20-HETE activates the Raf/MEK/ERK pathway in renal epithelial cells through an EGFR- and c-Src-dependent mechanism
20-HETE activates the Raf/MEK/ERK pathway in renal epithelial cells through an EGFR- and c-Src-dependent mechanism
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DOI：
10.1152/ajprenal.00146.2009
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发表时间：
2009-09-01
影响因子：
4.2
通讯作者：
Park, Frank
中科院分区：
文献类型：
--
作者：
Akbulut, Talha;Regner, Kevin R.;Park, Frank
[20]李建军，李建军，李建军，李建军，李建军，李建军。hete通过egfr和c- src依赖性机制激活肾上皮细胞Raf/MEK/ERK通路。[J]中国生物医学工程学报，2009,31(2):563 - 567。首次发表于2009年7月1日；doi: 10.1152 / ajprenal.00146.2009。据报道，-20-羟基二碳四烯酸（20-HETE）可促进多种细胞类型的有丝分裂性，包括肾上皮细胞。然而，20-HETE激活的信号转导通路尚未完全确定。本研究评估了20-HETE及其更稳定的激动剂类似物20-羟基糖糖-5(Z), 14(Z)-二烯酸（5,14-20- hede）和N-[20-羟基糖糖-5(Z), 14(Z)-二烯基]甘氨酸（5,14-20- hedge）对LLC-PK1肾上皮细胞Raf/MEK/ERK和磷脂酰肌醇3-激酶(PI3K)- akt通路的影响。与载体处理的细胞相比，20- hete （20 μ M）增加了Raf-1（2.5 +/- 0.2倍）、MEK1/2（6.3 +/- 1.6倍）和ERK1/2（5.8 +/- 0.3倍）的磷酸化。同样，20-HETE类似物也以依赖raf -1和mek1 /2的方式强烈激活ERK1/2。此外，5,14-20- hede使Akt磷酸化增加2.2 +/- 0.3倍。20-HETE和5,14-20- hede也分别促进表皮生长因子受体（EGFR; Y1086）的激活（Y1086） 1.9 +/- 0.2和2.5 +/- 0.2倍。这些作用被EGFR抑制剂EKB-569 （0.1 μ M）完全阻断。此外，EKB-569 （0.1 μ M）以及c-Src抑制剂SKI-606 （0.05 μ M）完全消除了20- hete介导的Raf/MEK/ERK和PI3K-Akt通路的激活。用双吲酞马来酰亚胺I阻断PKC对20- hete诱导的ERK1/2激活没有影响。本研究表明，20-HETE激活了肾上皮细胞中继发于c-Src和EGFR激活的Raf/MEK/ERK和Akt通路。
Akbulut T, Regner KR, Roman RJ, Avner ED, Falck JR, Park F. 20-HETE activates the Raf/MEK/ERK pathway in renal epithelial cells through an EGFR-and c-Src-dependent mechanism. Am J Physiol Renal Physiol 297: F662-F670, 2009. First published July 1, 2009; doi:10.1152/ajprenal.00146.2009.-20-Hydroxyeicosatetraenoic acid (20-HETE) has been reported to promote mitogenicity in a variety of cell types, including renal epithelial cells. However, the signal transduction pathways activated by 20-HETE have not been fully defined. The present study evaluated the effects of 20-HETE and its more stable agonist analogs 20-hydroxyeicosa-5(Z), 14(Z)-dienoic acid (5,14-20-HEDE) and N-[20-hydroxyeicosa-5(Z), 14(Z)-dienoyl] glycine (5,14-20-HEDGE) on the Raf/MEK/ERK and phosphatidylinositol 3-kinase (PI3K)-Akt pathway in LLC-PK1 renal epithelial cells. 20-HETE (20 mu M) increased phosphorylation of Raf-1 (2.5 +/- 0.2-fold), MEK1/2 (6.3 +/- 1.6-fold), and ERK1/2 (5.8 +/- 0.3-fold) compared with vehicle-treated cells. Similarly, the 20-HETE analogs also strongly activated ERK1/2 in a Raf-1-and MEK1/2-dependent manner. Moreover, 5,14-20-HEDE increased Akt phosphorylation by 2.2 +/- 0.3-fold. 20-HETE and 5,14-20-HEDE also promoted activation (Y1086) of epidermal growth factor receptor (EGFR; Y1086) by 1.9 +/- 0.2- and 2.5 +/- 0.2-fold, respectively. These effects were completely blocked by the EGFR inhibitor EKB-569 (0.1 mu M). Moreover, EKB-569 (0.1 mu M), as well as a c-Src inhibitor, SKI-606 (0.05 mu M), completely abolished the 20-HETE-mediated activation of the Raf/MEK/ERK and PI3K-Akt pathways. Blockade of PKC with bisindolylmaleimide I had no effect on 20-HETE-induced ERK1/2 activation. This study demonstrated that 20-HETE activated the Raf/MEK/ERK and Akt pathways in renal epithelial cells secondary to the activation of c-Src and EGFR.