Defective nitrovasodilator-stimulated protein phosphorylation and calcium regulation in cGMP-dependent protein kinase-deficient human platelets of chronic myelocytic leukemia

Eigenthaler, Martin; Ullrich, H.; Geiger, Jörg; Horstrup, Karen; Hönig-Liedl, Petra; Wiebecke, D; Walter, Ulrich

doi:10.1016/s0021-9258(19)38681-8

Cited by 77 publications

(9 citation statements)

References 24 publications

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“…10,16,17 The platelet inhibitory effects of cGMP-elevating agents or membrane permeable cGMP analogs are strongly impaired in human or murine platelets lacking PKG I, whereas the cAMP/PKA system was not affected. 14,33 Previously, a small numbers of PKA and/or PKG substrates were identified in platelets such as G-proteins/G-protein-associated proteins, cytoskeletal proteins, proteins associated with intracellular Ca 2þ -stores/-release, cell membranes, and cAMP/cGMP phosphodiesterases. 16,34 Selective stimulation of the human platelet cAMP/PKA system (by the PGI 2 analog iloprost) or of platelet PKG (by the soluble guanylyl cyclase stimulator riociguat) increased the phosphorylation of 299 (iloprost) and more than 150 (riociguat) proteins, and decreased the phosphorylation of more than 60 proteins (with riociguat).…”

Section: St-pks In Human and Murine Platelets-agc (Pka Pkg Pkc)mentioning

confidence: 99%

“…11,12 Two endothelial cell-derived factors, PGI 2 and nitric oxide (NO), increase the second messengers cAMP and cyclic guanosine monophosphate (cGMP), respectively, which activate their targets cAMP-and cGMP-dependent protein kinases (PKA, PKG), resulting in platelet inhibition. 3,4,10,[13][14][15][16][17] Additional second messengers including 1,2-diacylglycerol (DAG), inositol 1,4,5-trisphosphate (IP3), phosphoinositides, and Ca 2þ / calmodulins stimulate distinct serine/threonine protein kinases (ST-PKs), for example, protein kinase C (PKC), calmodulin-dependent protein kinases (CAMKs), myosin light chain kinase (MLCK), and protein kinase B (PKB/Akt), which support platelet activation. 6,18 Following the discovery of the protooncogene c-src in nondividing human platelets, 19 tyrosine protein kinases (TKs) c-src and other src family kinase (SFK) members (e.g., Lyn, Yes, Fyn, Fgr) were shown to mediate platelet activation in response of glycoprotein (GP) VI, GPIbα, integrins, and CLEC-2.…”

Section: Introductionmentioning

confidence: 99%

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Fine-Tuning of Platelet Responses by Serine/Threonine Protein Kinases and Phosphatases—Just the Beginning

2021

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Comprehensive proteomic analyses of human and murine platelets established an extraordinary intracellular repertoire of signaling components, which control crucial functions. The spectrum of platelet serine/threonine protein kinases (more than 100) includes the AGC family (protein kinase A, G, C [PKA, PKG, PKC]), the mitogen-activated protein kinases (MAPKs), and others. PKA and PKG have multiple significantly overlapping substrates in human platelets, which possibly affect functions with clear “signaling nodes” of regulation by multiple protein kinases/phosphatases. Signaling nodes are intracellular Ca2+ stores, the contractile system (myosin light chains), and other signaling components such as G-proteins, protein kinases, and protein phosphatases. An example for this fine-tuning is the tyrosine kinase Syk, a crucial component of platelet activation, which is controlled by several serine/threonine and tyrosine protein kinases as well as phosphatases. Other protein kinases including PKA/PKG modulate protein phosphatase 2A, which may be a master regulator of MAPK signaling in human platelets. Protein kinases and in particular MAPKs are targeted by an increasing number of clinically used inhibitors. However, the precise regulation and fine-tuning of these protein kinases and their effects on other signaling components in platelets are only superficially understood—just the beginning. However, promising future approaches are in sight.

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Section: St-pks In Human and Murine Platelets-agc (Pka Pkg Pkc)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fine-Tuning of Platelet Responses by Serine/Threonine Protein Kinases and Phosphatases—Just the Beginning

2021

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“…Platelets, as well as endothelial cells, express high concentrations of cGKI (6)(7)(8). In vitro cGMP acting via cGKI lowers cytosolic Ca 2 ϩ concentrations in platelets, inhibits platelet activation by potent agonists, and initiates phosphorylation of target proteins, including the vasodilator-stimulated phosphoprotein (VASP) and the thromboxane receptor (9)(10)(11). However, the in vivo importance of cGKI-dependent signaling for the homeostasis of platelet-endothelium interactions remains to be established, since an identical role has been assigned to the prostacyclin/cAMP/cAMP kinase (cAK) pathway (12).…”

mentioning

confidence: 99%

Increased Adhesion and Aggregation of Platelets Lacking Cyclic Guanosine 3′,5′-Monophosphate Kinase I

Maßberg

Sausbier

Klatt

et al. 1999

The Journal of Experimental Medicine

213

168

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Atherosclerotic vascular lesions are considered to be a major cause of ischemic diseases, including myocardial infarction and stroke. Platelet adhesion and aggregation during ischemia–reperfusion are thought to be the initial steps leading to remodeling and reocclusion of the postischemic vasculature. Nitric oxide (NO) inhibits platelet aggregation and smooth muscle proliferation. A major downstream target of NO is cyclic guanosine 3′,5′-monophosphate kinase I (cGKI). To test the intravascular significance of the NO/cGKI signaling pathway in vivo, we have studied platelet–endothelial cell and platelet–platelet interactions during ischemia/reperfusion using cGKI-deficient (cGKI−/−) mice. Platelet cGKI but not endothelial or smooth muscle cGKI is essential to prevent intravascular adhesion and aggregation of platelets after ischemia. The defect in platelet cGKI is not compensated by the cAMP/cAMP kinase pathway supporting the essential role of cGKI in prevention of ischemia-induced platelet adhesion and aggregation.

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“…cGMP has been shown to activate cAMP-PKA signaling pathway by inhibiting phosphodiesterase 3 ( Jang et al, 2002 ). PKG-deficient mice or patients also showed PKA-dependent cellular responses to cGMP ( Eigenthaler et al, 1993 ; Sausbier et al, 2000 ). Furthermore, H89, a potent PKA inhibitor with a Ki for PKA 10 times less than its Ki for PKG ( Chijiwa et al, 1990 ), was shown to inhibit cGMP-induced VASP phosphorylation ( Burkhardt et al, 2000 ), suggesting that PKA is possible involved in cGMP-induced VASP phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Naringenin Inhibits Platelet Activation and Arterial Thrombosis Through Inhibition of Phosphoinositide 3-Kinase and Cyclic Nucleotide Signaling

et al. 2021

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Citrus flavanoids intake can reduce the risk of cardiovascular diseases. Naringenin, a natural predominant flavonoid abundant in citrus fruits, possesses protective effects against atherothrombotic diseases. As platelet activation plays central roles in atherothrombogenesis, we studied the effects of naringenin on platelet activation, signaling, thrombosis and hemostasis. Naringenin dose-dependently inhibited agonist-induced platelet aggregation in vitro, and exhibited more-potent efficacy on ADP-induced platelet aggregation. It also suppressed platelet aggregation stimulated by ADP ex vivo. Naringenin inhibited ADP-induced platelet α-granule secretion, fibrinogen binding, intracellular calcium mobilization and platelet adhesion on collagen-coated surface. Naringenin also inhibited platelet spreading on fibrinogen and clot retraction, processes mediated by outside-in integrin signaling. Mechanism studies indicated that naringenin suppressed PI3K-mediated signaling and phosphodiesterase activity in platelets, in addition to increasing cGMP levels and VASP phosphorylation at Ser239. Furthermore, naringenin-induced VASP phosphorylation and inhibition of platelet aggregation were reversed by a PKA inhibitor treatment. Interestingly, naringenin inhibited thrombus formation in the (FeCl3)-induced rat carotid arterial thrombus model, but not cause a prolonged bleeding time in mice. This study suggests that naringenin may represent a potential antiplatelet agent targeting PI3K and cyclic nucleotide signaling, with a low bleeding risk.

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Defective nitrovasodilator-stimulated protein phosphorylation and calcium regulation in cGMP-dependent protein kinase-deficient human platelets of chronic myelocytic leukemia

Cited by 77 publications

References 24 publications

Fine-Tuning of Platelet Responses by Serine/Threonine Protein Kinases and Phosphatases—Just the Beginning

Fine-Tuning of Platelet Responses by Serine/Threonine Protein Kinases and Phosphatases—Just the Beginning

Increased Adhesion and Aggregation of Platelets Lacking Cyclic Guanosine 3′,5′-Monophosphate Kinase I

Naringenin Inhibits Platelet Activation and Arterial Thrombosis Through Inhibition of Phosphoinositide 3-Kinase and Cyclic Nucleotide Signaling

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