Phosphorylation of initiation factor 2α by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast
Abstract
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. In vitro, GCN2 specifically phosphorylates the alpha subunit of rabbit or yeast eIF-2. In vivo, phosphorylation of eIF-2 alpha increases in response to amino acid starvation, which is dependent on GCN2. Substitution of Ser-51 with alanine eliminates phosphorylation of eIF-2 alpha by GCN2 in vivo and in vitro and abolishes increased expression of GCN4 and amino acid biosynthetic genes under its control in amino acid-starved cells. The Asp-51 substitution mimics the phosphorylated state and derepresses GCN4 in the absence of GCN2. Thus, an established mechanism for regulating total protein synthesis in mammalian cells mediates gene-specific translational control in yeast.
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When phosphorylated, eIF2α becomes a competitive inhibitor of the 5-subunit guanine nucleotide exchange factor eIF2B, decreasing TC assembly.
“When phosphorylated, eIF2α becomes a competitive inhibitor of the 5-subunit guanine nucleotide exchange factor, eIF2B, and decreasing TC assembly [44, 45] (Fig. 1).”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [45]
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- Authors
- Dever, T. E., Feng, L., Wek, R. C., Cigan, A. M., Donahue, T. F., & Hinnebusch, A. G.
- Affiliations
- National Institutes of Health (US)
- Indiana University Bloomington (US)
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1992-02
- Volume
- 68
- Issue
- 3
- Pages
- 585-596
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1968727721
- Cited by
- 776
- References
- 1
- Citations by year
- 2026: 24 · 2025: 40 · 2024: 31 · 2023: 22 · 2022: 21 · 2021: 42 · 2020: 31 · 2019: 21 · 2018: 22 · 2017: 16 · 2016: 26 · 2015: 22 · 2014: 17 · 2013: 13 · 2012: 30
- FWCI
- 16.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- eIF2α phosphorylation, translational regulation, amino acid starvation, gene-specific regulation, Saccharomyces cerevisiae, protein synthesis regulation
- MeSH terms
- Animals, Base Sequence, DNA Mutational Analysis, DNA-Binding Proteins, Fungal Proteins, Humans, Infant, Newborn, Models, Genetic, Molecular Sequence Data, Peptide Initiation Factors, Phosphorylation, Plasmids, Protein Kinases, Rabbits, Saccharomyces cerevisiae, Serine, Transcription Factors, Protein Biosynthesis, Oligonucleotide Probes, Open Reading Frames, Protein Serine-Threonine Kinases, Saccharomyces cerevisiae Proteins, Prokaryotic Initiation Factor-2
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