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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.


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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Sequential activation of p38 and ERK pathways by cGMP-dependent protein kinase leading to activation of the platelet integrin {alpha}IIbbeta3

Zhenyu Li, Guoying Zhang, Robert Feil, Jiahuai Han, and Xiaoping Du

From the Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL; Institut für Pharmakolgie und Toxikologie der Technischen Universität München, Munchen, Germany; and the Department of Immunology, The Scripps Research Institute, La Jolla, CA.

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}IIbbeta3 induced by VWF and thrombin. A dominant-negative mutant of p38, p38AF, inhibits {alpha}IIbbeta3 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.


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