Focal Adhesion Kinase Activity and Localization is Critical for TNF-α-Induced Nuclear Factor-κB Activation.
Focal Adhesion Kinase Activity and Localization is Critical for TNF-α-Induced Nuclear Factor-κB Activation.
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粘着斑激酶的活性和定位是肿瘤坏死因子-α诱导的核因子-κB激活的关键。
DOI：
10.1007/s10753-020-01408-5
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发表时间：
2021-06
期刊：
影响因子：
5.1
通讯作者：
Lim SS
中科院分区：
文献类型：
--
作者：
Murphy JM;Jeong K;Cioffi DL;Campbell PM;Jo H;Ahn EE;Lim SS
虽然持续的核因子-κB（NF-κB）活化对于促炎分子表达至关重要，但慢性炎症期间NF-κB活性的调节剂尚不清楚。我们研究了粘着斑激酶（FAK）在肿瘤坏死因子-α（TNF-α）刺激的内皮细胞（EC）中持续NF-κB活化中的作用。我们发现FAK抑制通过破坏TNF-α受体复合物-I（TNFRC-I）的形成而消除了TNF-α介导的内皮细胞中持续的NF-κB活性。此外，FAK抑制减少了受体相互作用丝氨酸/苏氨酸蛋白激酶1（RIPK 1）和NF-κB（IκB）激酶抑制剂（IKK）复合物对TNFRC-I的募集，导致IκBα蛋白的稳定性升高。在给予TNF-α的小鼠中，药理学和遗传学FAK抑制剂阻断了TNF-α诱导的主动脉EC中IKK-NF-κB活化。在机制上，TNF-α激活FAK并将其从细胞核重新分配到细胞质，导致IKK-NF-κB激活升高。另一方面，即使在TNF-α刺激下，FAK抑制也将FAK捕获在EC的核中，导致IKK-NF-κB活性降低。总之，这些发现支持FAK抑制剂在治疗慢性炎症性疾病中的潜在用途。
While sustained nuclear factor-κB (NF-κB) activation is critical for proinflammatory molecule expression, regulators of NF-κB activity during chronic inflammation are not known. We investigated the role of focal adhesion kinase (FAK) on sustained NF-κB activation in tumor necrosis factor-α (TNF-α)–stimulated endothelial cells (ECs) both in vitro and in vivo. We found that FAK inhibition abolished TNF-α-mediated sustained NF-κB activity in ECs by disrupting formation of TNF-α receptor complex-I (TNFRC-I). Additionally, FAK inhibition diminished recruitment of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and the inhibitor of NF-κB (IκB) kinase (IKK) complex to TNFRC-I, resulting in elevated stability of IκBα protein. In mice given TNF-α, pharmacological and genetic FAK inhibition blocked TNF-α-induced IKK-NF-κB activation in aortic ECs. Mechanistically, TNF-α activated and redistributed FAK from the nucleus to the cytoplasm, causing elevated IKK-NF-κB activation. On the other hand, FAK inhibition trapped FAK in the nucleus of ECs even upon TNF-α stimulation, leading to reduced IKK-NF-κB activity. Together, these findings support a potential use for FAK inhibitors in treating chronic inflammatory diseases.
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影响因子：
16
作者：
Kim JH;Baddoo MC;Park EY;Stone JK;Park H;Butler TW;Huang G;Yan X;Pauli-Behn F;Myers RM;Tan M;Flemington EK;Lim ST;Ahn EY
通讯作者：
Ahn EY
DOI：
10.1161/atvbaha.117.310097
发表时间：
2017-11
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Baylis RA;Gomez D;Mallat Z;Pasterkamp G;Owens GK
通讯作者：
Owens GK
影响因子：
9
作者：
Pescatore A;Esposito E;Draber P;Walczak H;Ursini MV
通讯作者：
Ursini MV
影响因子：
4.8
作者：
Funakoshi-Tago, M;Sonoda, Y;Kasahara, T
通讯作者：
Kasahara, T
影响因子：
16
作者：
Annibaldi A;Wicky John S;Vanden Berghe T;Swatek KN;Ruan J;Liccardi G;Bianchi K;Elliott PR;Choi SM;Van Coillie S;Bertin J;Wu H;Komander D;Vandenabeele P;Silke J;Meier P
通讯作者：
Meier P