A Mitogen-activated Protein Kinase-dependent Signaling Pathway in the Activation of Platelet Integrin αIIbβ3

Li, Zhenyu; Xi, Xiaodong; Du, Xiaoping

doi:10.1074/jbc.m106129200

Cited by 120 publications

(235 citation statements)

References 49 publications

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“…This hypothesis is in agreement with a recent study demonstrating that human platelets contain a calcium-and a PKC-regulated pathway, downstream of PLC activation, which independently regulate agonists-induced fibrinogen receptor activation. 32 Although we failed to find an additive effect with low doses of PLC and PKC inhibitors on platelet calcium mobilization, this issue needs to be investigated further.…”

Section: Discussionmentioning

confidence: 96%

Identifying pathways involved in leptin-dependent aggregation of human platelets

et al. 2004

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OBJECTIVE:To investigate the role of phospholipase C (PLC), phospholipase A 2 (PLA 2 ), calcium, and protein kinase C (PKC) in mediating leptin-enhanced aggregation of human platelets. DESIGN: In vitro, ex vivo study. SETTING: Outpatient's Service for Prevention and Treatment of Obesity at the University Hospital of Messina, Italy. SUBJECTS: In total, 14 healthy normal-weight male (age 31.471.9 y; body mass index 22.770.6 kg/m 2 ) subjects. MEASUREMENTS: Adenosine diphosphate-(ADP-) induced platelet aggregation and platelet free calcium were measured after incubation of platelets with leptin alone (5-500 ng/ml), or leptin (50 and 100 ng/ml) in combination with anti-human leptin receptor long form antibody (anti-ObRb-Ab, 1:800-1:100 dilutions), PLC inhibitor U73122 (3.125-25 mM), PLA 2 inhibitor AACOCF3 (1.25-10 mM), or PKC inhibitor Ro31-8220 (1.25-10 mM). RESULTS: Platelet stimulation with leptin leads to a significant and dose-dependent increase in ADP-induced platelet aggregation and platelet free calcium concentrations. Leptin effects on both platelet aggregation and calcium mobilization were completely abated by the co-incubation with leptin and anti-ObRb-Ab. Leptin-induced platelet aggregation was dosedependently inhibited by U73122, AACOCF3, or Ro31-8220. The effect of leptin on intracellular calcium was inhibited in a dosedependent manner by incubation with U73122 and AACOCF3, but not with Ro31-8220. CONCLUSIONS: Our study confirms that leptin is able to enhance ADP-induced aggregation of human platelets, and raise the possibility that PLC, PKC, PLA 2 , and calcium could play a relevant role in mediating the proaggregating action of leptin.

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Section: Discussionmentioning

confidence: 96%

Identifying pathways involved in leptin-dependent aggregation of human platelets

et al. 2004

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“…GPIb-IX is a unique receptor that, unlike thromboxane A2 or collagen receptors, does not appear to require secretion of granules to induce activation of integrin. GPIb-IX-mediated integrin activation can be reconstituted in the cultured Chinese hamster ovary cells that do not have platelet-specific granules (19,20,33,44), although it is significantly amplified by ADP secre- FIG. 6.…”

Section: Discussionmentioning

confidence: 99%

“…The GPIb-IX-dependent activation pathway mediates von Willebrand factor-induced platelet activation (11,(31)(32)(33) and is also important in low dose thrombininduced platelet activation (34 -37). We reported recently that PKG plays a stimulatory role in GPIb-IX-dependent integrin activation (19,20). To investigate whether and how PKG plays roles in platelet activation via various pathways, we examined the platelet aggregation response of PKG I knock-out mouse or PKG inhibitor-treated human platelets to GPIb-IX-independent platelet agonists.…”

Section: Pkg Plays a Stimulatory Role In Platelet Aggregationmentioning

confidence: 99%

A Platelet Secretion Pathway Mediated by cGMP-dependent Protein Kinase

Zhang

Marjanovic

et al. 2004

Journal of Biological Chemistry

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Platelet secretion (exocytosis) is critical in amplifying platelet activation, in stabilizing thrombi, and in arteriosclerosis and vascular remodeling. The signaling mechanisms leading to secretion have not been well defined. We have shown previously that cGMP-dependent protein kinase (PKG) plays a stimulatory role in platelet activation via the glycoprotein Ib-IX pathway. Here we show that PKG also plays an important stimulatory role in mediating aggregation-dependent platelet secretion and secretion-dependent second wave platelet aggregation, particularly those induced via G q -coupled agonist receptors, the thromboxane A2 (TXA2) receptor, and protease-activated receptors (PARs). PKG I knock-out mouse platelets and PKG inhibitor-treated human platelets showed diminished aggregation-dependent secretion and also showed a diminished secondary wave of platelet aggregation induced by a TXA2 analog and thrombin receptor-activating peptides that were rescued by the granule content ADP. Low dose collageninduced platelet secretion and aggregation were also reduced by PKG inhibitors. Furthermore PKG I knockout and PKG inhibitors significantly attenuated activation of the G i pathway that is mediated by secreted ADP. These data unveil a novel PKG-dependent platelet secretion pathway and a mechanism by which PKG promotes platelet activation.

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“…U0126, a MEKK1 inhibitor (44), also had no effect on the aggregation induced by co-activation of either G 12/13 and G i or G q and G i signaling. Thus, although Erk2 has been implicated in the GP1b-IX-mediated platelet fibrinogen receptor activation (27), the MEKK-Erk pathway does not play any significant role in either G 12/13 -and G i -or G q -and G i -mediated GPIIb/IIIa activation in human platelets.…”

Section: Signaling Events Downstream Of Concomitant Activation Of G Pmentioning

confidence: 99%

“…The ␣-subunit of the heterotrimeric G protein G i pathway inhibits the activity of adenylyl cyclase while the ␤␥-subunit activates PI 3-kinase (25). Together, these pathways lead to the activation of numerous kinases including protein kinase B (PKB/Akt) (26), PKC (4), Map kinase kinase (MEKK1) (27), Src family tyrosine kinases (28), among many others.…”

mentioning

confidence: 99%

Coordinated Signaling through Both G12/13 and Gi Pathways Is Sufficient to Activate GPIIb/IIIa in Human Platelets

Dorsam

Kim

Jin

et al. 2002

Journal of Biological Chemistry

112

102

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Activation of GPIIb/IIIa is known to require agonistinduced inside-out signaling through G q , G i , and G z . Although activated by several platelet agonists, including thrombin and thromboxane A 2 , the contribution of the G 12/13 signaling pathway to GPIIb/IIIa activation has not been investigated. In this study, we used selective stimulation of G protein pathways to investigate the contribution of G 12/13 activation to platelet fibrinogen receptor activation. YFLLRNP is a PAR-1-specific partial agonist that, at low concentrations (60 M), selectively activates the G 12/13 signaling cascade resulting in platelet shape change without stimulating the G q or G i signaling pathways. YFLLRNP-mediated shape change was completely inhibited by the p160 ROCK inhibitor, Y-27632. At this low concentration, YFLLRNP-mediated G 12/13 signaling caused platelet aggregation and enhanced PAC-1 binding when combined with selective G i or G z signaling, via selective stimulation of the P2Y 12 receptor or ␣ 2A -adrenergic receptor, respectively. Similar data were obtained when using low dose U46619 (10 nM), a thromboxane A 2

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A Mitogen-activated Protein Kinase-dependent Signaling Pathway in the Activation of Platelet Integrin αIIbβ3

Cited by 120 publications

References 49 publications

Identifying pathways involved in leptin-dependent aggregation of human platelets

Identifying pathways involved in leptin-dependent aggregation of human platelets

A Platelet Secretion Pathway Mediated by cGMP-dependent Protein Kinase

Coordinated Signaling through Both G12/13 and Gi Pathways Is Sufficient to Activate GPIIb/IIIa in Human Platelets

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