Document Detail

c-Src interacts with and phosphorylates RelA/p65 to promote thrombin-induced ICAM-1 expression in endothelial cells.
MedLine Citation:
PMID:  17012367     Owner:  NLM     Status:  MEDLINE    
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-kappaB-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-kappaB-dependent reporter activity and ICAM-1 expression. Analysis of the NF-kappaB pathway revealed that the effect of c-Src inhibition occurred independently of IkappaBalpha degradation and NF-kappaB DNA binding function and was not associated with exchange of NF-kappaB 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-kappaB and thereby ICAM-1 expression in endothelial cells.
Kaiser M Bijli; Mohd Minhajuddin; Fabeha Fazal; Michael A O'Reilly; Leonidas C Platanias; Arshad Rahman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2006-09-29
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  292     ISSN:  1040-0605     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-02-09     Completed Date:  2007-03-14     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L396-404     Citation Subset:  IM    
Department of Pediatrics, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
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MeSH Terms
DNA / metabolism
Endothelial Cells / drug effects,  enzymology*
Gene Expression Regulation / drug effects
I-kappa B Proteins / metabolism
Intercellular Adhesion Molecule-1 / genetics,  metabolism*
Phosphorylation / drug effects
Phosphoserine / metabolism
Phosphotyrosine / metabolism
Protein Binding / drug effects
Protein Processing, Post-Translational / drug effects
Protein-Tyrosine Kinases / antagonists & inhibitors,  deficiency,  metabolism*
Proto-Oncogene Proteins / antagonists & inhibitors,  deficiency,  metabolism*
RNA, Messenger / genetics,  metabolism
Thrombin / pharmacology*
Transcription Factor RelA / metabolism*
Grant Support
Reg. No./Substance:
0/I-kappa B Proteins; 0/Proto-Oncogene Proteins; 0/RNA, Messenger; 0/Transcription Factor RelA; 126547-89-5/Intercellular Adhesion Molecule-1; 139874-52-5/NF-kappaB inhibitor alpha; 17885-08-4/Phosphoserine; 21820-51-9/Phosphotyrosine; 9007-49-2/DNA; EC Kinases; EC tyrosine-protein kinase; EC

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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