Translational Control: Regulation of eIF4E and p70 S6 Kinase

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Pathway Description:

eIF4F and p70 S6 kinase play critical roles in translational regulation. eIF4F is a complex whose functions include the recognition of the mRNA 5’ cap structure (eIF4E), delivery of an RNA helicase to the 5’ region (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 FRAP/mTOR kinase. FRAP/mTOR phosphorylates 4E-BP, leading to its dissociation from and activation of eIF4E. The tuberin/hamartin (TSC2/TSC1) complex inhibits mTOR activity indirectly by inhibiting Rheb via tuberin’s GAP activity. MNK1/2, activated by Erk and p38 MAPK, phosphorylates eIF4E. The 4E-BP regulated availability of eIF4E controls the association of eIF4E and eIF4G to form the active eIF4F, a necessary component of the 48S initiation complex, while the role of MNK1/2-dependent phosphorylation of eIF4E remains controversial. Phosphorylation of ribosomal protein S6 by p70 S6 kinase was initially thought to stimulate the translation of mRNAs with a 5’ tract of oligopyrimidine (5’TOP), which typically encode components of the protein synthesis apparatus. However, more recent work has shown that, while S6 phosphorylation is important for glucose homeostasis and controlling cell size, it is not essential for regulation of 5’TOP mRNAs.

Selected Reviews:

• Huang J, Manning BD (2008) The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem. J. 412(2), 179–90.
• Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12(1), 9–22.
• Ruvinsky I, Meyuhas O (2006) Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem. Sci. 31(6), 342–8.
• Sarbassov DD, Ali SM, Sabatini DM (2005) Growing roles for the mTOR pathway. Curr. Opin. Cell Biol. 17(6), 596–603.
• Yang Q, Guan KL (2007) Expanding mTOR signaling. Cell Res. 17(8), 666–81.

CST would like to thank Prof. Nahum Sonenberg and Mark Livingstone, Department of Biochemistry, McGill University, Montreal, Quebec, for reviewing these diagrams.