Journal
BLOOD
Volume 107, Issue 3, Pages 965-972Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2005-03-1308
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Funding
- NHLBI NIH HHS [HL68819, R01 HL068819, HL62350, R01 HL062350] Funding Source: Medline
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Integrin activation (inside-out signaling) in platelets can be initiated by agonists such as von Willebrand factor (VWF) and thrombin. Here we show that a mitogen-activated protein kinase (MAPK), p38, plays an important role in the activation of integrin alpha(IIb)beta(3) induced by VWF and thrombin. A dominant-negative mutant of p38, p38AF, inhibits alpha(IIb)beta(3) activation induced by VWF binding to its receptor, the platelet glycoprotein Ib-IX (GPIb-IX), and p38 inhibitors diminish platelet aggregation induced by VWF or low-dose thrombin. The inhibitory effect of p38 inhibitor is unlikely to be caused by the previous suggested effect on cyclo-oxygenase, as inhibition also was observed in the presence of high concentrations of cyclooxygenase inhibitor, aspirin. VWF or thrombin induces p38 activation, which is inhibited in cGMP-dependent protein kinase (PKG)-knockout mouse platelets and PKG inhibitor-treated human platelets, indicating that activation of p38 is downstream from PKG in the signaling pathway. p38AF or p38 inhibitors diminish PKG-induced phosphorylation of extracellular stimuli-responsive kinase (ERK), which also is important in integrin activation. Thus, p38 plays an important role in mediating PKG-dependent activation of ERK. These data delineate a novel signaling pathway in which platelet agonists sequentially activate PKG, p38, and ERK pathways leading to integrin activation.
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