Sequential activation of p38 and ERK pathways by cGMP-dependent protein kinase leading to activation of the platelet integrin alphaIIb beta3.
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 alphaIIb beta3 induced by VWF and thrombin. A dominant-negative mutant of p38, p38AF, inhibits alphaIIb beta3 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 cyclo-oxygenase 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.
Li
Zhenyu
Z
Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
Zhang
Guoying
G
Feil
Robert
R
Han
Jiahuai
J
Du
Xiaoping
X
D019943:Amino Acid Substitution; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism; D002460:Cell Line; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006490:Hemostatics / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000819:agonists* / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D017354:Point Mutation; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D006490:Hemostatics; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor; D017869:Cyclic GMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; D001241:Aspirin