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Gene Review

EIF2AK1  -  eukaryotic translation initiation factor 2...

Homo sapiens

Synonyms: Eukaryotic translation initiation factor 2-alpha kinase 1, HCR, HRI, Heme-controlled repressor, Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase, ...
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Disease relevance of EIF2AK1


High impact information on EIF2AK1

  • In both cases, lack of HRI adversely modifies the phenotype: HRI deficiency exacerbates EPP and renders beta-thalassemia embryonically lethal [3].
  • However, to date, HRI has not been implicated in the pathogenesis of any known human disease or mouse phenotype [3].
  • HRI is also activated by a number of cytoplasmic stresses other than heme deficiency, including oxidative stress and heat shock [3].
  • The high levels of HRI in reticulocytes indicate that its major physiological role is the regulation of protein synthesis, particularly of hemoglobin, according to the concentration of heme in these cells [6].
  • HRI is activated under conditions of heme deficiency in immature erythroid cells, and its activity is inhibited by heme [6].

Biological context of EIF2AK1


Anatomical context of EIF2AK1

  • The resulting increase of fibrinolytic activity of endothelial cells may contribute to the beneficial effects of HRI in the progression of atherosclerosis [9].
  • HRI mRNA is present at low levels in uninduced mouse erythroleukemic (MEL) cells and human K562 cells and accumulates to higher levels upon induction [10].
  • The effect of HRI was associated with a disruption of cellular actin filaments without modification of microtubules [9].
  • HRI is present in the bone marrow and peripheral blood of both nonanemic and anemic rabbits but not in any of the other tissues tested [10].
  • In this study, we show that eIF-2B activity was inhibited in parental CHO cell extracts upon addition of purified reticulocyte heme-regulated inhibitor (HRI), an eIF-2 alpha kinase that phosphorylates Ser-51 [11].

Associations of EIF2AK1 with chemical compounds

  • A C-terminal truncated mutant of p50(cdc37) inhibited HRI's activation, prevented the interaction of Hsp90 with HRI, and bound to HRI irrespective of geldanamycin treatment [1].
  • Autophosphorylation of threonine 485 in the activation loop is essential for attaining eIF2alpha kinase activity of HRI [12].
  • Novobiocin specifically inhibited the maturation of the heme-regulated eIF2alpha kinase (HRI) in a concentration-dependent manner [13].
  • In addition, autophosphorylation of Thr485 was necessary for arsenite-induced activation of the eIF2alpha kinase activity of HRI, while autophosphorylation at Thr483 was not required for activation by arsenite [12].
  • The addition of 3-amino-1,2,4-triazole (AT), an inhibitor of heme biosynthesis, to the induction medium markedly reduced HRI mRNA accumulation [10].

Regulatory relationships of EIF2AK1


Other interactions of EIF2AK1


Analytical, diagnostic and therapeutic context of EIF2AK1

  • Isoelectric focusing analysis of eIF2alpha followed by detection using anti-eIF2alpha and anti-phosphotyrosine-specific antibodies demonstrated that PKR and HRI phosphorylated eIF2alpha-S51Y on Tyr in vivo [16].
  • The predictive accuracy of hourly %VLFI (frequency-domain HRI variable obtained from nocturnal ECG Holter monitoring) was analysed by comparison with an hour-by-hour respiratory disturbances index assessed by complete polysomnography in 28 consecutive clinically suspected OSAHS patients for group 1 and in 35 patients for group 2 [17].
  • These values were compared with the results obtained for a quantitative Western blot of HRI in the blood cell lysates of drug- and lead-induced anaemic rabbits [18].
  • Results: Mean HRI value obtained in the control group was 0.415 (range 0.305 -0.555; median 0.402) [19].
  • After adjustment, deployers with fair/poor SRH had an increased risk for hospitalization (hazard ratio [HRI, 1.6; 95% confidence interval [CI], 1.0,2.7); the risk was lower for those with good SRH (HR, 1.3; 95% CI,1.1,1.5) [20].


  1. Hsp90 regulates p50(cdc37) function during the biogenesis of the activeconformation of the heme-regulated eIF2 alpha kinase. Shao, J., Grammatikakis, N., Scroggins, B.T., Uma, S., Huang, W., Chen, J.J., Hartson, S.D., Matts, R.L. J. Biol. Chem. (2001) [Pubmed]
  2. Cloning of hHRI, human heme-regulated eukaryotic initiation factor 2alpha kinase: down-regulated in epithelial ovarian cancers. Hwang, S.Y., Kim, M.K., Kim, J.C. Mol. Cells (2000) [Pubmed]
  3. Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia. Han, A.P., Fleming, M.D., Chen, J.J. J. Clin. Invest. (2005) [Pubmed]
  4. Inhibition of protein synthesis in insect cells by baculovirus-expressed heme-regulated eIF-2 alpha kinase. Chefalo, P.J., Yang, J.M., Ramaiah, K.V., Gehrke, L., Chen, J.J. J. Biol. Chem. (1994) [Pubmed]
  5. Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. Agarwal, B., Bhendwal, S., Halmos, B., Moss, S.F., Ramey, W.G., Holt, P.R. Clin. Cancer Res. (1999) [Pubmed]
  6. Regulation of protein synthesis by heme-regulated eIF-2 alpha kinase. Chen, J.J., London, I.M. Trends Biochem. Sci. (1995) [Pubmed]
  7. High affinity binding of Hsp90 is triggered by multiple discrete segments of its kinase clients. Scroggins, B.T., Prince, T., Shao, J., Uma, S., Huang, W., Guo, Y., Yun, B.G., Hedman, K., Matts, R.L., Hartson, S.D. Biochemistry (2003) [Pubmed]
  8. Functional dissection of cdc37: characterization of domain structure and amino acid residues critical for protein kinase binding. Shao, J., Irwin, A., Hartson, S.D., Matts, R.L. Biochemistry (2003) [Pubmed]
  9. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranylgeranylation and Rho proteins. Essig, M., Nguyen, G., Prié, D., Escoubet, B., Sraer, J.D., Friedlander, G. Circ. Res. (1998) [Pubmed]
  10. Erythroid expression of the heme-regulated eIF-2 alpha kinase. Crosby, J.S., Lee, K., London, I.M., Chen, J.J. Mol. Cell. Biol. (1994) [Pubmed]
  11. Expression of mutant eukaryotic initiation factor 2 alpha subunit (eIF-2 alpha) reduces inhibition of guanine nucleotide exchange activity of eIF-2B mediated by eIF-2 alpha phosphorylation. Ramaiah, K.V., Davies, M.V., Chen, J.J., Kaufman, R.J. Mol. Cell. Biol. (1994) [Pubmed]
  12. Autophosphorylation of threonine 485 in the activation loop is essential for attaining eIF2alpha kinase activity of HRI. Rafie-Kolpin, M., Han, A.P., Chen, J.J. Biochemistry (2003) [Pubmed]
  13. Novobiocin induces a distinct conformation of Hsp90 and alters Hsp90-cochaperone-client interactions. Yun, B.G., Huang, W., Leach, N., Hartson, S.D., Matts, R.L. Biochemistry (2004) [Pubmed]
  14. Activation of hemin-regulated initiation factor-2 kinase in heat-shocked HeLa cells. De Benedetti, A., Baglioni, C. J. Biol. Chem. (1986) [Pubmed]
  15. Phosphorylation of eukaryotic initiation factor 2 by heme-regulated inhibitor kinase-related protein kinases in Schizosaccharomyces pombe is important for fesistance to environmental stresses. Zhan, K., Vattem, K.M., Bauer, B.N., Dever, T.E., Chen, J.J., Wek, R.C. Mol. Cell. Biol. (2002) [Pubmed]
  16. The interferon-induced double-stranded RNA-activated protein kinase PKR will phosphorylate serine, threonine, or tyrosine at residue 51 in eukaryotic initiation factor 2alpha. Lu, J., O'Hara, E.B., Trieselmann, B.A., Romano, P.R., Dever, T.E. J. Biol. Chem. (1999) [Pubmed]
  17. Heart rate increment: an electrocardiological approach for the early detection of obstructive sleep apnoea/hypopnoea syndrome. Roche, F., Sforza, E., Duverney, D., Borderies, J.R., Pichot, V., Bigaignon, O., Ascher, G., Barthélémy, J.C. Clin. Sci. (2004) [Pubmed]
  18. The haem-regulated eukaryotic initiation factor 2alpha kinase: a molecular indicator of lead-toxicity anaemia in rabbits. Anand, S., Pal, J.K. Biotechnol. Appl. Biochem. (2002) [Pubmed]
  19. Value of high resistance index - HRI calculated from Doppler spectrum of popliteal arteries in patients with systemic lupus erythematosus (SLE). Walecka, A., Sawicki, M., Brzosko, M., Ostanek, L., Fischer, K., Kordowski, J. Med. Sci. Monit. (2004) [Pubmed]
  20. Self-rated health and health care utilization after military deployments. Trump, D.H. Military medicine. (2006) [Pubmed]
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