Nuclear-localized focal adhesion kinase regulates inflammatory VCAM-1 expression.
Nuclear-localized focal adhesion kinase regulates inflammatory VCAM-1 expression.
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DOI：
10.1083/jcb.201109067
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发表时间：
2012-06-25
期刊：
影响因子：
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通讯作者：
Schlaepfer DD
中科院分区：
文献类型：
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作者：
Lim ST;Miller NL;Chen XL;Tancioni I;Walsh CT;Lawson C;Uryu S;Weis SM;Cheresh DA;Schlaepfer DD
激酶抑制的FAK通过核定位和促进GATA4的周转来限制VCAM-1的产生。血管细胞粘附分子-1 （VCAM-1）在细胞发育和炎症反应中起重要作用。肿瘤坏死因子-α (TNF-α)和局灶黏附激酶（FAK）分别是炎症和整合素基质信号传导的关键调节因子。整合素共刺激信号调节炎症基因表达，但这些途径之间的重要控制点仍未解决。我们报道，在体内，药理学FAK抑制可阻止TNF-α -诱导的VCAM-1在心脏血管相关内皮细胞内的表达，而遗传或药理学FAK抑制可阻断VCAM-1在发育过程中的表达。FAK信号传导促进了TNF-α诱导的、丝裂原激活的蛋白激酶的激活，令人惊讶的是，FAK抑制导致TNF-α诱导的VCAM-1产生所需的GATA4转录因子的缺失。FAK抑制也触发FAK核定位。在细胞核中，FAK-FERM（4.1波段，ezrin, radixin， moesin同源）结构域直接结合到GATA4上，并增强其CHIP （hsp70相互作用蛋白的C端）E3连接酶依赖的多泛素化和降解。这些研究揭示了激酶抑制FAK通过核定位和促进GATA4的转换来限制VCAM-1的产生的新的发育和抗炎作用。
Kinase-inhibited FAK limits VCAM-1 production via nuclear localization and promotion of GATA4 turnover. Vascular cell adhesion molecule–1 (VCAM-1) plays important roles in development and inflammation. Tumor necrosis factor–α (TNF-α) and focal adhesion kinase (FAK) are key regulators of inflammatory and integrin–matrix signaling, respectively. Integrin costimulatory signals modulate inflammatory gene expression, but the important control points between these pathways remain unresolved. We report that pharmacological FAK inhibition prevented TNF-α–induced VCAM-1 expression within heart vessel–associated endothelial cells in vivo, and genetic or pharmacological FAK inhibition blocked VCAM-1 expression during development. FAK signaling facilitated TNF-α–induced, mitogen-activated protein kinase activation, and, surprisingly, FAK inhibition resulted in the loss of the GATA4 transcription factor required for TNF-α–induced VCAM-1 production. FAK inhibition also triggered FAK nuclear localization. In the nucleus, the FAK-FERM (band 4.1, ezrin, radixin, moesin homology) domain bound directly to GATA4 and enhanced its CHIP (C terminus of Hsp70-interacting protein) E3 ligase–dependent polyubiquitination and degradation. These studies reveal new developmental and anti-inflammatory roles for kinase-inhibited FAK in limiting VCAM-1 production via nuclear localization and promotion of GATA4 turnover.