Affinage

EIF2AK4

eIF-2-alpha kinase GCN2 · UniProt Q9P2K8

Length
1649 aa
Mass
186.9 kDa
Annotated
2026-06-09
100 papers in source corpus 46 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF2AK4/GCN2 is a serine/threonine eIF2α kinase that functions as the central translational sensor of amino acid insufficiency, coupling nutrient and ribosomal stress to a programmed reduction in bulk protein synthesis and preferential translation of stress mRNAs (PMID:12215525, PMID:8798780). Catalysis requires its conserved kinase domain, and active GCN2 phosphorylates eIF2α specifically at Ser-51 through recognition determinants that include residues flanking the phospho-acceptor and a distal surface in the K79GYID83 motif (PMID:2188100, PMID:8798780, PMID:15798194). Activation is gated by a bipartite tRNA-binding module formed by the HisRS-related domain plus a C-terminal ribosome-binding segment: uncharged tRNA binding relieves an inhibitory intramolecular interaction between the regulatory regions and the kinase, while aminoacylation weakens tRNA binding (PMID:10983975, PMID:8798780). Crystallographic and biochemical work shows the resting kinase adopts an autoinhibited closed conformation, and that productive signaling additionally requires kinase-domain dimerization through a conserved intermolecular salt bridge, an interdigitated C-terminal dimer, and allosteric stimulation of the kinase by the pseudokinase (YKD) domain (PMID:15964839, PMID:17202131, PMID:24719324, PMID:24811037). In mammals GCN2 is potently activated by the ribosomal P-stalk (uL10 and the P1/P2 C-terminal tails) and by ribosomal collisions, with distinct stress types—amino acid depletion versus elongation stalling—engaging uncharged-tRNA sensing or collision sensing respectively through the same HisRS-like domain (PMID:30804176, PMID:37043534, PMID:38281137). GCN2 activity is further set by the Hsp90 chaperone, TOR-dependent Ser-577 phosphorylation, and the Gcn1/Gcn20 co-activators that are antagonized by the Yih1/IMPACT competitor (PMID:10567567, PMID:12654728, PMID:21239490), and GCN2 itself extends signaling beyond eIF2α by phosphorylating eIF2β to restrict ternary-complex recycling and by phosphorylating FBXO22 to drive K27-linked ubiquitination of mTOR at Lys-2066 and suppress mTORC1 (PMID:33743194, PMID:37979583). Downstream, GCN2 acts largely through the ATF4 axis to control diverse processes—synaptic plasticity and memory via ATF4/CREB, tumor amino-acid adaptation and SLC transporter expression, angiogenesis via VEGF, myeloid and macrophage polarization, autophagy, wound-healing cell migration, and hematopoietic stem cell proteostasis (PMID:16121183, PMID:20473272, PMID:36107759, PMID:29570992, PMID:31836669, PMID:26986695, PMID:34597669, PMID:35803229). GCN2 also functions in antiviral defense, restricting RNA and DNA viruses and directly phosphorylating HIV-1 integrase at Ser-255 (PMID:16601681, PMID:22114338, PMID:28536474). Biallelic loss-of-function mutations in EIF2AK4 underlie pulmonary veno-occlusive disease, where GCN2 deficiency derepresses collagen I via loss of ATF3-dependent p38 MAPK control (PMID:33988041).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1990 High

    Establishing that GCN2 is a genuine protein kinase whose catalytic activity drives GCN4 induction defined the core of the general amino acid control pathway.

    Evidence Catalytic-lysine mutagenesis abolishing autophosphorylation and in vivo GCN4-lacZ regulation, plus deletion of flanking regulatory domains, in yeast

    PMID:2188100

    Open questions at the time
    • Direct physiological substrate not yet identified at this stage
    • Mechanism by which flanking domains lower the tRNA-activation threshold unresolved
  2. 1996 High

    Mapping eIF2α as the substrate and showing the HisRS-related domain is required for its phosphorylation linked nutrient sensing to translation initiation.

    Evidence Cell-free kinase assay on recombinant eIF2α with HisRS-domain point mutants, correlated to in vivo defects

    PMID:8798780

    Open questions at the time
    • Did not establish how the HisRS domain transmits signal to the kinase
    • Structural basis of Ser-51 selectivity unknown
  3. 2000 High

    Defining a bipartite tRNA-binding module that intramolecularly inhibits the kinase, relieved by uncharged tRNA, explained how amino acid status is decoded.

    Evidence In vitro binding of HisRS+C-term to the kinase domain, aminoacylation-dependent tRNA binding, and activating E803V mutant analysis; parallel demonstration that mouse GCN2 phosphorylates eIF2α at Ser-51

    PMID:10655230 PMID:10983975

    Open questions at the time
    • Conformational details of activation not resolved
    • Whether mammalian and yeast activation modes are identical not addressed
  4. 1991 High

    Demonstrating GCN2 association with 60S subunits and polysomes via its extreme C-terminus placed the kinase at the ribosome where deacylated tRNAs accumulate.

    Evidence Sucrose-gradient sedimentation, salt-dependent dissociation, and C-terminal deletion analysis in yeast

    PMID:2038314

    Open questions at the time
    • Molecular contact on the ribosome not identified
    • Functional consequence of ribosome binding for activation not yet dissected
  5. 2005 High

    Structural and dimer-interface studies revealed the activation logic of the kinase domain: a closed autoinhibited conformation relieved by hinge remodeling and obligatory dimerization.

    Evidence Crystal structures of WT and R794G kinase domains; charge-swap mutagenesis of a conserved dimer salt bridge across GCN2/PKR/PERK with in vitro and yeast validation; eIF2α surface-residue mutagenesis defining substrate recognition

    PMID:15798194 PMID:15964839 PMID:17202131

    Open questions at the time
    • Full-length activation conformation not visualized
    • How HisRS/tRNA binding mechanically opens the kinase not directly observed
  6. 2003 High

    Identifying TOR-driven Ser-577 phosphorylation and Hsp90 dependence showed GCN2 activity is set by upstream signaling and chaperone maturation, not tRNA alone.

    Evidence S577A mutagenesis with rapamycin/TAP42 epistasis (1999 Hsp90 work used reciprocal Co-IP, inhibitors, and ts mutants)

    PMID:10567567 PMID:12654728

    Open questions at the time
    • Mammalian conservation of Ser-577 control not tested here
    • Kinase responsible for Ser-577 not directly identified
  7. 2002 High

    Knockout mice established GCN2 as the essential eIF2α kinase for amino acid deprivation in mammals, validating physiological relevance in vivo.

    Evidence Gcn2-/- ES cells and perfused liver failing to induce eIF2α phosphorylation under amino acid limitation, with dietary lethality phenotype

    PMID:12215525

    Open questions at the time
    • Tissue-specific downstream programs not yet defined
    • Non-eIF2α substrates not explored
  8. 2006 High

    Showing GCN2 senses viral RNA and restricts viral replication extended its sensor role beyond nutrients into innate antiviral defense.

    Evidence In vitro activation by Sindbis genomic RNA via the HisRS domain, plus GCN2-/- cells/mice with increased viral susceptibility and kinase-dead K618R rescue failure; later ENU loss-of-function mice showed susceptibility to DNA viruses

    PMID:16601681 PMID:22114338

    Open questions at the time
    • How viral RNA and tRNA inputs are distinguished by the same domain unclear
    • Breadth of viral ligands not mapped
  9. 2005 High

    Linking GCN2 to ATF4/CREB-dependent synaptic plasticity opened the neuronal arm of GCN2 signaling.

    Evidence Gcn2-/- mice with altered LTP, memory behavior, and reduced hippocampal ATF4

    PMID:16121183

    Open questions at the time
    • Local translational targets in neurons not enumerated
    • Activating stimulus in resting neurons not defined
  10. 2014 High

    Dissecting C-terminal dimerization and pseudokinase-kinase allostery revealed the intramolecular architecture coupling sensing domains to catalysis.

    Evidence Crystal structures of murine/yeast CTD dimers with disruption mutants, and YKD αE/αI mutagenesis modulating YKD-KD interaction and GCN4 reporter output

    PMID:24719324 PMID:24811037

    Open questions at the time
    • Mammalian CTD does not stably bind ribosomes, leaving its in vivo role open
    • Order of dimerization and tRNA-binding events not resolved
  11. 2019 High

    Identifying the ribosomal P-stalk as the principal mammalian activator and distinguishing collision- versus tRNA-driven activation reframed GCN2 as a ribosome-state sensor.

    Evidence In vitro reconstitution with purified P-stalk and HDX-MS (human); yeast genetic epistasis separating tethered-P-stalk from uncharged-tRNA activation; later domain/collision analysis across stresses

    PMID:30804176 PMID:37043534 PMID:38281137

    Open questions at the time
    • Quantitative contribution of each input in cells under physiological stress not settled
    • How P-stalk and tRNA signals converge structurally on the kinase unclear
  12. 2017 Medium

    Defining Gcn1/Gcn20 co-activation and Yih1/IMPACT competition for Gcn1 established the activator/inhibitor checkpoint controlling GCN2 at ribosomes.

    Evidence RWD-domain mutagenesis and reciprocal binding assays (Yih1/IMPACT, 2011) and S. pombe tRNA-site and Gcn1-deletion epistasis across multiple stresses

    PMID:21239490 PMID:28771613

    Open questions at the time
    • Stoichiometry of the Gcn1/Gcn20/GCN2 complex on the ribosome not defined
    • Cross-stress findings rely on genetic, not reconstituted, evidence
  13. 2021 High

    Discovery of non-eIF2α substrates (eIF2β, Gcn20, FBXO22, HIV-1 integrase) broadened GCN2's output to direct control of ternary-complex recycling, feedback, mTORC1, and viral targets.

    Evidence Phosphoproteomics with eIF2β-eIF5 and Gcn20 feedback validation; in vitro kinase/ubiquitination reconstitution for FBXO22→mTOR K2066; in vitro kinase mapping of HIV-1 integrase Ser-255 with infectivity assays

    PMID:28536474 PMID:33743194 PMID:37979583

    Open questions at the time
    • Full substrate repertoire in mammalian cells not catalogued
    • Relative physiological weighting of eIF2α versus alternative substrates unknown
  14. 2023 High

    Mapping diverse downstream physiology placed GCN2/ATF4 upstream of amino-acid transport, angiogenesis, immune polarization, autophagy, migration, and stem-cell proteostasis.

    Evidence Genetic and pharmacological loss-of-function with in vivo models across tumors (SLC/transporters, MYC feedback), endothelium (VEGF), myeloid cells, intestinal autophagy (ATF4 ChIP), keratinocyte migration, and HSCs

    PMID:20473272 PMID:26986695 PMID:29570992 PMID:31836669 PMID:34597669 PMID:35803229 PMID:36107759

    Open questions at the time
    • Whether these effects are all ATF4-dependent or involve alternative substrates not uniformly resolved
    • Tissue-specific activating signals not always defined
  15. 2024 Medium

    Defining bidirectional GCN2-mTOR crosstalk and paradoxical inhibitor-induced activation refined the pharmacology and regulatory wiring of the kinase.

    Evidence mTOR→GCN2 Ser-230 phosphorylation (Co-IP, in vitro kinase); ATP-competitive inhibitors (Gcn2iB, neratinib) that bind and activate GCN2, validated in patient-derived kinase-domain mutants and CRISPR screens

    PMID:34949839 PMID:36898579 PMID:39013537

    Open questions at the time
    • Ser-230 phosphorylation is single-lab and awaits independent confirmation
    • Structural basis of inhibitor-induced activation not solved
  16. 2017 Medium

    Patient-derived models tied biallelic EIF2AK4 loss to pulmonary veno-occlusive disease through derepressed collagen I.

    Evidence CRISPR GCN2 KO lines and PVOD patient iPSC-derived smooth muscle cells showing ATF3/p38-dependent collagen I upregulation

    PMID:33988041

    Open questions at the time
    • Single-lab mechanism not independently replicated
    • Causal chain from eIF2α/ATF4 to ATF3/p38 incompletely defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple activating inputs (uncharged tRNA, P-stalk/collisions, viral RNA, mTOR phosphorylation, kinase-directed inhibitors) are integrated into a single quantitative output, and how non-eIF2α substrate phosphorylation is prioritized in vivo, remains unresolved.
  • No unified structural model of full-length activated GCN2 on the ribosome
  • Relative in vivo contribution of eIF2α versus eIF2β/FBXO22 substrates unknown
  • Mammalian conservation of several yeast-defined regulatory phosphosites not fully established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016740 transferase activity 3 GO:0003723 RNA binding 2 GO:0140098 catalytic activity, acting on RNA 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005840 ribosome 3 GO:0005730 nucleolus 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2 R-HSA-1643685 Disease 1 R-HSA-8953854 Metabolism of RNA 1
Partners
EIF2S1FBXO22GCN1GCN20HSP90IMPACTMTOR

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 GCN2 contains a bipartite tRNA-binding domain composed of the HisRS-related domain plus a C-terminal ribosome-binding segment (C-term); the combined HisRS+C-term segment binds the isolated kinase domain in vitro, and uncharged tRNA impedes this inhibitory intramolecular interaction, thereby activating the kinase moiety. Aminoacylation of tRNA weakens its interaction with GCN2, and an activating mutation (E803V) that weakens PK-C-term association greatly enhanced tRNA binding. In vitro binding assays, tRNA binding assays with aminoacylated vs. deacylated tRNAs, activating mutant analysis, domain dissection Molecular cell High 10983975
1990 GCN2 acts as a protein kinase to stimulate GCN4 expression; substitution of the conserved lysine in the kinase domain abolished both GCN2 regulatory function in vivo and autophosphorylation in vitro. The HisRS-related sequences and C-terminal segment flanking the kinase domain are positive-acting regulatory domains required for physiological substrate recognition or lowering the threshold for uncharged tRNA activation. In vitro autophosphorylation assay, in vivo reporter (GCN4-lacZ), site-directed mutagenesis, deletion analysis Molecular and cellular biology High 2188100
1996 The HisRS-related sequences of GCN2 are required for phosphorylation of eIF-2α in vitro; mutations in this domain that block the general amino acid control pathway in vivo also greatly reduce eIF-2α phosphorylation in a cell-free assay using recombinant eIF-2α substrate (phosphorylation requires Ser-51 of eIF-2α). In vitro kinase assay with purified recombinant eIF-2α substrate, HisRS-domain point mutations The Journal of biological chemistry High 8798780
1991 GCN2 physically associates with 60S ribosomal subunits and polysomes in yeast cell extracts; it can be dissociated from 60S subunits by 0.5 M KCl. The extreme C-terminal segment of GCN2 is essential for ribosome interaction, and this segment is also required for GCN4 translational activation in vivo. Sucrose gradient sedimentation, nondenaturing gel electrophoresis, ribosome dissociation experiments, C-terminal deletion analysis Molecular and cellular biology High 2038314
2000 Mouse GCN2, a mammalian homologue of yeast GCN2, phosphorylates recombinant eIF-2α in vitro requiring the kinase catalytic domain and HisRS-related sequences, and the phosphorylation requires Ser-51 of eIF-2α. Three mouse GCN2 isoforms are encoded by a single gene with differential N-terminal sequences. In vitro kinase assay with recombinant eIF-2α, expression of mGCN2 in yeast, Ser-51 mutagenesis Genetics High 10655230
2005 Crystal structures of the GCN2 protein kinase domain (wild-type and R794G mutant) reveal that autoinhibition results from stabilization of a closed conformation that restricts ATP binding. The R794G mutation increases hinge-region flexibility between N- and C-lobes, enhancing ATP binding and hydrolysis, and provides a model for how tRNA binding to the HisRS domain remodels the hinge for kinase activation. X-ray crystallography of apo and ATP/AMPPNP-bound kinase domain; biochemical validation of R794G activating mutant The Journal of biological chemistry High 15964839
2003 The TOR pathway negatively regulates GCN2 in yeast by promoting phosphorylation of Ser-577 in GCN2, which reduces tRNA binding activity and inhibits kinase function. Rapamycin-induced TOR inhibition leads to Ser-577 dephosphorylation via TAP42-regulated type 2A-related phosphatases, thereby activating GCN2 and increasing eIF2α phosphorylation and GCN4 translation. Phosphorylation-site mutagenesis (S577A), rapamycin treatment, GCN4-lacZ reporter, eIF2α phosphorylation assays, TAP42 genetic analysis Genes & development High 12654728
2005 GCN2 and PKR phosphorylate eIF2α on Ser-51; residues flanking Ser-51 (Glu-49) and a remote surface residue Asp-83 in the K79GYID83 motif are critical for kinase-substrate recognition. Ala substitution of Asp-83 eliminates phosphorylation by both GCN2 and PKR in vivo and in vitro, establishing that distal surface residues contribute to substrate recognition. Separately, mutations that block translational regulation but not Ser-51 phosphorylation impair eIF2B binding to phospho-eIF2α. In vivo and in vitro phosphorylation assays, eIF2α mutagenesis, eIF2B binding assays Molecular and cellular biology High 15798194
2007 A conserved intermolecular salt bridge between an Arg and Asp/Glu residue (equivalent to Arg-262/Asp-266 in PKR) at the kinase domain dimer interface is essential for GCN2 (and PKR, PERK) activity. Single charge-reversal mutations in either residue abolish kinase function in yeast cells and in vitro; double mutations restoring salt bridge with opposite polarity restore function, demonstrating that dimerization via this interface is required for eIF2α kinase activation. Site-directed mutagenesis, in vivo yeast functional assay, in vitro kinase assay The Journal of biological chemistry High 17202131
1999 GCN2 forms a complex with the molecular chaperone Hsp90 both in vitro and in vivo in yeast. Hsp90 inhibitors (geldanamycin, macbecin I) enhance GCN2-Hsp90 association and inhibit GCN2 kinase activity in vitro; in vivo, macbecin I strongly reduces GCN2 protein levels. Hsp90 cochaperones Cdc37, Sti1, and Sba1 are required for the amino acid starvation response, indicating Hsp90 is required for GCN2 maturation and regulation. Co-immunoprecipitation in vitro and in vivo, Hsp90 inhibitor treatment, temperature-sensitive Hsp90 mutant analysis, GCN4-lacZ reporter Molecular and cellular biology High 10567567
2019 Human GCN2 is potently stimulated by ribosomes and, to a lesser extent, by uncharged tRNA in a reconstituted in vitro system. The ribosomal P-stalk domain II of uL10 is the principal binding site for GCN2; the conserved 14-residue C-terminal tails of P1/P2 P-stalk proteins are also essential for GCN2 activation. HDX-MS showed conformational changes in both the HisRS-like and kinase domains of GCN2 upon P-stalk binding. In vitro reconstitution with purified components, HDX-MS, recombinant P-stalk complex binding assays Proceedings of the National Academy of Sciences of the United States of America High 30804176
2002 GCN2 is essential for eIF2α phosphorylation in response to amino acid deprivation in mammals. Gcn2-/- mice fail to induce eIF2α phosphorylation in leucine-deprived embryonic stem cells, and perfused livers from Gcn2-/- mice fail to show increased eIF2α phosphorylation or decreased eIF2B activity upon histidine limitation. Loss of GCN2 increases prenatal/neonatal mortality when mothers are fed amino acid-deficient diets. Gcn2 knockout mouse, eIF2α phosphorylation assay in ES cells and perfused liver, eIF2B activity assay Molecular and cellular biology High 12215525
2006 Mammalian GCN2 is specifically activated in vitro by binding of two nonadjacent regions of Sindbis virus genomic RNA to its HisRS-related domain. Endogenous GCN2 is activated during Sindbis virus infection in cells. GCN2-/- mouse fibroblasts show increased permissiveness to Sindbis virus and VSV infection, and GCN2-/- mice are highly susceptible to intranasal SV infection with higher brain virus titers. Catalytically inactive GCN2-K618R fails to impair viral replication, and GCN2 inhibits SV replication by blocking early viral translation. In vitro RNA-binding and kinase activation assay, GCN2 knockout fibroblasts and mice, viral infection assays, kinase-dead mutant (K618R) The EMBO journal High 16601681
2005 GCN2 regulates hippocampal synaptic plasticity and memory through modulation of ATF4/CREB pathway. In GCN2-/- mice, ATF4 expression is reduced and CREB activity is increased in the hippocampus, consistent with GCN2-activated eIF2α phosphorylation normally promoting ATF4 mRNA translation which antagonizes CREB. GCN2 knockout mouse, electrophysiology (LTP), behavioral testing (Morris water maze), ATF4 and CREB activity measurements Nature High 16121183
2010 Both amino acid and glucose deprivation activate GCN2 to upregulate ATF4 target genes involved in amino acid synthesis and transport in tumour cells. GCN2 activation and increased phospho-eIF2α are observed in human and mouse tumours; abrogation of GCN2 or ATF4 expression significantly inhibits tumour growth in vivo. GCN2 knockdown/overexpression, eIF2α phosphorylation assay, in vivo tumour growth experiments, ATF4 target gene expression analysis The EMBO journal High 20473272
2014 Crystal structures of murine and yeast GCN2 C-terminal domains (CTDs) reveal an unusual interdigitated dimeric form; disruption of the dimeric form of murine CTD eliminates GCN2 translational control function. Despite shared core structure, murine GCN2 CTD does not stably associate with ribosomes whereas yeast GCN2 CTD does, indicating regulatory differences between yeast and mammalian GCN2. X-ray crystallography, dimerization-disrupting mutations with functional assays, ribosome association assay The Journal of biological chemistry High 24719324
2014 The GCN2 pseudokinase domain (YKD) directly interacts with the kinase domain (KD) to allosterically stimulate kinase activity in amino acid-starved cells. Substitutions in predicted helices αE and αI of the YKD impair GCN2 activation without reducing uncharged tRNA binding; αI substitutions identified as Gcd- (constitutively active) enhance YKD-KD interactions in vitro, while αE/αI Gcn- substitutions suppress this effect. Mutational analysis of YKD, in vitro YKD-KD interaction assay, in vivo GCN4-lacZ reporter, tRNA binding assays PLoS genetics High 24811037
2021 Gcn2 phosphorylates the β-subunit of eIF2 to promote its association with eIF5, preventing spontaneous nucleotide exchange on eIF2 and restricting recycling of the initiator Met-tRNA-bound eIF2-GDP ternary complex in amino-acid-starved cells—a mechanism parallel to eIF2α phosphorylation-dependent eIF2B sequestration. Gcn2 also phosphorylates Gcn20 to antagonize formation of the Gcn2-stimulatory Gcn1-Gcn20 complex in a negative feedback loop. Quantitative phosphoproteomics, Co-immunoprecipitation, translation initiation assays Molecular cell High 33743194
2011 Yih1 (yeast) / IMPACT (mammalian) inhibits GCN2 by competing with GCN2 for binding to the GCN2 activator Gcn1 via its RWD domain. Gcn1 binding and GCN2 inhibition require residues Asp-102 and Glu-106 in helix 3 of the RWD domain. Yih1 also binds G-actin independently of Gcn1 binding, but actin binding is dispensable for GCN2 inhibition. Co-immunoprecipitation, in vitro binding assays, site-directed mutagenesis of Yih1 RWD domain, in vivo GCN4-lacZ reporter The Journal of biological chemistry High 21239490
2019 In yeast, GCN2 activation by ribosome stalling (starvation-independent conditions) requires at least one P1/P2 P-stalk heterodimer tethered to uL10 of the ribosomal P-stalk, the tRNA- and ribosome-binding domains of Gcn2, and the positive effectors Gcn1/Gcn20. By contrast, amino acid starvation-induced GCN2 activation does not require tethered P1/P2 proteins, suggesting that uncharged tRNAs can substitute for the P-stalk in activating GCN2 at ribosomes with empty A-sites. Genetic analysis in yeast (P-stalk deletion mutants, GCN2 domain mutants, epistasis), eIF2α phosphorylation assays Proceedings of the National Academy of Sciences of the United States of America High 37043534
2024 Multiple mechanisms activate GCN2 depending on stress type: ribosomal collisions are essential for GCN2 activation by translational elongation inhibitors (stalling conditions), while direct association of GCN2 with uncharged tRNAs is the primary mechanism when amino acid depletion causes tRNA deacylation. Both mechanisms require the HisRS-like regulatory domain of GCN2. UV irradiation activates GCN2 via decreased amino acids and increased uncharged tRNAs rather than ribosome collisions. Domain mutagenesis, ribosome collision assays, tRNA deacylation assays, selective inhibitor treatment, eIF2α phosphorylation assays under multiple stress conditions Nucleic acids research High 38281137
2017 Mutation of tRNA-binding site on GCN2 or deletion of Gcn1 abolishes GCN2 activation under all investigated stress conditions (amino acid starvation, UV irradiation, and oxidative stress) in fission yeast, indicating that tRNA binding to GCN2 is required for activation not only by starvation but also by other stresses. GCN2 tRNA-binding site mutagenesis, Gcn1 deletion, eIF2α phosphorylation assays under multiple stress conditions in S. pombe PloS one Medium 28771613
2013 GCN2 activation upon HIV-1 infection requires GCN2's interaction with HIV-1 integrase. GCN2 phosphorylates HIV-1 integrase in vitro at Ser-255 in the C-terminal domain, and the integrase active site is required for GCN2 to target this residue. HIV-1 lentiviral particles with S255 mutation (preventing phosphorylation) show increased infectivity and viral DNA integration; MLV infectivity is also higher in GCN2 knockout cells. In vitro kinase assay with HIV-1 integrase substrate, phosphorylation site mapping (mass spectrometry), site-directed mutagenesis (S255), GCN2 Co-IP with integrase, viral infectivity assays in GCN2 KO cells Scientific reports High 28536474
2018 Amino acid restriction triggers angiogenesis via the GCN2/ATF4 pathway, independently of hypoxia or HIF1α. Sulfur amino acid restriction promotes VEGF expression, EC migration and sprouting via GCN2/ATF4 signaling in vitro and increased capillary density in mouse skeletal muscle in vivo. GCN2 knockout/knockdown experiments, endothelial cell migration and sprouting assays, in vivo capillary density measurement, VEGF expression analysis, ATF4 pathway analysis Cell High 29570992
2023 GCN2 phosphorylates FBXO22 in response to accumulation of uncharged tRNAs caused by amino acid depletion; phosphorylated FBXO22 translocates to the cytoplasm and ubiquitinates mTOR at Lys-2066 in a K27-linked manner, inhibiting mTORC1 kinase activity by preventing substrate recruitment. Mutation of mTOR Lys-2066 abolishes this regulation, rendering mTOR insensitive to amino acid starvation. In vitro kinase assay (GCN2→FBXO22 phosphorylation), ubiquitination assay, mTOR K2066 mutagenesis, cellular fractionation, mTORC1 substrate recruitment assay Cell metabolism High 37979583
2016 GCN2 (EIF2AK4) drives ATF4-dependent maturation and polarization of macrophages and MDSCs; myeloid-lineage deletion of GCN2 shifts macrophage/MDSC phenotype toward pro-inflammatory activation and promotes antitumor immunity in melanoma. ATF4 translation is a key downstream mediator of this effect. Myeloid-specific GCN2 conditional knockout, CyTOF mass cytometry, single-cell RNA-seq, ATF4 siRNA knockdown, transcription factor binding analysis Science immunology High 31836669
2021 GCN2 directs keratinocyte collective cell migration during wound healing by maintaining intracellular free amino acids (particularly cysteine) and coordinating RAC1-GTP-driven reactive oxygen species generation, lamellipodia formation, and focal adhesion dynamics. GCN2 deletion or pharmacological inhibition significantly delays collective cell migration and wound closure in vitro and in vivo. GCN2 knockout cells and mice, pharmacological inhibition, wound scratch assay, RAC1-GTP pulldown, ROS measurement, transcriptomics, focal adhesion imaging The Journal of biological chemistry High 34597669
2022 GCN2 regulates expression of over 60 solute carrier (SLC) transporter genes including amino acid transporters; loss of GCN2 reduces amino acid import and levels in prostate cancer cells. Addition of essential amino acids or expression of SLC3A2 (4F2 heavy chain) partially restores growth following GCN2 loss, placing GCN2 upstream of SLC transporter expression for amino acid homeostasis. GCN2 knockout in prostate cancer cells, RNA-seq, CRISPR phenotypic screen, amino acid measurement, rescue experiments with amino acid supplementation and SLC3A2 overexpression, in vivo mouse models eLife High 36107759
2022 GCN2 maintains proteostasis in hematopoietic stem cells (HSCs) by sensing amino acid levels and inhibiting protein synthesis via the eIF2α axis; GCN2 also inhibits Src-mediated AKT activation to repress mitochondrial OXPHOS. GCN2 deletion impairs HSC repopulation and regeneration capacity. GCN2 knockout mice, HSC functional assays (repopulation, transplantation), protein synthesis measurement, Src/AKT phosphorylation analysis Cell stem cell High 35803229
2013 GCN2 promotes macrophage inflammatory cytokine production (IL-6, IL-12) in response to LPS under amino acid-deficient conditions; GCN2 knockout macrophages show significantly reduced cytokine gene expression after LPS stimulation. Monocytic-lineage GCN2 knockout mice show reduced inflammatory responses and significantly decreased mortality in a lethal LPS septicemia model. GCN2 knockout macrophages and monocyte-specific conditional knockout mice, LPS challenge, cytokine measurement, in vivo septicemia model Molecular and cellular biology High 24248597
2021 GCN2 interacts with NRF2 and decreases NRF2 expression in a KEAP1-dependent manner. Activation of GCN2 by halofuginone or leucine deprivation decreases NRF2 expression in hepatocytes by increasing GSK-3β activity. This defines a GCN2→GSK-3β→KEAP1→NRF2 regulatory axis in oxidative stress response. Co-immunoprecipitation (GCN2-NRF2), GCN2 knockdown (AAV8-shGcn2), pharmacological GCN2 activation and inhibition, GSK-3β activity assay, NRF2 expression analysis, in vivo hepatic steatosis models Redox biology Medium 34954499
2016 GCN2 (EIF2AK4) activation upon infection with adherent-invasive E. coli (AIEC) drives autophagy by promoting ATF4 binding to promoters of autophagy genes (MAP1LC3B, BECN1, SQSTM1, ATG3, ATG7). EIF2AK4 depletion inhibits autophagy, increases AIEC intracellular replication, and elevates pro-inflammatory cytokines. In vivo, eif2ak4-/- mice show increased intestinal AIEC colonization and aggravated inflammation. EIF2AK4 siRNA knockdown in intestinal epithelial cells, eif2ak4-/- mice, autophagy flux assay, ChIP for ATF4 binding to autophagy gene promoters, bacterial colony counting Autophagy High 26986695
2023 ATP-competitive GCN2 inhibitor Gcn2iB can paradoxically activate GCN2 at low concentrations, increasing eIF2 phosphorylation and ATF4 expression. This activation occurs even in GCN2 mutants lacking functional regulatory domains or with kinase domain substitutions found in GCN2-deficient human patients, suggesting the inhibitor directly engages the kinase domain to cause activation. In vitro GCN2 kinase assay, cell-based eIF2α phosphorylation and ATF4 reporter assays, GCN2 regulatory domain deletion mutants, patient-derived GCN2 kinase domain mutants The Journal of biological chemistry High 36898579
2021 ATP-competitive kinase inhibitors including the pan-ErbB inhibitor neratinib directly bind and activate GCN2. Several FDA-approved kinase inhibitors (erlotinib, sunitinib) also bind and activate GCN2. GCN2 loss confers neratinib resistance by preventing neratinib-induced GCN2 binding and activation. Genome-wide CRISPR KO screen, direct binding assay (neratinib-GCN2 interaction), eIF2α phosphorylation assay, ISR activation assay Nature chemical biology High 34949839
2021 Halofuginone (HF) activates GCN2 by inhibiting aminoacylation of tRNA-Pro, causing accumulation of uncharged tRNA. GCN2 deletion reduces cell survival to HF, while mTORC1 inhibition affords protection. In vivo, HF simultaneously activates both the GCN2-ISR pathway and mTORC1 in mouse liver; Gcn2-null mice show greater mTORC1 activation and develop liver steatosis and cell death. Gcn2-/- mice, HF treatment, eIF2α phosphorylation assay, mTORC1 signaling analysis, liver histology, pharmacological mTORC1 inhibition Nucleic acids research High 34023907
2024 mTOR directly phosphorylates GCN2 at Ser-230 via a labile physical interaction between GCN2 and mTOR. This mTOR-mediated phosphorylation enhances GCN2 activity under conditions of sustained mTORC1 activation during amino acid starvation, and the resulting GCN2 activation is independent of tRNA sensing. This phosphorylation promotes cell survival under prolonged amino acid starvation. Co-immunoprecipitation (GCN2-mTOR), in vitro kinase assay (mTOR phosphorylating GCN2-Ser230), phosphorylation site mutagenesis, eIF2α and ATF4 assays, cell survival assays The Journal of biological chemistry Medium 39013537
2011 A loss-of-function mutation in Eif2ak4 (GCN2) in mice increases susceptibility to mouse cytomegalovirus (MCMV) and human adenovirus (double-stranded DNA viruses). Macrophages from Eif2ak4(atc/atc) mice fail to phosphorylate eIF2α in response to MCMV infection, demonstrating that GCN2-dependent translational arrest contributes to the antiviral response to DNA viruses in vivo. ENU-induced loss-of-function mutation screen, eIF2α phosphorylation assay in macrophages, in vivo viral infection model Journal of virology High 22114338
2017 GCN2 deficiency in PVOD leads to decreased ATF3-dependent p38 MAPK phosphorylation inhibition, resulting in enhanced transcription of collagen I genes (col1a1, col1a2) and increased collagen deposition in pulmonary arterial smooth muscle cells. This mechanism was validated in GCN2 KO cell lines and iPSC-derived smooth muscle cells from PVOD patients. CRISPR-generated GCN2 KO cell lines, iPSC differentiation from PVOD patient PBMCs, collagen I expression assay, p38 phosphorylation assay, ATF3 analysis Journal of cardiovascular pharmacology and therapeutics Medium 33988041
2012 IFN-γ promotes tryptophan depletion in human kidney epithelial cells, which activates GCN2 and leads to increased autophagic flux. Tryptophan supplementation and siRNA knockdown of GCN2 inhibit IFN-γ-induced autophagy. GCN2-mediated autophagy regulates secretion of inflammatory cytokines and growth factors in response to IFN-γ. siRNA knockdown of GCN2, autophagy flux assay, tryptophan supplementation rescue, cytokine secretion measurement Journal of immunology Medium 22896630
2017 Tryptophan deprivation increases kynurenine uptake by upregulating SLC7A5 (LAT1) expression in a GCN2-dependent manner, linking GCN2 activation to enhanced kynurenine transport and downstream AHR pathway sensitization. GCN2 knockdown/inhibition, kynurenine uptake assay, SLC7A5 expression analysis, LAT1 functional transport assay Journal for immunotherapy of cancer Medium 37344101
2020 In amygdalar PKC-δ neurons, leucine deficiency activates GCN2/ATF4 signaling to promote white adipose tissue (WAT) browning via sympathetic nervous system activation. GCN2 knockdown in amygdalar PKC-δ neurons blocks leucine deprivation-induced WAT browning, which is reversed by ATF4 overexpression. Amygdala-specific GCN2 knockdown (viral vector), PKC-δ neuronal inhibition, WAT browning markers, ATF4 overexpression rescue Nature communications Medium 32504036
2017 GCN2 is constitutively localized to the nucleolus or recruited there by amino acid starvation stress. siRNA-mediated GCN2 depletion increases small RNA transcripts (tRNA, 5S rRNA) via RNA polymerase III and activates the p53 pathway. This derepression and p53 activation are restored by co-depletion of BRF1 (an RNA pol III subunit), suggesting GCN2 negatively regulates RNA pol III activity in the nucleolus. Immunofluorescence (nucleolar localization), siRNA knockdown, small RNA quantification, p53 pathway analysis, BRF1 co-knockdown rescue Biochemical and biophysical research communications Medium 28189689
2013 GCN2 regulates hepatic gluconeogenesis through regulation of C/EBPβ expression. Gcn2-deficient mice show reduced gluconeogenic capacity and failure to induce C/EBPβ during fasting; liver-specific Cebpβ knockout mice phenocopy the reduced fasting gluconeogenesis seen in Gcn2-deficient mice, placing GCN2 upstream of C/EBPβ in this pathway. Gcn2-/- mice, pyruvate tolerance test, gluconeogenic enzyme expression, TCA cycle intermediate measurement, C/EBPβ expression analysis, liver-specific Cebpβ KO mice American journal of physiology. Endocrinology and metabolism Medium 23900421
2016 Drosophila GCN2 is required for 4E-BP transcriptional induction via ATF4; the 4E-BP intron contains ATF4-binding sites. GCN2 is required for lifespan extension in response to dietary amino acid restriction, and gcn2 mutant flies have reduced levels of stress-responsive protein synthesis as measured by metabolic labeling combined with click chemistry. GCN2 mutant Drosophila, 4E-BP reporter assays, ATF4 binding site analysis, metabolic labeling (click chemistry) for nascent protein synthesis, lifespan assays The Journal of cell biology Medium 27979906
2022 In nutrient-rich conditions, GCN2 supports cancer cell proliferation by stimulating 47S rRNA transcription via nuclear translocation of methionyl-tRNA synthetase (MetRS). GCN2 inhibition prevents nuclear translocation of MetRS, causing nucleolar stress, mTORC1 inhibition, and autophagy induction. Under metabolic stress, GCN2 represses 47S rRNA expression through the canonical ISR axis. GCN2 inhibition (pharmacological and genetic), MetRS nuclear/cytoplasmic fractionation, 47S rRNA quantification, mTORC1 activity assay, autophagy assay, patient-derived tumoroids Molecular oncology Medium 37452637
2019 High MYC levels in APC-deficient colorectal cancer cells induce phosphorylation of eIF2α via GCN2 (and PKR), forming a negative feedback loop. Pharmacological inhibition of GCN2 phenocopies eIF2B5 depletion, causing MYC-dependent apoptosis and demonstrating therapeutic efficacy in patient-derived tumor organoids. GCN2 pharmacological inhibition, eIF2α phosphorylation assay, tumor organoid model, genetic epistasis (APC, MYC, GCN2) Nature cell biology Medium 31685988

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. The EMBO journal 600 20473272
2000 Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain. Molecular cell 423 10983975
2002 The GCN2 eIF2alpha kinase is required for adaptation to amino acid deprivation in mice. Molecular and cellular biology 377 12215525
2005 Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature 341 16121183
2013 EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nature genetics 317 24292273
2018 Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production. Cell 279 29570992
2003 Translational control by TOR and TAP42 through dephosphorylation of eIF2alpha kinase GCN2. Genes & development 241 12654728
2000 A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2alpha. Genetics 239 10655230
2014 Keeping the eIF2 alpha kinase Gcn2 in check. Biochimica et biophysica acta 238 24732012
2019 Activation of GCN2 by the ribosomal P-stalk. Proceedings of the National Academy of Sciences of the United States of America 173 30804176
2006 Antiviral effect of the mammalian translation initiation factor 2alpha kinase GCN2 against RNA viruses. The EMBO journal 162 16601681
1991 Ribosome association of GCN2 protein kinase, a translational activator of the GCN4 gene of Saccharomyces cerevisiae. Molecular and cellular biology 148 2038314
2014 EIF2AK4 mutations in pulmonary capillary hemangiomatosis. Chest 142 24135949
2022 GCN2 inhibition sensitizes arginine-deprived hepatocellular carcinoma cells to senolytic treatment. Cell metabolism 134 35839757
2020 Branched chain amino acids exacerbate myocardial ischemia/reperfusion vulnerability via enhancing GCN2/ATF6/PPAR-α pathway-dependent fatty acid oxidation. Theranostics 120 32373236
2019 GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment. Science immunology 116 31836669
2017 Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension. Circulation 114 28972005
2005 Structural basis for autoinhibition and mutational activation of eukaryotic initiation factor 2alpha protein kinase GCN2. The Journal of biological chemistry 109 15964839
2019 Towards a model of GCN2 activation. Biochemical Society transactions 107 31647517
1990 Identification of positive-acting domains in GCN2 protein kinase required for translational activation of GCN4 expression. Molecular and cellular biology 105 2188100
1996 Histidyl-tRNA synthetase-related sequences in GCN2 protein kinase regulate in vitro phosphorylation of eIF-2. The Journal of biological chemistry 103 8798780
2023 Tryptophan depletion sensitizes the AHR pathway by increasing AHR expression and GCN2/LAT1-mediated kynurenine uptake, and potentiates induction of regulatory T lymphocytes. Journal for immunotherapy of cancer 91 37344101
2016 4E-BP is a target of the GCN2-ATF4 pathway during Drosophila development and aging. The Journal of cell biology 89 27979906
2022 Amino acid catabolism regulates hematopoietic stem cell proteostasis via a GCN2-eIF2α axis. Cell stem cell 80 35803229
2019 A MYC-GCN2-eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer. Nature cell biology 75 31685988
2013 GCN2-dependent metabolic stress is essential for endotoxemic cytokine induction and pathology. Molecular and cellular biology 73 24248597
2018 GCN2 deficiency ameliorates doxorubicin-induced cardiotoxicity by decreasing cardiomyocyte apoptosis and myocardial oxidative stress. Redox biology 66 29660505
2017 Activation of Gcn2 in response to different stresses. PloS one 66 28771613
2016 Activation of the EIF2AK4-EIF2A/eIF2α-ATF4 pathway triggers autophagy response to Crohn disease-associated adherent-invasive Escherichia coli infection. Autophagy 64 26986695
1999 Hsp90 binds and regulates Gcn2, the ligand-inducible kinase of the alpha subunit of eukaryotic translation initiation factor 2 [corrected]. Molecular and cellular biology 62 10567567
2009 eIF2alpha kinases GCN2 and PERK modulate transcription and translation of distinct sets of mRNAs in mouse liver. Physiological genomics 60 19509078
2016 EIF2AK4 Mutations in Patients Diagnosed With Pulmonary Arterial Hypertension. Chest 59 27884767
2005 PKR and GCN2 kinases and guanine nucleotide exchange factor eukaryotic translation initiation factor 2B (eIF2B) recognize overlapping surfaces on eIF2alpha. Molecular and cellular biology 58 15798194
2022 GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis. eLife 56 36107759
2017 Pulmonary vascular remodeling patterns and expression of general control nonderepressible 2 (GCN2) in pulmonary veno-occlusive disease. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 56 29108819
2023 Activation of Gcn2 by small molecules designed to be inhibitors. The Journal of biological chemistry 52 36898579
2023 The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid insufficiency. Cell metabolism 51 37979583
2018 GCN2 deficiency ameliorates cardiac dysfunction in diabetic mice by reducing lipotoxicity and oxidative stress. Free radical biology & medicine 50 30389499
2007 Conserved intermolecular salt bridge required for activation of protein kinases PKR, GCN2, and PERK. The Journal of biological chemistry 49 17202131
2015 Disruption of Proline Synthesis in Melanoma Inhibits Protein Production Mediated by the GCN2 Pathway. Molecular cancer research : MCR 48 26082174
2015 A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies. Clinical genetics 47 25512148
2019 GCN2 is essential for CD8+ T cell survival and function in murine models of malignant glioma. Cancer immunology, immunotherapy : CII 45 31844909
2020 Activation of GCN2/ATF4 signals in amygdalar PKC-δ neurons promotes WAT browning under leucine deprivation. Nature communications 43 32504036
2019 The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation. Oncogene 43 30626938
2024 Multiple mechanisms activate GCN2 eIF2 kinase in response to diverse stress conditions. Nucleic acids research 42 38281137
2021 Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulation. Redox biology 42 34954499
2021 GCN2 kinase activation by ATP-competitive kinase inhibitors. Nature chemical biology 41 34949839
2023 Differential requirements for P stalk components in activating yeast protein kinase Gcn2 by stalled ribosomes during stress. Proceedings of the National Academy of Sciences of the United States of America 39 37043534
2021 Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress. Nucleic acids research 39 34023907
2012 Tryptophan depletion and the kinase GCN2 mediate IFN-γ-induced autophagy. Journal of immunology (Baltimore, Md. : 1950) 39 22896630
2016 EIF2AK4 mutation as "second hit" in hereditary pulmonary arterial hypertension. Respiratory research 38 27809840
2016 GCN2- and eIF2α-phosphorylation-independent, but ATF4-dependent, induction of CARE-containing genes in methionine-deficient cells. Amino acids 37 27613409
2018 GCN2 deficiency protects against high fat diet induced hepatic steatosis and insulin resistance in mice. Biochimica et biophysica acta. Molecular basis of disease 36 30006154
2012 New functions of protein kinase Gcn2 in yeast and mammals. IUBMB life 36 23129244
2022 Tong-Xie-Yao-Fang alleviates diarrhea-predominant irritable bowel syndrome in rats via the GCN2/PERK-eIF2α-ATF4 signaling pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 35 36194974
2012 A novel role for protein kinase Gcn2 in yeast tolerance to intracellular acid stress. The Biochemical journal 35 21919885
2011 Gcn1 and actin binding to Yih1: implications for activation of the eIF2 kinase GCN2. The Journal of biological chemistry 33 21239490
2011 Increased susceptibility to DNA virus infection in mice with a GCN2 mutation. Journal of virology 33 22114338
2022 GCN2: roles in tumour development and progression. Biochemical Society transactions 32 35311890
2007 The Gcn2 kinase as a cell cycle regulator. Cell cycle (Georgetown, Tex.) 32 17986863
2021 GCN2 adapts protein synthesis to scavenging-dependent growth. Cell systems 31 34706266
2014 Enhanced interaction between pseudokinase and kinase domains in Gcn2 stimulates eIF2α phosphorylation in starved cells. PLoS genetics 30 24811037
2024 Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy. Cell reports. Medicine 27 38460518
2023 Multiple Roles of the Stress Sensor GCN2 in Immune Cells. International journal of molecular sciences 27 36901714
2020 The Amino Acid Sensor Eif2ak4/GCN2 Is Required for Proliferation of Osteoblast Progenitors in Mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 27 32453500
2013 GCN2-like eIF2α kinase manages the amino acid starvation response in Toxoplasma gondii. International journal for parasitology 27 24126185
2022 Ghost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability. Proceedings of the National Academy of Sciences of the United States of America 26 35177476
2018 GCN2 reduces inflammation by p-eIF2α/ATF4 pathway after intracerebral hemorrhage in mice. Experimental neurology 26 30529503
2017 GCN2 phosphorylates HIV-1 integrase and decreases HIV-1 replication by limiting viral integration. Scientific reports 26 28536474
2024 Crosstalk between ferroptosis and necroptosis in cerebral ischemia/reperfusion injury and Naotaifang formula exerts neuroprotective effect via HSP90-GCN2-ATF4 pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 25 38850632
2022 Mitochondrial ROS-mediated ribosome stalling and GCN2 activation are partially involved in 1-nitropyrene-induced steroidogenic inhibition in testes. Environment international 25 35843074
2021 Global phosphoproteomics pinpoints uncharted Gcn2-mediated mechanisms of translational control. Molecular cell 25 33743194
2019 Ginseng metabolite Protopanaxadiol induces Sestrin2 expression and AMPK activation through GCN2 and PERK. Cell death & disease 25 30952841
2014 Crystal structures of GCN2 protein kinase C-terminal domains suggest regulatory differences in yeast and mammals. The Journal of biological chemistry 25 24719324
2020 GZD824 Inhibits GCN2 and Sensitizes Cancer Cells to Amino Acid Starvation Stress. Molecular pharmacology 24 33033108
2020 Gcn2 eIF2α kinase mediates combinatorial translational regulation through nucleotide motifs and uORFs in target mRNAs. Nucleic acids research 20 32710633
2013 Activation of GCN2 upon HIV-1 infection and inhibition of translation. Cellular and molecular life sciences : CMLS 20 23417324
2020 GCN2 regulates pancreatic β cell mass by sensing intracellular amino acid levels. JCI insight 19 32376799
2020 Reciprocal regulation between GCN2 (eIF2AK4) and PERK (eIF2AK3) through the JNK-FOXO3 axis to modulate cancer drug resistance and clonal survival. Molecular and cellular endocrinology 19 32615282
2019 A Novel SNP in EIF2AK4 Gene Is Associated with Thermal Tolerance Traits in Chinese Cattle. Animals : an open access journal from MDPI 19 31248194
2013 GCN2 regulates the CCAAT enhancer binding protein beta and hepatic gluconeogenesis. American journal of physiology. Endocrinology and metabolism 19 23900421
2024 Downregulation of nutrition sensor GCN2 in macrophages contributes to poor wound healing in diabetes. Cell reports 18 38175755
2022 Review: Emerging roles of the signaling network of the protein kinase GCN2 in the plant stress response. Plant science : an international journal of experimental plant biology 18 35643606
2022 The Role of GCN2 Kinase in Mediating the Effects of Amino Acids on Longevity and Feeding Behaviour in Drosophila. Frontiers in aging 17 35821827
2022 The amino acid sensor GCN2 controls red blood cell clearance and iron metabolism through regulation of liver macrophages. Proceedings of the National Academy of Sciences of the United States of America 17 35994670
2013 Crosstalk between the Tor and Gcn2 pathways in response to different stresses. Cell cycle (Georgetown, Tex.) 17 24280780
1994 Genetic and biochemical evidence for yeast GCN2 protein kinase polymerization. Gene 17 8200534
2022 Limiting glutamine utilization activates a GCN2/TRAIL-R2/Caspase-8 apoptotic pathway in glutamine-addicted tumor cells. Cell death & disease 16 36302756
2021 GCN2 Regulates ATF3-p38 MAPK Signaling Transduction in Pulmonary Veno-Occlusive Disease. Journal of cardiovascular pharmacology and therapeutics 16 33988041
2019 Nutrient Sensing and Redox Balance: GCN2 as a New Integrator in Aging. Oxidative medicine and cellular longevity 16 31249645
2017 A new role of GCN2 in the nucleolus. Biochemical and biophysical research communications 16 28189689
2013 GCN2, an old dog with new tricks. Biochemical Society transactions 16 24256275
2024 Phosphorylation of GCN2 by mTOR confers adaptation to conditions of hyper-mTOR activation under stress. The Journal of biological chemistry 14 39013537
2024 Multifaceted role of GCN2 in tumor adaptation and therapeutic targeting. Translational oncology 14 39178574
2023 Disruption of GCN2 Pathway Aggravates Vascular and Parenchymal Remodeling during Pulmonary Fibrosis. American journal of respiratory cell and molecular biology 14 36476191
2021 The eIF2 kinase GCN2 directs keratinocyte collective cell migration during wound healing via coordination of reactive oxygen species and amino acids. The Journal of biological chemistry 14 34597669
2019 Effects of GCN2/eIF2α on myocardial ischemia/hypoxia reperfusion and myocardial cells injury. American journal of translational research 14 31632531
2016 A GCN2-Like eIF2α Kinase (LdeK1) of Leishmania donovani and Its Possible Role in Stress Response. PloS one 14 27248816
2012 Implication of eIF2α kinase GCN2 in induction of apoptosis and endoplasmic reticulum stress-responsive genes by sodium salicylate. The Journal of pharmacy and pharmacology 14 23356852
2023 The stress sensor GCN2 differentially controls ribosome biogenesis in colon cancer according to the nutritional context. Molecular oncology 13 37452637

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