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Regulation of eIF4E and p70 S6 Kinase

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Regulation eIF4E, p70 S6 Kinase

Pathway Description:

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:

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

created January 2002

revised June 2014

Acetylase
Acetylase
Metabolic Enzyme
Metabolic Enzyme
Adaptor
Adaptor
Methyltransferase or G-protein
Methyltransferase or G-protein
Adaptor
Apoptosis/Autophagy Regulator
Phosphatase
Phosphatase
Cell Cycle Regulator
Cell Cycle Regulator
Protein Complex
Protein Complex
Deacetylase or Cytoskeletal Protein
Deacetylase or Cytoskeletal Protein
Ubiquitin/SUMO Ligase or Deubiquitinase
Ubiquitin/SUMO Ligase or Deubiquitinase
Growth Factor/Cytokine/Development Protein
Growth Factor/Cytokine/Development Protein
Transcription Factor or Translation Factor
Transcription Factor or Translation Factor
GTPase/GAP/GEF
GTPase/GAP/GEF
Receptor
Receptor
Kinase
Kinase
Other
Other
 
Direct Process
Direct Process
Tentative Process
Tentative Process
Translocation Process
Translocation Process
Stimulatory Modification
Stimulatory Modification
Inhibitory Modification
Inhibitory Modification
Transcriptional Modification
Transcriptional Modification