| First Author | Yurdagul A Jr | Year | 2016 |
| Journal | J Cell Sci | Volume | 129 |
| Issue | 8 | Pages | 1580-91 |
| PubMed ID | 26906414 | Mgi Jnum | J:247283 |
| Mgi Id | MGI:5922143 | Doi | 10.1242/jcs.182097 |
| Citation | Yurdagul A Jr, et al. (2016) Oxidized LDL induces FAK-dependent RSK signaling to drive NF-kappaB activation and VCAM-1 expression. J Cell Sci 129(8):1580-91 |
| abstractText | Oxidized low-density lipoprotein (oxLDL) accumulates early in atherosclerosis and promotes endothelial nuclear factor kappaB (NF-kappaB) 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-kappaB signaling has yet to be revealed. We now show that oxLDL induces NF-kappaB activation and VCAM-1 expression through FAK-dependent IkappaB kinase beta (IKKbeta, 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 IKKbeta and NF-kappaB signaling, as inhibiting RSK blocks oxLDL-induced IKKbeta and NF-kappaB 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 IKKbeta and NF-kappaB signaling and proinflammatory gene expression. |
