TGFβ-induced PI 3 kinase-dependent Mnk-1 activation is necessary for Ser-209 phosphorylation of eIF4E and mesangial cell hypertrophy.
TGFβ-induced PI 3 kinase-dependent Mnk-1 activation is necessary for Ser-209 phosphorylation of eIF4E and mesangial cell hypertrophy.
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DOI：
10.1002/jcp.24327
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发表时间：
2013-07
影响因子：
5.6
通讯作者：
Choudhury, Goutam Ghosh
中科院分区：
文献类型：
--
作者：
Das, Falguni;Ghosh-Choudhury, Nandini;Bera, Amit;Kasinath, Balakuntalam S.;Choudhury, Goutam Ghosh
转化生长因子β（TGFβ）诱导的经典信号转导参与肾小球系膜细胞肥大;然而，非经典TGFβ信号转导所起的作用仍在很大程度上未被探索。TGFβ时间依赖性地刺激系膜细胞中eIF 4 E的Ser-209磷酸化，同时Erk 1/2（细胞外信号调节激酶1/2）和MEK（有丝分裂原激活和细胞外信号调节激酶）的磷酸化增强。通过MEK抑制剂或显性负性Erk 2表达抑制Erk 1/2可阻断eIF 4 E磷酸化，导致TGFβ诱导的蛋白质合成减弱和系膜细胞肥大。组成型活性（CA）MEK的表达足以诱导蛋白质合成和肥大，与TGFβ诱导的蛋白质合成和肥大相似。磷脂酰肌醇（PI）3激酶的药理学或显性负抑制降低了MEK/Erk 1/2磷酸化，导致eIF 4 E磷酸化的抑制。eIF 4 E在Ser-209处的可诱导磷酸化由Mnk-1（丝裂原活化蛋白激酶信号整合激酶-1）介导。PI 3激酶和Erk 1/2均能促进TGFβ诱导的Mnk 1磷酸化。显性负性Mnk-1显著抑制TGFβ刺激的蛋白质合成和肥大。有趣的是，mTORC 1活性的抑制，阻断了eIF 4 E-4 EBP-1复合物的解离，降低了TGFβ刺激的eIF 4 E磷酸化，而对Mnk-1磷酸化没有任何影响。此外，模拟磷酸化eIF 4 E的突变体eIF 4 E S209 D促进蛋白质合成和肥大，类似于TGFβ。使用eIF 4 E的磷酸化缺陷突变体证实了这些结果。总之，我们的结果突出了4 EBP-1-eIF 4 E复合物的解离对于Mnk-1介导的eIF 4 E磷酸化的重要作用。此外，我们认为TGFβ诱导的非经典信号通路（包括PI 3激酶依赖的Mnk-1介导的eIF 4 E在Ser-209的磷酸化）是促进系膜细胞肥大所必需的。
Transforming growth factorβ (TGFβ)-induced canonical signal transduction is involved in glomerular mesangial cell hypertrophy; however, the role played by the noncanonical TGFβ signaling remains largely unexplored. TGFβ time-dependently stimulated eIF4E phosphorylation at Ser-209 concomitant with enhanced phosphorylation of Erk1/2 (extracellular signal regulated kinase1/2) and MEK (mitogen-activated and extracellular signal-regulated kinase kinase) in mesangial cells. Inhibition of Erk1/2 by MEK inhibitor or by expression of dominant negative Erk2 blocked eIF4E phosphorylation, resulting in attenuation of TGFβ-induced protein synthesis and mesangial cell hypertrophy. Expression of constitutively active (CA) MEK was sufficient to induce protein synthesis and hypertrophy similar to those induced by TGFβ. Pharmacological or dominant negative inhibition of phosphatidylinositol (PI) 3 kinase decreased MEK/Erk1/2 phosphorylation leading to suppression of eIF4E phosphorylation. Inducible phosphorylation of eIF4E at Ser-209 is mediated by Mnk-1 (mitogen-activated protein kinase signal-integrating kinase-1). Both PI 3 kinase and Erk1/2 promoted phosphorylation of Mnk-1 in response to TGFβ. Dominant negative Mnk-1 significantly inhibited TGFβ-stimulated protein synthesis and hypertrophy. Interestingly, inhibition of mTORC1 activity, which blocks dissociation of eIF4E-4EBP-1 complex, decreased TGFβ-stimulated phosphorylation of eIF4E without any effect on Mnk-1 phosphorylation. Furthermore, mutant eIF4E S209D, which mimics phosphorylated eIF4E, promoted protein synthesis and hypertrophy similar to TGFβ. These results were confirmed using phosphorylation deficient mutant of eIF4E. Together our results highlight a significant role of dissociation of 4EBP-1-eIF4E complex for Mnk-1-mediated phosphorylation of eIF4E. Moreover, we conclude that TGFβ-induced noncanonical signaling circuit involving PI 3 kinase-dependent Mnk-1-mediated phosphorylation of eIF4E at Ser-209 is required to facilitate mesangial cell hypertrophy.
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DOI：
10.1073/pnas.120055097
发表时间：
2000-07-05
影响因子：
11.1
作者：
Ziyadeh, FN;Hoffman, BB;Sharma, K
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2010-08-10
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