Oxidized LDL induces FAK-dependent RSK signaling to drive NF-κB activation and VCAM-1 expression
| Autor: | Florian J. Sulzmaier, David D. Schlaepfer, A. Wayne Orr, Christopher B. Pattillo, Arif Yurdagul, Xiao L. Chen |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
PTK2 Vascular Cell Adhesion Molecule-1 Mice Transgenic IκB kinase Ribosomal Protein S6 Kinases 90-kDa Proinflammatory cytokine Ribosomal s6 kinase Focal adhesion 03 medical and health sciences chemistry.chemical_compound Mice Cell Adhesion Animals Humans VCAM-1 Cell adhesion biology Macrophages NF-kappa B Endothelial Cells Cell Biology Atherosclerosis Cell biology I-kappa B Kinase Lipoproteins LDL Mice Inbred C57BL 030104 developmental biology HEK293 Cells chemistry Gene Expression Regulation Focal Adhesion Kinase 1 Cancer research biology.protein lipids (amino acids peptides and proteins) Signal transduction Research Article Signal Transduction |
| Zdroj: | Yurdagul, A; Sulzmaier, FJ; Chen, XL; Pattillo, CB; Schlaepfer, DD; & Orr, AW. (2016). Oxidized LDL induces FAK-dependent RSK signaling to drive NF-κB activation and VCAM-1 expression.. Journal of cell science, 129(8), 1580-1591. doi: 10.1242/jcs.182097. UC San Diego: Retrieved from: http://www.escholarship.org/uc/item/0741h8wk |
| DOI: | 10.1242/jcs.182097. |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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