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Gene Review

EIF2AK4  -  eukaryotic translation initiation factor 2...

Homo sapiens

Synonyms: Eukaryotic translation initiation factor 2-alpha kinase 4, GCN2, GCN2-like protein, KIAA1338, PVOD2
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Disease relevance of EIF2AK4

  • Residues corresponding to amino acids at the dimer interface of Escherichia coli HisRS were required for dimerization of recombinant HisRS-N and for tRNA binding by full-length GCN2, suggesting that HisRS-N dimerization promotes tRNA binding and kinase activation [1].
  • Liver steatosis in Gcn2(-/-) mice was found to be caused by unrepressed expression of lipogenic genes, including Srebp-1c and Fas [2].

High impact information on EIF2AK4

  • The cell cycle delay was totally dependent on the Gcn2 kinase, a sensor of the nutritional status, and was accompanied by phosphorylation of the translation initiation factor eIF2alpha and by a general depression of translation [3].
  • These mutations also bypass the requirement for ribosome binding, dimerization, and association with the GCN1/GCN20 regulatory complex, suggesting that all of these functions facilitate tRNA binding to wild-type GCN2 [4].
  • The tRNA-binding moiety in GCN2 contains a dimerization domain that interacts with the kinase domain and is required for tRNA binding and kinase activation [1].
  • Additionally, our data indicate that translation is regulated in a Gcn2-independent manner because protein synthesis was still inhibited in response to H(2)O(2) in a gcn2 mutant [5].
  • Our data show that H(2)O(2) causes an inhibition of translation initiation dependent on the Gcn2 protein kinase, which phosphorylates the alpha-subunit of eukaryotic initiation factor-2 [5].

Biological context of EIF2AK4

  • In this issue of Cell Metabolism, present a much broader role for GCN2 in controlling lipid homeostasis in response to amino acid deprivation [6].


  1. The tRNA-binding moiety in GCN2 contains a dimerization domain that interacts with the kinase domain and is required for tRNA binding and kinase activation. Qiu, H., Dong, J., Hu, C., Francklyn, C.S., Hinnebusch, A.G. EMBO J. (2001) [Pubmed]
  2. 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]
  3. A novel checkpoint mechanism regulating the G1/S transition. Tvegård, T., Soltani, H., Skjølberg, H.C., Krohn, M., Nilssen, E.A., Kearsey, S.E., Grallert, B., Boye, E. Genes Dev. (2007) [Pubmed]
  4. Mutations that bypass tRNA binding activate the intrinsically defective kinase domain in GCN2. Qiu, H., Hu, C., Dong, J., Hinnebusch, A.G. Genes Dev. (2002) [Pubmed]
  5. Global Translational Responses to Oxidative Stress Impact upon Multiple Levels of Protein Synthesis. Shenton, D., Smirnova, J.B., Selley, J.N., Carroll, K., Hubbard, S.J., Pavitt, G.D., Ashe, M.P., Grant, C.M. J. Biol. Chem. (2006) [Pubmed]
  6. The Metabolic Sensor GCN2 Branches out. Towle, H.C. Cell Metab. (2007) [Pubmed]
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