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Regulation of eIF2

© Cell Signaling Technology. All Rights Reserved.
Regulation of eIF2

Pathway Description:

The eIF2 initiation complex integrates a diverse array of stress-related signals to regulate both global and specific mRNA translation. Under permissive conditions, eIF2 binds GTP and Met-tRNAi to form the ternary complex (TC), which then associates with the 40S ribosomal subunit, eIF1, eIF1A, eIF5, and eIF3 to form the 43S pre-initiation complex (PIC). The 43S PIC scans the mRNA UTR for an AUG start codon. Upon AUG recognition, eIF2 hydrolyzes GTP to GDP with the help of the GTPase activating protein eIF5 and dissociates from the mRNA, permitting the binding of the 60S ribosomal subunit and elongation of the polypeptide chain. eIF2 remains bound to GDP in the presence of eIF5 acting as a GDI. To permit another round of initiation, eIF2B must act as both a GDI displacement factor (GDF) and a guanine exchange factor (GEF) to allow exchange of GDP for GTP on eIF2. This step is tightly regulated, and phosphorylation of eIF2α by a diverse family of four stress activated kinases—PKR (dsRNA), PERK (ER stress), GCN2 (amino acid starvation), and HRI (heme deficiency)—prevents nucleotide exchange by causing eIF2 to act as a dominant negative complex to sequester eIF2B. The resulting increase in eIF2α-GDP limits the availability of the ternary complex and causes a decrease in global protein synthesis and an enhancement of the translation of specific stressrelated mRNA transcripts, such as the transcription factors ATF-4 and CHOP.

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