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

Kaiser M. Bijli, Mohd Minhajuddin, Fabeha Fazal, Michael A. O'Reilly, Leonidas C. Platanias, Arshad Rahman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

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-κB-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-κB-dependent reporter activity and ICAM-1 expression. Analysis of the NF-κB pathway revealed that the effect of c-Src inhibition occurred independently of IκBα degradation and NF-κB DNA binding function and was not associated with exchange of NF-κB dimers. Phosphorylation of RelA/p65 at Ser 536, 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-κB and thereby ICAM-1 expression in endothelial cells.

Original languageEnglish (US)
Pages (from-to)L396-L404
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume292
Issue number2
DOIs
StatePublished - Feb 2007

Keywords

  • Adhesion molecules
  • NF-κB
  • Tyrosine kinases

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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