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This Article Full Text Full Text (PDF) All Versions of this Article: 292/2/L396    most recent 00163.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Bijli, K. M. Articles by Rahman, A. Search for Related Content PubMed PubMed Citation Articles by Bijli, K. M. Articles by Rahman, A.

c-Src interacts with and phosphorylates RelA/p65 to promote thrombin-induced ICAM-1 expression in endothelial cells

¹Department of Pediatrics, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York; and ²Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois

Submitted 29 April 2006 ; accepted in final form 27 September 2006

The procoagulant thrombin promotes polymorphonuclear leukocyte (PMN) adhesion to endothelial cells by a mechanism involving expression of intercellular adhesion molecule-1 (ICAM-1) via an NF-B-dependent pathway. We now provide evidence that activation of c-Src is crucial in signaling thrombin-induced ICAM-1 expression via tyrosine phosphorylation of RelA/p65. Stimulation of human umbilical vein endothelial cells with thrombin resulted in a time-dependent activation of c-Src, with maximal activation occurring at 30 min after thrombin challenge. Inhibition of c-Src by pharmacological and genetic approaches impaired thrombin-induced NF-B-dependent reporter activity and ICAM-1 expression. Analysis of the NF-B pathway revealed that the effect of c-Src inhibition occurred independently of IB degradation and NF-B DNA binding function and was not associated with exchange of NF-B dimers. Phosphorylation of RelA/p65 at Ser⁵³⁶, an event mediating the transcriptional activity of DNA-bound RelA/p65, was also insensitive to c-Src inhibition. Interestingly, thrombin induced association of c-Src with RelA/p65, and inhibition of c-Src prevented this response, indicating that this interaction is contingent on activation of c-Src. We also observed that thrombin induced tyrosine phosphorylation of RelA/p65, and this phosphorylation was lost upon inhibition of c-Src, consistent with the requirement of activated c-Src for interaction with RelA/p65. These data implicate an important role of c-Src in phosphorylating RelA/p65 to promote the transcriptional activity of NF-B and thereby ICAM-1 expression in endothelial cells.

tyrosine kinases; NF-B; adhesion molecules