Translational Control: Regulation of eIF2

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

Pathway Description:

Protein phosphorylation plays an important role in the control of translation by eukaryotic initiation factor 2 (eIF2). eIF2 binds GTP and Met-tRNA and transfers the Met-tRNA to the 40S subunit to form the 43S pre-initiation complex. Later in the cycle, prior to elongation, the bound GTP is hydrolyzed, releasing eIF2-GDP. For eIF2 to promote another round of initiation, GDP must be exchanged for GTP, a reaction catalyzed by eIF2B. Kinases activated by viral infection (PKR), endoplasmic reticulum stress (PERK/PEK), amino acid deprivation (GCN2), and hemin deficiency (HRI) can dimerize and autophosphorylate, thus greatly increasing their ability to phosphorylate eIF2α. This phosphorylation stabilizes the eIF2-GDP-eIF2B complex, inhibiting the turnover of eIF2B. These events result in a shutdown of global cellular protein synthesis, but enhance the translation of select mRNAs, including the transcriptional regulator ATF-4, which in turn activates genes involved in metabolism, oxidative stress and apoptosis. Signaling also enters at the level of the epsilon subunit of eIF2B, which is inhibited by GSK-3β phosphorylation.

Selected Reviews:

• Raven JF, Koromilas AE (2008) PERK and PKR: old kinases learn new tricks. Cell Cycle 7(9), 1146–50.
• Schmitt E, Naveau M, Mechulam Y (2010) Eukaryotic and archaeal translation initiation factor 2: a heterotrimeric tRNA carrier. FEBS Lett. 584(2), 405–12.
• Wek RC, Jiang HY, Anthony TG (2006) Coping with stress: eIF2 kinases and translational control. Biochem. Soc. Trans. 34(Pt 1), 7–11.

We would like to thank Prof. Nahum Sonenberg and Mark Livingstone, Department of Biochemistry, McGill University, Montreal, Quebec, for reviewing this diagram.