of integrin αIIbβ3-mediated spreading. These results provide genetic evidence for a crucial and selective role of PI3Kβ in signaling through GPVI and integrin αIIbβ3.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 10
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    Biology and Role of Extracellular Vesicles (EVs) in the Pathogenesis of Thrombosis (2019)
    Molecular Diversity Preservation International
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    Publication Date: 2019-06-11
    Description: Extracellular vesicles (EVs) are well-established mediators of cell-to-cell communication. EVs can be released by every cell type and they can be classified into three major groups according to their biogenesis, dimension, density, and predominant protein markers: exosomes, microvesicles, and apoptotic bodies. During their formation, EVs associate with specific cargo from their parental cell that can include RNAs, free fatty acids, surface receptors, and proteins. The biological function of EVs is to maintain cellular and tissue homeostasis by transferring critical biological cargos to distal or neighboring recipient cells. On the other hand, their role in intercellular communication may also contribute to the pathogenesis of several diseases, including thrombosis. More recently, their physiological and biochemical properties have suggested their use as a therapeutic tool in tissue regeneration as well as a novel option for drug delivery. In this review, we will summarize the impact of EVs released from blood and vascular cells in arterial and venous thrombosis, describing the mechanisms by which EVs affect thrombosis and their potential clinical applications.
    Print ISSN: 1661-6596
    Electronic ISSN: 1422-0067
    Topics: Chemistry and Pharmacology
    Published by Molecular Diversity Preservation International
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