%0 Journal Article %A Yurdagul, Arif %A Sulzmaier, Florian J. %A Chen, Xiao L. %A Pattillo, Christopher B. %A Schlaepfer, David D. %A Orr, A. Wayne %T Oxidized LDL induces FAK-dependent RSK signaling to drive NF-κB activation and VCAM-1 expression %D 2016 %R 10.1242/jcs.182097 %J Journal of Cell Science %P 1580-1591 %V 129 %N 8 %X Oxidized low-density lipoprotein (oxLDL) accumulates early in atherosclerosis and promotes endothelial nuclear factor κB (NF-κB) activation, proinflammatory gene expression and monocyte adhesion. Like for other atherogenic factors, oxLDL-induced proinflammatory responses requires integrin-dependent focal adhesion kinase (FAK, also known as PTK2) signaling; however, the mechanism by which FAK mediates oxLDL-dependent NF-κB signaling has yet to be revealed. We now show that oxLDL induces NF-κB activation and VCAM-1 expression through FAK-dependent IκB kinase β (IKKβ, also known as IKBKB) activation. We further identify FAK-dependent activation of p90 ribosomal S6 kinase family proteins (RSK) as a crucial mediator of oxLDL-dependent IKKβ and NF-κB signaling, as inhibiting RSK blocks oxLDL-induced IKKβ and NF-κB activation, VCAM-1 expression and monocyte adhesion. Finally, transgenic mice containing a kinase-dead mutation in FAK specifically in the endothelial cells show reduced RSK activity, decreased VCAM-1 expression and reduced macrophage accumulation in regions of early atherosclerosis. Taken together, our data elucidates a new mechanism whereby oxLDL-induced endothelial FAK signaling drives an ERK–RSK pathway to activate IKKβ and NF-κB signaling and proinflammatory gene expression. %U https://jcs.biologists.org/content/joces/129/8/1580.full.pdf