Translational Control: Regulation of eIF4E and p70 S6 Kinase

• 
• Description
• Reviews
• Key
• Download PDF
• Product Pathways

Search this pathway for protein information from PhosphoSitePlus^®, our expert-curated knowledge base of protein phosphorylation and other post-translational modifications.

Pathway Description:

eIF4F and p70 S6 kinase play critical roles in translational regulation. eIF4F is a complex with functions including the recognition of the mRNA 5’ cap structure (eIF4E), helicase activity towards RNA secondary structure (eIF4A), bridging of the mRNA and the ribosome (eIF4G), and circularization of the mRNA via interaction between eIF4G and poly(A) binding protein (PABP). Several stimuli, including growth factors and cytokines, regulate the eIF4F complex and p70 S6 kinase by initiating a phosphorylation cascade involving the sequential activation of PI3K, PDK1, Akt/PKB, and mTORC1 (mTOR Complex 1: mTOR, GβL, Raptor, Deptor). mTORC1 phosphorylates 4E-BP, leading to its dissociation from eIF4E, thus allowing eIF4E:eIF4G binding to form active eIF4F, a necessary component of the 48S initiation complex. Phosphorylation of targets, including ribosomal protein S6 and eIF4B by p70 S6 kinase may regulate translation of specific mRNAs, while p70 S6 kinase-mediated negative feedback to IRS-1 and Rictor suppress mTORC2 (mTOR Complex 2: mTOR, GβL, Rictor, PRR5, Deptor) signaling to Akt.

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.
• 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.
• Huang J, Manning BD (2008) The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem. J. 412(2), 179–90.
• 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 Prof. Nahum Sonenberg and Mark Livingstone, Department of Biochemistry, McGill University, Montreal, Quebec, for reviewing this diagram.