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GCN2  -  Gcn2p

Saccharomyces cerevisiae S288c

Synonyms: AAS1, AAS102, NDR2, Serine/threonine-protein kinase GCN2, YDR283C
 
 
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Disease relevance of GCN2

 

High impact information on GCN2

  • The ability of cells to react appropriately to nutritional cues is of fundamental importance, and in budding yeast, a small number of intracellular protein kinases, PKA, Snf1p/AMP-activated kinase, TOR, Gcn2p, and the cyclin-dependent kinase Pho85p have key roles [4].
  • We show that phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2) by the protein kinase GCN2 mediates translational control of the yeast transcriptional activator GCN4 [5].
  • In vivo, phosphorylation of eIF-2 alpha increases in response to amino acid starvation, which is dependent on GCN2 [5].
  • Such an increase is effected when the cellular amount of the GCN2 protein kinase is increased or when the function of the GCD1 gene product is defective [6].
  • Here, we report conditions that result in a dramatic transient increase in the rate of GCN4 protein synthesis, which also requires the prior translation of the 5' most proximal open reading frame but is independent of the GCN2 protein [6].
 

Biological context of GCN2

 

Anatomical context of GCN2

  • This sequence similarity raises the possibility that GCN1 interacts with ribosomes or tRNA molecules and functions in conjunction with GCN2 in monitoring uncharged tRNA levels during the process of translation elongation [11].
  • Polyribosome binding by GCN1 is required for full activation of eukaryotic translation initiation factor 2{alpha} kinase GCN2 during amino acid starvation [12].
  • Cloning of the cDNA of the heme-regulated eukaryotic initiation factor 2 alpha (eIF-2 alpha) kinase of rabbit reticulocytes: homology to yeast GCN2 protein kinase and human double-stranded-RNA-dependent eIF-2 alpha kinase [13].
  • Gcn2p induction of GCN4 translation during carbohydrate limitation enhances storage of amino acids in the vacuoles and facilitates entry into exponential growth during a shift from low-glucose to high-glucose medium [14].
 

Associations of GCN2 with chemical compounds

  • This GCN2-independent pathway was also stimulated to a lesser extent by the multicopy tRNA(His) constructs in histidine-deprived cells [9].
  • Translation of the yeast transcriptional activator GCN4 is stimulated by purine limitation: implications for activation of the protein kinase GCN2 [15].
  • GCN1 expression conferred sensitivity to paromomycin in a manner dependent on its ribosome binding domain, supporting the idea that GCN1 binds near the ribosomal acceptor site to promote GCN2 activation by uncharged tRNA [10].
  • PKR and GCN2 kinases and guanine nucleotide exchange factor eukaryotic translation initiation factor 2B (eIF2B) recognize overlapping surfaces on eIF2alpha [16].
  • Substitution of a highly conserved lysine residue in the kinase domain abolished GCN2 regulatory function in vivo and its ability to autophosphorylate in vitro, indicating that GCN2 acts as a protein kinase in stimulating GCN4 expression [17].
 

Physical interactions of GCN2

  • A C-terminal segment of GCN1 (residues 2052-2428) was found to be necessary and sufficient for binding GCN2 in vivo and in vitro [10].
  • Induction of GCN4 translation in amino acid-starved cells involves the inhibition of initiator tRNA(Met) binding to eukaryotic translation initiation factor 2 (eIF2) in response to eIF2 phosphorylation by protein kinase GCN2 [18].
 

Enzymatic interactions of GCN2

  • Here we describe that yeast eIF-2 alpha is a constitutively phosphorylated protein species that is multiply phosphorylated by a GCN2-independent mechanism [19].
 

Regulatory relationships of GCN2

  • We isolated a null mutation in a previously unidentified gene, GCN20, that suppresses the growth-inhibitory effect of eIF-2 alpha hyperphosphorylation catalyzed by mutationally activated forms of GCN2 [20].
  • Interestingly, deletion of the GCN2 gene suppressed FK506-dependent Hog1p hyperphosphorylation and restored Hog1p-dependent reporter activity [21].
  • YIH1 is an actin-binding protein that inhibits protein kinase GCN2 and impairs general amino acid control when overexpressed [22].
  • Starvation-induced adhesive growth requires Flo11p and is under control of Gcn2p and Gcn4p, elements of the general amino acid control system [23].
 

Other interactions of GCN2

  • We describe here 17 dominant GCN2 mutations that lead to derepression of GCN4 expression in the absence of amino acid starvation [24].
  • 32Pi labeling and isoelectric focusing analysis of a SUI2+ delta gcn2 strain identifies eIF-2 alpha as radiolabeled and a single isoelectric protein species [19].
  • In addition, the gcd1-101 mutation suppressed the low translational efficiency of GCN4-lacZ mRNA observed in gcn2- and gcn3- cells [25].
  • Four GCD7 suppressors were shown to reduce the derepression of GCN4 translation in cells containing wild-type GCN2 under starvation conditions or in GCN2c strains [26].
  • In accordance with this conclusion, GCN20 was co-immunoprecipitated from cell extracts with GCN1, another factor required to activate GCN2, and the two proteins interacted in the yeast two-hybrid system [20].
 

Analytical, diagnostic and therapeutic context of GCN2

References

  1. The protein kinase Gcn2p mediates sodium toxicity in yeast. Goossens, A., Dever, T.E., Pascual-Ahuir, A., Serrano, R. J. Biol. Chem. (2001) [Pubmed]
  2. Expression of vaccinia virus K3L protein in yeast inhibits eukaryotic initiation factor-2 kinase GCN2 and the general amino acid control pathway. Qian, W., Zhu, S., Sobolev, A.Y., Wek, R.C. J. Biol. Chem. (1996) [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. Nutrient-regulated protein kinases in budding yeast. Wilson, W.A., Roach, P.J. Cell (2002) [Pubmed]
  5. Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Dever, T.E., Feng, L., Wek, R.C., Cigan, A.M., Donahue, T.F., Hinnebusch, A.G. Cell (1992) [Pubmed]
  6. Coupling of GCN4 mRNA translational activation with decreased rates of polypeptide chain initiation. Tzamarias, D., Roussou, I., Thireos, G. Cell (1989) [Pubmed]
  7. A protein complex of translational regulators of GCN4 mRNA is the guanine nucleotide-exchange factor for translation initiation factor 2 in yeast. Cigan, A.M., Bushman, J.L., Boal, T.R., Hinnebusch, A.G. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  8. Negative regulatory gene for general control of amino acid biosynthesis in Saccharomyces cerevisiae. Myers, P.L., Skvirsky, R.C., Greenberg, M.L., Greer, H. Mol. Cell. Biol. (1986) [Pubmed]
  9. Multicopy tRNA genes functionally suppress mutations in yeast eIF-2 alpha kinase GCN2: evidence for separate pathways coupling GCN4 expression to unchanged tRNA. Vazquez de Aldana, C.R., Wek, R.C., Segundo, P.S., Truesdell, A.G., Hinnebusch, A.G. Mol. Cell. Biol. (1994) [Pubmed]
  10. Separate domains in GCN1 for binding protein kinase GCN2 and ribosomes are required for GCN2 activation in amino acid-starved cells. Sattlegger, E., Hinnebusch, A.G. EMBO J. (2000) [Pubmed]
  11. GCN1, a translational activator of GCN4 in Saccharomyces cerevisiae, is required for phosphorylation of eukaryotic translation initiation factor 2 by protein kinase GCN2. Marton, M.J., Crouch, D., Hinnebusch, A.G. Mol. Cell. Biol. (1993) [Pubmed]
  12. Polyribosome binding by GCN1 is required for full activation of eukaryotic translation initiation factor 2{alpha} kinase GCN2 during amino acid starvation. Sattlegger, E., Hinnebusch, A.G. J. Biol. Chem. (2005) [Pubmed]
  13. Cloning of the cDNA of the heme-regulated eukaryotic initiation factor 2 alpha (eIF-2 alpha) kinase of rabbit reticulocytes: homology to yeast GCN2 protein kinase and human double-stranded-RNA-dependent eIF-2 alpha kinase. Chen, J.J., Throop, M.S., Gehrke, L., Kuo, I., Pal, J.K., Brodsky, M., London, I.M. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  14. Glucose limitation induces GCN4 translation by activation of Gcn2 protein kinase. Yang, R., Wek, S.A., Wek, R.C. Mol. Cell. Biol. (2000) [Pubmed]
  15. Translation of the yeast transcriptional activator GCN4 is stimulated by purine limitation: implications for activation of the protein kinase GCN2. Rolfes, R.J., Hinnebusch, A.G. Mol. Cell. Biol. (1993) [Pubmed]
  16. PKR and GCN2 kinases and guanine nucleotide exchange factor eukaryotic translation initiation factor 2B (eIF2B) recognize overlapping surfaces on eIF2alpha. Dey, M., Trieselmann, B., Locke, E.G., Lu, J., Cao, C., Dar, A.C., Krishnamoorthy, T., Dong, J., Sicheri, F., Dever, T.E. Mol. Cell. Biol. (2005) [Pubmed]
  17. Identification of positive-acting domains in GCN2 protein kinase required for translational activation of GCN4 expression. Wek, R.C., Ramirez, M., Jackson, B.M., Hinnebusch, A.G. Mol. Cell. Biol. (1990) [Pubmed]
  18. Defects in tRNA processing and nuclear export induce GCN4 translation independently of phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Qiu, H., Hu, C., Anderson, J., Björk, G.R., Sarkar, S., Hopper, A.K., Hinnebusch, A.G. Mol. Cell. Biol. (2000) [Pubmed]
  19. Casein kinase II mediates multiple phosphorylation of Saccharomyces cerevisiae eIF-2 alpha (encoded by SUI2), which is required for optimal eIF-2 function in S. cerevisiae. Feng, L., Yoon, H., Donahue, T.F. Mol. Cell. Biol. (1994) [Pubmed]
  20. GCN20, a novel ATP binding cassette protein, and GCN1 reside in a complex that mediates activation of the eIF-2 alpha kinase GCN2 in amino acid-starved cells. Vazquez de Aldana, C.R., Marton, M.J., Hinnebusch, A.G. EMBO J. (1995) [Pubmed]
  21. The immunosuppressant FK506 uncovers a positive regulatory cross-talk between the Hog1p and Gcn2p pathways. Rodriguez-Hernandez, C.J., Sanchez-Perez, I., Gil-Mascarell, R., Rodríguez-Afonso, A., Torres, A., Perona, R., Murguia, J.R. J. Biol. Chem. (2003) [Pubmed]
  22. YIH1 is an actin-binding protein that inhibits protein kinase GCN2 and impairs general amino acid control when overexpressed. Sattlegger, E., Swanson, M.J., Ashcraft, E.A., Jennings, J.L., Fekete, R.A., Link, A.J., Hinnebusch, A.G. J. Biol. Chem. (2004) [Pubmed]
  23. Amino acid starvation and Gcn4p regulate adhesive growth and FLO11 gene expression in Saccharomyces cerevisiae. Braus, G.H., Grundmann, O., Brückner, S., Mösch, H.U. Mol. Biol. Cell (2003) [Pubmed]
  24. Mutations activating the yeast eIF-2 alpha kinase GCN2: isolation of alleles altering the domain related to histidyl-tRNA synthetases. Ramirez, M., Wek, R.C., Vazquez de Aldana, C.R., Jackson, B.M., Freeman, B., Hinnebusch, A.G. Mol. Cell. Biol. (1992) [Pubmed]
  25. A hierarchy of trans-acting factors modulates translation of an activator of amino acid biosynthetic genes in Saccharomyces cerevisiae. Hinnebusch, A.G. Mol. Cell. Biol. (1985) [Pubmed]
  26. Mutations in the GCD7 subunit of yeast guanine nucleotide exchange factor eIF-2B overcome the inhibitory effects of phosphorylated eIF-2 on translation initiation. Vazquez de Aldana, C.R., Hinnebusch, A.G. Mol. Cell. Biol. (1994) [Pubmed]
  27. Dimerization by translation initiation factor 2 kinase GCN2 is mediated by interactions in the C-terminal ribosome-binding region and the protein kinase domain. Qiu, H., Garcia-Barrio, M.T., Hinnebusch, A.G. Mol. Cell. Biol. (1998) [Pubmed]
  28. Ribosome association of GCN2 protein kinase, a translational activator of the GCN4 gene of Saccharomyces cerevisiae. Ramirez, M., Wek, R.C., Hinnebusch, A.G. Mol. Cell. Biol. (1991) [Pubmed]
  29. Transcriptional-translational regulatory circuit in Saccharomyces cerevisiae which involves the GCN4 transcriptional activator and the GCN2 protein kinase. Roussou, I., Thireos, G., Hauge, B.M. Mol. Cell. Biol. (1988) [Pubmed]
  30. Dimerization is required for activation of eIF2 kinase Gcn2 in response to diverse environmental stress conditions. Narasimhan, J., Staschke, K.A., Wek, R.C. J. Biol. Chem. (2004) [Pubmed]
 
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