Eukaryotic translation initiation factor 2-alpha kinase family (EIF2AK1, EIF2AK2, EIF2AK4) (EIF2AK family)

The Eukaryotic translation initiation factor 2-alpha kinase (EIF2AK) family members EIF2AK1 (HRI), EIF2AK2 (PKR), and EIF2AK4 (GCN2) are essential regulators of the Integrated Stress Response (ISR) (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116144/; Frontiers in Cell and Developmental Biology, https://www.frontiersin.org/articles/10.3389/fcell.2020.00167). These kinases function as sensors for distinct cellular stressors: EIF2AK1 responds to heme deficiency and oxidative stress, EIF2AK2 is activated by viral double-stranded RNA, and EIF2AK4 senses amino acid starvation via uncharged tRNAs (Reactome, https://reactome.org/content/detail/R-HSA-380953; Wikipedia, https://en.wikipedia.org/wiki/EIF2AK4). Upon activation, they phosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) at Ser51, which attenuates global protein synthesis while selectively enhancing the translation of stress-adaptive mRNAs like ATF4 (UniProt, https://www.uniprot.org/uniprot/Q9BQI3; Abcam, https://www.abcam.com/pathways/integrated-stress-response). This pathway is frequently co-opted by cancer cells to survive metabolic stress and is implicated in the progression of neurodegenerative diseases, viral infections, and pulmonary veno-occlusive disease (GeneCards, https://www.genecards.org/cgi-bin/carddisp.pl?gene=EIF2AK4; BioRxiv, https://www.biorxiv.org/content/10.1101/2024.04.23.590745v1). Pharmacological modulators, including small-molecule inhibitors like GCN2iB and PKR inhibitors, are being developed to either disrupt tumor adaptation or restore translational homeostasis in chronic disease states (GlobalData, https://www.pharmaceutical-technology.com/data-insights/eif-2-alpha-kinase-gcn2-eif2ak4-pipeline-analysis-and-market-forecast/).

Other names

Heme-regulated inhibitor (HRI)Protein kinase R (PKR)General control nonderepressible 2 (GCN2)EIF2AK1EIF2AK2EIF2AK4Heme-controlled repressor (HCR)Eukaryotic translation initiation factor 2-alpha kinase 1Eukaryotic translation initiation factor 2-alpha kinase 2Eukaryotic translation initiation factor 2-alpha kinase 4

Inhibition of eIF2α phosphorylation to modulate the integrated stress response (ISR), thereby restoring global protein synthesis or inducing apoptosis in stressed cells (Frontiers in Oncology, https://www.frontiersin.org/articles/10.3389/fonc.2021.654398; Nature Communications, https://www.nature.com/articles/s41467-023-40823-8).