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Blood, 1 February 2006, Vol. 107, No. 3, pp. 965-972. Prepublished online as a Blood First Edition Paper on October 6, 2005; DOI 10.1182/blood-2005-03-1308. This Article Full Text (PDF) All Versions of this Article: 2005-03-1308v1 107/3/965    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Li, Z. Articles by Du, X. Search for Related Content PubMed PubMed Citation Articles by Li, Z. Articles by Du, X. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 5, 2005 Accepted September 23, 2005 Sequential activation of p38 and ERK pathways by cGMP-dependent protein kinase leading to activation of the platelet integrin IIb3 Zhenyu Li, Guoying Zhang, Robert Feil, Jiahuai Han, and Xiaoping Du* Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL, USA Institut fur Pharmakolgie und Toxikologie der Technischen Universitat Munchen, Munchen, Germany Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA * Corresponding author; email: xdu{at}uic.edu. 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 IIb3 induced by VWF and thrombin. A dominant negative mutant of p38, p38AF, inhibits IIb3 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 cyclooxygenase as inhibition was also 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 is also 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: MAPkinaseQuest: novel roadway to IIb3 activation Edward F. Plow and Elzbieta Pluskota Blood 2006 107: 851. [Full Text] [PDF] This article has been cited by other articles: H. Yin, J. Liu, Z. Li, M. C. Berndt, C. A. Lowell, and X. Du Src family tyrosine kinase Lyn mediates VWF/GPIb-IX-induced platelet activation via the cGMP signaling pathway Blood, August 15, 2008; 112(4): 1139 - 1146. [Abstract] [Full Text] [PDF] K. Chen, M. Febbraio, W. Li, and R. L. Silverstein A Specific CD36-Dependent Signaling Pathway Is Required for Platelet Activation by Oxidized Low-Density Lipoprotein Circ. Res., June 20, 2008; 102(12): 1512 - 1519. [Abstract] [Full Text] [PDF] F. C. Gushiken, V. Patel, Y. Liu, S. Pradhan, A. L. Bergeron, Y. Peng, and K. V. Vijayan Protein Phosphatase 2A Negatively Regulates Integrin {alpha}IIb{beta}3 Signaling J. Biol. Chem., May 9, 2008; 283(19): 12862 - 12869. [Abstract] [Full Text] [PDF] J. S. Isenberg, M. J. Romeo, C. Yu, C. K. Yu, K. Nghiem, J. Monsale, M. E. Rick, D. A. Wink, W. A. Frazier, and D. D. Roberts Thrombospondin-1 stimulates platelet aggregation by blocking the antithrombotic activity of nitric oxide/cGMP signaling Blood, January 15, 2008; 111(2): 613 - 623. [Abstract] [Full Text] [PDF] H. Yin, A. Stojanovic, N. Hay, and X. Du The role of Akt in the signaling pathway of the glycoprotein Ib-IX induced platelet activation Blood, January 15, 2008; 111(2): 658 - 665. [Abstract] [Full Text] [PDF] P. Flevaris, A. Stojanovic, H. Gong, A. Chishti, E. Welch, and X. Du A molecular switch that controls cell spreading and retraction J. Cell Biol., November 5, 2007; 179(3): 553 - 565. [Abstract] [Full Text] [PDF] I. Russo, P. Del Mese, G. Doronzo, A. De Salve, M. Secchi, M. Trovati, and G. Anfossi Platelet Resistance to the Antiaggregatory Cyclic Nucleotides in Central Obesity Involves Reduced Phosphorylation of Vasodilator-Stimulated Phosphoprotein Clin. Chem., June 1, 2007; 53(6): 1053 - 1060. [Abstract] [Full Text] [PDF] A. J. Begonja, J. Geiger, N. Rukoyatkina, S. Rauchfuss, S. Gambaryan, and U. Walter Thrombin stimulation of p38 MAP kinase in human platelets is mediated by ADP and thromboxane A2 and inhibited by cGMP/cGMP-dependent protein kinase Blood, January 15, 2007; 109(2): 616 - 618. [Abstract] [Full Text] [PDF] C. Gao and P. J. Newman PECAM-1 Inhibits Signaling Pathways That Amplify Platelet Aggregation. Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 1505 - 1505. [Abstract] [PDF] A. Stojanovic, J. A. Marjanovic, V. M. Brovkovych, X. Peng, N. Hay, R. A. Skidgel, and X. Du A Phosphoinositide 3-Kinase-AKT-Nitric Oxide-cGMP Signaling Pathway in Stimulating Platelet Secretion and Aggregation J. Biol. 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