KLF2-induced actin shear fibers control both alignment to flow and JNK signaling in vascular endothelium.
The shear stress-induced transcription factor Krüppel-like factor 2 (KLF2) confers antiinflammatory properties to endothelial cells through the inhibition of activator protein 1, presumably by interfering with mitogen-activated protein kinase (MAPK) cascades. To gain insight into the regulation of these cascades by KLF2, we used antibody arrays in combination with time-course mRNA microarray analysis. No gross changes in MAPKs were detected; rather, phosphorylation of actin cytoskeleton-associated proteins, including focal adhesion kinase, was markedly repressed by KLF2. Furthermore, we demonstrate that KLF2-mediated inhibition of Jun NH(2)-terminal kinase (JNK) and its downstream targets ATF2/c-Jun is dependent on the cytoskeleton. Specifically, KLF2 directs the formation of typical short basal actin filaments, termed shear fibers by us, which are distinct from thrombin- or tumor necrosis factor-alpha-induced stress fibers. KLF2 is shown to be essential for shear stress-induced cell alignment, concomitant shear fiber assembly, and inhibition of JNK signaling. These findings link the specific effects of shear-induced KLF2 on endothelial morphology to the suppression of JNK MAPK signaling in vascular homeostasis via novel actin shear fibers.
Boon
Reinier A
RA
Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 BT Amsterdam, The Netherlands.
Leyen
Thomas A
TA
Fontijn
Ruud D
RD
Fledderus
Joost O
JO
Baggen
Josefien M C
JM
Volger
Oscar L
OL
van Nieuw Amerongen
Geerten P
GP
Horrevoets
Anton J G
AJ
D008841:Actin Cytoskeleton / Q000378:metabolism*; D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005263:Femoral Artery / Q000166:cytology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D012039:Regional Blood Flow / Q000502:physiology; D012501:Saphenous Vein / Q000166:cytology; D013314:Stress, Mechanical; D014161:Transduction, Genetic; D014471:Umbilical Veins / Q000166:cytology; D054460:rho-Associated Kinases / Q000378:metabolism
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D054460:rho-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases