Translational Control / Regulation of eIF4E and p70 S6K
eIF4E and S6 kinase (S6K) play critical roles in translational regulation. eIF4E binds the 5’ cap-structure of cytoplasmic mRNA and nucleates the eIF4F pre-initiation complex, which also includes eIF4A, a helicase that unwinds complex secondary structure in the mRNA leader sequence, and eIF4G, a large scaffolding protein that coordinates delivery of the mRNA to eIF3 and circularizes the mRNA through an association with poly(A) binding protein (PABP). Several stimuli, including growth factors, cytokines, and nutrient availability, regulate both eIF4F and S6K through mTORC1 (mTOR Complex 1: mTOR, GβL, Raptor, and Deptor). mTORC1 directly phosphorylates the translational inhibitory eIF4E-binding proteins (4E-BPs), which, when hypo-phosphorylated, prevent the interaction between eIF4E and eIF4G. mTORC1 also directly phosphorylates S6K, which has many targets in the translational machinery: S6 small ribosomal subunit; eIF4B, an activator of the eIF4A helicase; PDCD4, an inhibitor of eIF4A that is inhibited by phosphorylation; and SKAR, an mRNA splicing factor. Activation of S6K can also lead to suppression of insulin signaling through a negative feedback loop that destabilizes IRS1.
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We would like to thank Carson Thoreen and Prof. David Sabatini, Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, for reviewing this diagram.
created January 2002
revised November 2012