Focal adhesion kinase modulates activation of NF-kappaB by flow in endothelial cells.
Atherogenesis involves activation of NF-kappaB in endothelial cells by fluid shear stress. Because this pathway involves integrins, we investigated the involvement of focal adhesion kinase (FAK). We found that FAK was not required for flow-stimulated translocation of the p65 NF-kappaB subunit to the nucleus but was essential for phosphorylation of p65 on serine 536 and induction of ICAM-1, an NF-kappaB-dependent gene. NF-kappaB activation by TNF-alpha or hydrogen peroxide was FAK independent. Events upstream of NF-kappaB, including integrin activation, Rac activation, reactive oxygen production, and degradation of IkappaB, were FAK independent. FAK therefore regulates NF-kappaB phosphorylation and transcriptional activity in response to flow by a novel mechanism.
Petzold
Tobias
T
Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22908, USA.
Orr
A Wayne
AW
Hahn
Cornelia
C
Jhaveri
Krishna A
KA
Parsons
J Thomas
JT
Schwartz
Martin Alexander
MA
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D016023:Integrins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D006861:Hydrogen Peroxide; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051550:I-kappa B Kinase; D020744:rac GTP-Binding Proteins