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Gene Review

Eif2ak4  -  eukaryotic translation initiation factor 2...

Mus musculus

Synonyms: 2610011M03, Eukaryotic translation initiation factor 2-alpha kinase 4, GCN2, GCN2-like protein, Gcn2, ...
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Disease relevance of Eif2ak4


Psychiatry related information on Eif2ak4


High impact information on Eif2ak4


Biological context of Eif2ak4

  • PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway [8].
  • Here we report a unique feature of hippocampal slices from GCN2(-/-) mice: in CA1, a single 100-Hz train induces a strong and sustained long-term potentiation (late LTP or L-LTP), which is dependent on transcription and translation [9].
  • Activated GCN2 stimulates mRNA translation of ATF4, an antagonist of cyclic-AMP-response-element-binding protein (CREB) [9].
  • Translational control directed by the eukaryotic translation initiation factor 2 alpha-subunit (eIF2alpha) kinase GCN2 is important for coordinating gene expression programs in response to nutritional deprivation [1].
  • Like their yeast counterpart, the mouse GCN2 isoforms contain HisRS-related sequences juxtaposed to the kinase catalytic domain [10].

Anatomical context of Eif2ak4

  • In vivo, proliferation of GCN2-knockout T cells was not inhibited by IDO-expressing DCs from tumor-draining lymph nodes [5].
  • This study indicates that loss of GCN2 eIF2 kinase activity shifts the normal maintenance of protein mass away from skeletal muscle to provide substrate for continued hepatic translation [11].
  • The primary eIF2alpha kinase activated by exposure of these fibroblast cells to proteasome inhibition is GCN2 (EIF2AK4), which has a central role in the recognition of cytoplasmic stress signals [12].
  • Thus, in the hippocampus of GCN2(-/-) mice, the expression of ATF4 is reduced and CREB activity is increased [9].

Associations of Eif2ak4 with chemical compounds

  • Histidine limitation in the presence of histidinol induced a twofold increase in the phosphorylation of eIF2alpha and a concomitant reduction in eIF2B activity in perfused livers from wild-type mice, but no changes in livers from Gcn2(-/-) mice [7].
  • Wild-type (GCN2(+/+)) and two strains of GCN2 null (GCN2(-/-)) mice were provided a nutritionally complete diet or a diet devoid of leucine or glycine for 1 h or 6 days [11].

Enzymatic interactions of Eif2ak4

  • Additionally, lysates prepared from yeast expressing mGCN2 were found to phosphorylate recombinant eIF-2alpha substrate [10].

Other interactions of Eif2ak4

  • MGCN2 has a conserved motif, N-terminal to the kinase subdomain V, and a large insert of 139 amino acids located between subdomains IV and V that are characteristic of the known eIF2alpha kinases [13].
  • Interestingly, in addition to a block in eIF2 phosphorylation, phosphorylation of 4E-BP1 and S6K1 was not decreased in GCN2(-/-) mice deprived of leucine for 6 days [11].

Analytical, diagnostic and therapeutic context of Eif2ak4

  • To assess the biochemical effects of the loss of GCN2 in the whole animal, liver perfusion experiments were conducted [7].


  1. IMPACT, a protein preferentially expressed in the mouse brain, binds GCN1 and inhibits GCN2 activation. Pereira, C.M., Sattlegger, E., Jiang, H.Y., Longo, B.M., Jaqueta, C.B., Hinnebusch, A.G., Wek, R.C., Mello, L.E., Castilho, B.A. J. Biol. Chem. (2005) [Pubmed]
  2. Role of Glutamine Depletion in Directing Tissue-specific Nutrient Stress Responses to L-Asparaginase. Reinert, R.B., Oberle, L.M., Wek, S.A., Bunpo, P., Wang, X.P., Mileva, I., Goodwin, L.O., Aldrich, C.J., Durden, D.L., McNurlan, M.A., Wek, R.C., Anthony, T.G. J. Biol. Chem. (2006) [Pubmed]
  3. The GCN2 eIF2alpha Kinase Regulates Fatty-Acid Homeostasis in the Liver during Deprivation of an Essential Amino Acid. Guo, F., Cavener, D.R. Cell Metab. (2007) [Pubmed]
  4. The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores. Maurin, A.C., Jousse, C., Averous, J., Parry, L., Bruhat, A., Cherasse, Y., Zeng, H., Zhang, Y., Harding, H.P., Ron, D., Fafournoux, P. Cell metabolism. (2005) [Pubmed]
  5. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Munn, D.H., Sharma, M.D., Baban, B., Harding, H.P., Zhang, Y., Ron, D., Mellor, A.L. Immunity (2005) [Pubmed]
  6. Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. Lee, J., Ryu, H., Ferrante, R.J., Morris, S.M., Ratan, R.R. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  7. The GCN2 eIF2alpha kinase is required for adaptation to amino acid deprivation in mice. Zhang, P., McGrath, B.C., Reinert, J., Olsen, D.S., Lei, L., Gill, S., Wek, S.A., Vattem, K.M., Wek, R.C., Kimball, S.R., Jefferson, L.S., Cavener, D.R. Mol. Cell. Biol. (2002) [Pubmed]
  8. PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway. Hamanaka, R.B., Bennett, B.S., Cullinan, S.B., Diehl, J.A. Mol. Biol. Cell (2005) [Pubmed]
  9. Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Costa-Mattioli, M., Gobert, D., Harding, H., Herdy, B., Azzi, M., Bruno, M., Bidinosti, M., Ben Mamou, C., Marcinkiewicz, E., Yoshida, M., Imataka, H., Cuello, A.C., Seidah, N., Sossin, W., Lacaille, J.C., Ron, D., Nader, K., Sonenberg, N. Nature (2005) [Pubmed]
  10. A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2alpha. Sood, R., Porter, A.C., Olsen, D.A., Cavener, D.R., Wek, R.C. Genetics (2000) [Pubmed]
  11. Preservation of liver protein synthesis during dietary leucine deprivation occurs at the expense of skeletal muscle mass in mice deleted for eIF2 kinase GCN2. Anthony, T.G., McDaniel, B.J., Byerley, R.L., McGrath, B.C., Cavener, D.R., McNurlan, M.A., Wek, R.C. J. Biol. Chem. (2004) [Pubmed]
  12. Phosphorylation of the alpha-subunit of the eukaryotic initiation factor-2 (eIF2alpha) reduces protein synthesis and enhances apoptosis in response to proteasome inhibition. Jiang, H.Y., Wek, R.C. J. Biol. Chem. (2005) [Pubmed]
  13. Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase. Berlanga, J.J., Santoyo, J., De Haro, C. Eur. J. Biochem. (1999) [Pubmed]
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