4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway

被引:730
作者
Gingras, AC
Kennedy, SG
O'Leary, MA
Sonenberg, N
Hay, N
机构
[1] McGill Univ, Dept Biochem, Quebec City, PQ H3G 1Y6, Canada
[2] Univ Chicago, Ben May Inst Canc Res, Chicago, IL 60637 USA
[3] Univ Chicago, Dept Pharmacol & Physiol Sci, Chicago, IL 60637 USA
关键词
protein synthesis; phosphorylation; PI; 3-kinase; protein kinase B; eIF4E; FRAP/mTOR;
D O I
10.1101/gad.12.4.502
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:502 / 513
页数:12
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