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J. Biol. Chem., Vol. 283, Issue 21, 14674-14684, May 23, 2008

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Activation of Syk by Protein Kinase C- Regulates Thrombin-induced Intercellular Adhesion Molecule-1 Expression in Endothelial Cells via Tyrosine Phosphorylation of RelA/p65^*

From the Department of Pediatrics (Neonatology), Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Protein kinase C- (PKC-) plays a pivotal role in mediating thrombin-induced NF-B activation and ICAM-1 expression in endothelial cells. However, the downstream mechanisms mediating its function are unclear. In this study, we show that PKC--mediated activation of protein-tyrosine kinase Syk plays an important role in thrombin signaling of NF-B activation and intercellular adhesion molecule-1 (ICAM-1) expression in endothelial cells. Stimulation of human vascular endothelial cells with thrombin resulted in a time-dependent phosphorylation of Syk on tyrosine 525 and 526, an indication of Syk activation. Inhibition of PKC- by pharmacological and genetic approaches prevented Syk activation by thrombin. These results place Syk downstream of PKC- in transmitting thrombin-activated signaling in endothelial cells. Consistent with this, thrombin-induced NF-B activity and ICAM-1 expression were prevented by the expression of a kinase-defective mutant or RNA interference knockdown of Syk. Similarly, inhibiting Syk also impaired NF-B activity and ICAM-1 expression induced by a constitutively active mutant of PKC-. Analysis of the NF-B pathway showed that Syk contributes to thrombin-induced NF-B activation by controlling its transactivation potential and that this response is associated with tyrosine phosphorylation of RelA/p65. Thus, these data unveil a novel pathway in which Syk signals downstream of PKC- to mediate thrombininduced ICAM-1 expression in endothelial cells by increasing transcriptional capacity of NF-B via a mechanism that relies on tyrosine phosphorylation of RelA/p65.

Received for publication, March 17, 2008

^* This work was supported, in whole or in part, by National Institutes of Health NHLBI Grant HL67424 (to A. R.) and by National Institutes of Health NIEHS Grant ES-01247. This work was also supported by a biomedical research grant from the American Lung Association (to F. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.

¹ To whom correspondence should be addressed: Dept. of Pediatrics, Box 850, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642. Tel.: 585-275-5948; Fax: 585-756-7780; E-mail: arshad_rahman{at}urmc.rochester.edu.

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