Gingras AC, Kennedy SG, O'Leary MA et al.4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev 12:502-513

Department of Biochemistry, McGill University Montreal, Quebec, Canada H3G 1Y6.
Genes & Development (Impact Factor: 10.8). 02/1998; 12(4):502-513. DOI: 10.1101/gad.12.4.502


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. FRAP/mTOR may lie downstream of Akt in this signaling cascade. These results demonstrate that the PI 3-kinase-Akt signaling pathway, in concert with FRAP/mTOR, induces the phosphorylation of 4E-BP1.

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    • "(EIF4EBP1), thus initiating protein translation (Pause et al. 1994; Gingras et al. 1998), and activates ribosomal protein S6 kinase, 70 kDa (RPS6KB) (Brown et al. 1995) and ribosomal protein S6 (RPS6) which plays a role in the translation of mRNA encoding ribosomal protein (Kawasome et al. 1998). Therefore, the MTOR/EIF4E and MTOR/RPS6KB pathways regulate skeletal muscle protein synthesis and growth (Lang et al. 2010). "
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    • "It also increased cap-dependent protein translation in the lungs through an increase in the phosphorylated form of 4E-BP1 (Fig. 2A) (Jin et al., 2007). 4E-BP1 represses mRNA translation, and is inactivated through phosphorylation by the Akt signaling pathway (Gingras et al., 1998). Moreover, a high dietary Pi intake increases proliferation, angiogenesis and cell cycle progression . "
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