4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway
4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway
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DOI：
10.1101/gad.12.4.502
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发表时间：
1998-02-15
影响因子：
10.5
通讯作者：
Hay, N
中科院分区：
文献类型：
--
作者：
Gingras, AC;Kennedy, SG;Hay, N
生长因子和激素通过渥曼青霉素和雷帕霉素敏感的信号传导途径，通过磷酸化和失活翻译阻遏物eIF 4 E结合蛋白（4 E-BPs）来激活蛋白质翻译。从细胞外信号发出的信号导致4 E-BP磷酸化的机制还不清楚。在这里，我们证明了丝氨酸/苏氨酸激酶Akt/PKB的活性是导致4 E-BP 1磷酸化和失活的信号级联反应所必需的。PI 3-激酶以渥曼青霉素和雷帕霉素敏感的方式激活4 E-BP 1的磷酸化，而激活的Akt介导的4 E-BP 1的磷酸化是渥曼青霉素抗性的但雷帕霉素敏感的。Akt的显性失活突变体阻断胰岛素介导的4 E-BP 1磷酸化，表明Akt是4 E-BP 1体内磷酸化所必需的。重要的是，激活的Akt在血清刺激后磷酸化的相同位点上诱导4 E-BP 1的磷酸化。与血清和生长因子中观察到的相似，Akt对4 E-BP 1的磷酸化抑制了4 E-BP 1和eIF-4 E之间的相互作用。此外，Akt对4 E-BP 1的磷酸化需要FRAP/mTOR的活性。ERAP/mTOR可能位于Akt的下游。这些结果表明PI 3-激酶-Akt信号通路与ERAP/mTOR一起诱导4 E-BP 1的磷酸化。
Growth factors and hormones activate protein translation by phosphorylation and inactivation of the translational repressors, the eIF4E-binding proteins (4E-BPs), through a wortmannin- and rapamycin-sensitive signaling pathway. The mechanism by which signals emanating from extracellular signals lead to phosphorylation of 4E-BPs is not well understood. Here we demonstrate that the activity of the serine/threonine kinase Akt/PKB is required in a signaling cascade that leads to phosphorylation and inactivation of 4E-BP1. PI 3-kinase elicits the phosphorylation of 4E-BP1 in a wortmannin- and rapamycin-sensitive manner, whereas activated Akt-mediated phosphorylation of 4E-BP1 is wortmannin resistant but rapamycin sensitive. A dominant negative mutant of Akt blocks insulin-mediated phosphorylation of 4E-BP1, indicating that Akt is required for the in vivo phosphorylation of 4E-BP1. Importantly, an activated Akt induces phosphorylation of 4E-BP1 on the same sites that are phosphorylated upon serum stimulation. Similar to what has been observed with serum and growth factors, phosphorylation of 4E-BP1 by Akt inhibits the interaction between 4E-BP1 and eIF-4E. Furthermore, phosphorylation of 4E-BP1 by Akt requires the activity of FRAP/mTOR. ERAP/mTOR may lie downstream of Akt in this signaling cascade. These results demonstrate that the PI 3-kinase-Akt signaling pathway, in concert with ERAP/mTOR, induces the phosphorylation of 4E-BP1.