Regulation of eIF4E and p70 S6 Kinase

Translation is a tightly regulated process, and the mTORC1-S6K signaling axis plays a critical role in this control. The rate of translation initiation is predominantly determined by 5’ cap recognition by eIF4F, a trimeric protein complex composed of eIF4E, which binds the 5ʹ cap; eIF4A, a helicase necessary for unwinding complex secondary structure in the leader sequence; and eIF4G, a large scaffolding protein that delivers the mRNA to eIF3 and mediates mRNA circularization through association with polyA binding protein (PABP). Binding of eIF4F to the cap is hindered by eIF4E binding proteins (4EBPs), which, when hypophosphorylated, sequester eIF4E and prevent its association with eIF4G. However, in response to positive stimuli such as growth factors, mitogens, and amino acids, mTORC1 phosphorylates 4EBPs and relieves this inhibition, allowing the formation of eIF4F and subsequent initiation of translation. In addition, mTORC1 - alongside PDK1 - phosphorylates S6 kinase, which in turn phosphorylates numerous substrates involved in translation. These include S6 small ribosomal subunit; eIF4B, an activator of the eIF4A helicase; PDCD4, an eIF4A inhibitor that is inhibited by phosphorylation; and SKAR, an mRNA splicing factor. Aside from the mTORC1 pathway, the Ras-MAPK pathway is another major regulator of translation and is responsible for the phosphorylation of eIF4B as well as eIF4E, via MNK kinases.

Selected Reviews:

• Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N (2010) Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim. Biophys. Acta 1804(3), 433–9.
• Fenton TR, Gout IT (2011) Functions and regulation of the 70kDa ribosomal S6 kinases. Int. J. Biochem. Cell Biol. 43(1), 47–59.
• Graff JR, Konicek BW, Carter JH, Marcusson EG (2008) Targeting the eukaryotic translation initiation factor 4E for cancer therapy. Cancer Res. 68(3), 631–4.
• Holcik M, Sonenberg N (2005) Translational control in stress and apoptosis. Nat. Rev. Mol. Cell Biol. 6(4), 318–27.
• Huang J, Manning BD (2008) The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem. J. 412(2), 179–90.
• Magnuson B, Ekim B, Fingar DC (2012) Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem. J. 441(1), 1–21.
• Ruvinsky I, Meyuhas O (2006) Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem. Sci. 31(6), 342–8.
• Sonenberg N, Hinnebusch AG (2009) Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136(4), 731–45.

We would like to thank Rachel Wolfson for reviewing this diagram.

created January 2002

revised June 2014