Angiotensin IV enhances phosphorylation of 4EBP1 by multiple signaling events in lung endothelial cells
Angiotensin IV enhances phosphorylation of 4EBP1 by multiple signaling events in lung endothelial cells
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DOI：
10.1007/s11010-005-1487-8
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发表时间：
2005-07-01
影响因子：
4.3
通讯作者：
Patel, JM
中科院分区：
文献类型：
--
作者：
Lu, JH;Zhang, JL;Patel, JM
血管紧张素IV（AngIV）刺激的细胞增殖通过激活肺内皮细胞（EC）中的多个信号模块来调节。由于真核启动因子4 E（eIF 4 E）结合蛋白1（4 EBP 1）在RNA翻译和细胞生长调节中起关键作用，我们研究了Ang IV是否调节eIF 4 E和4 EBP 1的表达和/或磷酸化以及与4 EBP 1磷酸化相关的多种信号事件在EC中的作用。Ang IV刺激增加eIF 4 E和4 EBP 1蛋白的磷酸化，但不表达。Ang IV刺激选择性磷酸化4 EBP 1中的Thr 46> Thr 70> Ser 65，但不磷酸化Thr 37残基。分别用PD-98059和雷帕霉素（丝裂原活化蛋白激酶（ERK 1/2）和雷帕霉素靶蛋白（mTOR）抑制剂）预处理细胞，可部分阻断Ang IV介导的4 EBP 1磷酸化。相反，p70核糖体S6激酶（p70 S6 K）和蛋白激酶B（Akt）的过表达增强了4 EBP 1的磷酸化和eIF 4 E与mRNA帽区的结合亲和力。这些结果支持了多种信号转导和4 EBP 1的磷酸化在翻译过程和蛋白质合成中的关键作用。
Angiotensin IV (Ang IV)-stimulated cell proliferation is regulated through activation of multiple signaling modules in lung endothelial cells (EC). Because eukaryotic intitiation factor 4E (eIF4E) binding protein 1 (4EBP1) plays a critical role in the RNA translation and the regulation of cell growth, we examined whether Ang IV modulates expression and/or phosphorylation of eIF4E and 4EBP1 as well as the role of multiple signaling events associated with 4EBP1 phosphorylation in EC. Ang IV stimulation increased phosphorylation but not expression of eIF4E and 4EBP1 proteins. Ang IV stimulation selectively phosphorylated Thr46 > Thr70 > Ser65 but not Thr37 residues in 4EBP1. Pretreatment of cells with PD-98059 and rapamycin, inhibitors of mitogen-activated protein kinase (ERK1/2) and mammalian target for rapamycin (mTOR), respectively, partially blocked Ang IV-mediated phosphorylation of 4EBP1. In contrast, overexpression of p70 ribosomal S6 kinase (p70S6K) and protein kinase B (Akt) enhanced phosphorylation of 4EBP1 and eIF4E binding affinity to the cap region of mRNA. These results support critical roles of multiple signaling and phosphorylation of 4EBP1 by Ang IV in translation process and protein synthesis.