| Tchem | eIF-2-alpha kinase GCN2 |
(Microbial infection) Plays a role in modulating the adaptive immune response to yellow fever virus infection; promotes dendritic cells to initiate autophagy and antigene presentation to both CD4(+) and CD8(+) T-cells under amino acid starvation (PubMed:24310610).
This gene encodes a member of a family of kinases that phosphorylate the alpha subunit of eukaryotic translation initiation factor-2 (EIF2), resulting in the downregulaton of protein synthesis. The encoded protein responds to amino acid deprivation by binding uncharged transfer RNAs. It may also be activated by glucose deprivation and viral infection. Mutations in this gene have been found in individuals suffering from autosomal recessive pulmonary venoocclusive-disease-2. [provided by RefSeq, Mar 2014]
This gene encodes a member of a family of kinases that phosphorylate the alpha subunit of eukaryotic translation initiation factor-2 (EIF2), resulting in the downregulaton of protein synthesis. The encoded protein responds to amino acid deprivation by binding uncharged transfer RNAs. It may also be activated by glucose deprivation and viral infection. Mutations in this gene have been found in individuals suffering from autosomal recessive pulmonary venoocclusive-disease-2. [provided by RefSeq, Mar 2014]
Comments
| Disease | Target Count | P-value |
|---|---|---|
| osteosarcoma | 7933 | 6.8e-07 |
| ovarian cancer | 8491 | 6.0e-06 |
| cystic fibrosis | 1670 | 1.6e-04 |
| atypical teratoid / rhabdoid tumor | 4369 | 1.7e-04 |
| glioblastoma | 5572 | 2.5e-04 |
| subependymal giant cell astrocytoma | 2287 | 5.4e-03 |
| ileal Crohn's disease | 9 | 4.3e-02 |
| Rheumatoid Arthritis | 1170 | 4.6e-02 |
| Disease | Target Count | Z-score | Confidence |
|---|---|---|---|
| Pulmonary venoocclusive disease | 3 | 6.664 | 3.3 |
| Disease | log2 FC | p |
|---|---|---|
| Rheumatoid Arthritis | 1.100 | 4.6e-02 |
| osteosarcoma | -1.779 | 6.8e-07 |
| cystic fibrosis | -1.290 | 1.6e-04 |
| atypical teratoid / rhabdoid tumor | 1.100 | 1.7e-04 |
| glioblastoma | 1.200 | 2.5e-04 |
| subependymal giant cell astrocytoma | 1.509 | 5.4e-03 |
| ovarian cancer | 2.400 | 6.0e-06 |
| ileal Crohn's disease | -1.345 | 4.3e-02 |
CHEMBL386051
pKd 7.59
CHEMBL388978
pKd 7.80
CHEMBL3407850
pIC50 7.92
CHEMBL3407851
pIC50 8.00
CHEMBL3407849
pIC50 8.30
CHEMBL603469
pKd 8.39
CHEMBL475251
pKd 8.48
| PMID | Text | |
|---|---|---|
| 26647830 | IDO, through GCN2 kinase activation, downregulates the levels of TCRcomplex tchain and cMyc, resulting in the suppression of Tcell proliferation and a reduction in the levels of LDHA and GLS2 | |
| 26543160 | Upon deprivation of various amino acids, activated GCN2 up-regulates ATF4 to induce expression of the stress response protein Sestrin2, which is required to sustain repression of mTORC1 by blocking its lysosomal localization | |
| 26541523 | EIF2AK4 mutation was associated with pulmonary veno-occlusive disease. PVOD patients who were not significantly exposed to trichloroethylene were more likely to harbour EIF2AK4 mutations. | |
| 26147366 | IDO through GCN2 kinase activation inhibits CD4(+) T-cell proliferation and down-regulates key enzymes that directly or indirectly promote FA synthesis, a prerequisite for CD4(+) T-cell proliferation and differentiation into effector cell lineages. | |
| 26082174 | Targeting ALDH18A1 activated the serine/threonine protein kinase GCN2 (general control nonderepressible 2) to inhibit protein synthesis in melanoma. | |
| 25759478 | GCN2 activation and phosphorylation of eIF2alpha in response to mTORC1 inhibition are necessary for autophagy. | |
| 25589675 | GCN2 can exert its proapoptotic function in cancer cell death by posttranslational mechanisms. | |
| 25512148 | Data show that sequenced eukaryotic translation initiation factor 2 alpha kinase 4 protein (EIF2AK4) with a homozygous mutation in all five families: c.3344C>T(p.P1115L). | |
| 25329545 | p58IPK is a general inhibitor of the eIF2alpha kinases in that it also interacts with GCN2. Thus forced overexpression of cytoplasmic p58 delays eIF2alpha phosphorylation, suppresses GCN2 phosphorylation and prolongs protein synthesis | |
| 25142489 | This study is the first to examine the perceptual response to CPET in patients with PVOD who were carriers of EIF2AK4 mutations compared with PAH patients matched for resting haemodynamics and pulmonary function | |
| 24827717 | Association of EIF2AKE with body mass index in Chinese has been confirmed and is suggested to be 'ethnic specific'. | |
| 24292273 | EIF2AK4 mutations cause pulmonary veno-occlusive disease. | |
| 24256275 | REVIEW: roles of GCN2 | |
| 24135949 | Mutations in EIF2AK4 are likely to cause autosomal-recessive pulmonary capillary hemangiomatosis in familial and some nonfamilial cases. | |
| 23908598 | Data indicate that suppressing GCN2 and activating transcription factor 4 (ATF4), expression decreased Amino acid deprivation (AAD)-induced VEGF expression. | |
| 23417324 | GCN2 has a role as an early mediator in the cellular response to HIV-1 infection | |
| 23417324 | HIV-1 PR directly cleaves GCN2 at amino acid residues 560-561, which leads to inactivate GCN2 activity | |
| 23417324 | Knockdown of GCN2 by siRNA enhances HIV-1 infectivity in HeLa P4 cells | |
| 23216249 | In this review, GCN2 senses the absence of one or more amino acids by virtue of direct binding to cognate tRNAs. | |
| 23110064 | GCN2 leading to inhibition of viral RNA translation, and that HIV-1 protease cleaves GCN2 to overcome its antiviral effect. | |
| 23110064 | HIV-1 PR directly cleaves GCN2 at amino acid residues 560-561, which leads to inactivate GCN2 activity | |
| 22896630 | The activation of autophagy in response to interferon (IFN)-gamma is promoted by tryptophan depletion and relies, at least in part, on the activation of GCN2-eIF2alpha kinase in kidney epithelial cells. | |
| 22435535 | Changes in translational control of mitochondrial proteins are signaled by the activation of AMPK (AMP-activated protein kinase) and GCN2, leading also to the activation of autophagy. | |
| 21203563 | the GCN2/eIF2alpha/ATF4 pathway is essential for the induction of the TRB3 gene transcription | |
| 21113813 | The results suggest that GCN2 pathways can mediate the limiting effects of Gln deprivation on protein synthesis according to its severity. | |
| 20551969 | GCN2 and its downstream target, the transcriptional activator ATF4, is critical for proliferation and survival of tumour cells after starvation for amino acids or glucose and is essential for growth in vivo in a xenograft model. | |
| 20473272 | The authors conclude that the GCN2-eIF2alpha-ATF4 pathway is critical for maintaining metabolic homeostasis in tumour cells, making it a novel and attractive target for anti-tumour approaches. | |
| 20168091 | Data show that impairment of autophagy stimulates PS1 expression and gamma-secretase activity through GCN2. | |
| 19586904 | UV-induced eIF2alpha phosphorylation by activation of both PERK and GCN2 via oxidative stress and l-arginine starvation signaling pathways. | |
| 18287093 | MEK functions to enhance GCN2-dependent eIF2alpha phosphorylation rather than suppressing dephosphorylation |
MAGGRGAPGRGRDEPPESYPQRQDHELQALEAIYGADFQDLRPDACGPVKEPPEINLVLYPQGLTGEEVY 1 - 70 VKVDLRVKCPPTYPDVVPEIELKNAKGLSNESVNLLKSRLEELAKKHCGEVMIFELAYHVQSFLSEHNKP 71 - 140 PPKSFHEEMLERRAQEEQQRLLEAKRKEEQEQREILHEIQRRKEEIKEEKKRKEMAKQERLEIASLSNQD 141 - 210 HTSKKDPGGHRTAAILHGGSPDFVGNGKHRANSSGRSRRERQYSVCNSEDSPGSCEILYFNMGSPDQLMV 211 - 280 HKGKCIGSDEQLGKLVYNALETATGGFVLLYEWVLQWQKKMGPFLTSQEKEKIDKCKKQIQGTETEFNSL 281 - 350 VKLSHPNVVRYLAMNLKEQDDSIVVDILVEHISGVSLAAHLSHSGPIPVHQLRRYTAQLLSGLDYLHSNS 351 - 420 VVHKVLSASNVLVDAEGTVKITDYSISKRLADICKEDVFEQTRVRFSDNALPYKTGKKGDVWRLGLLLLS 421 - 490 LSQGQECGEYPVTIPSDLPADFQDFLKKCVCLDDKERWSPQQLLKHSFINPQPKMPLVEQSPEDSEGQDY 491 - 560 VETVIPSNRLPSAAFFSETQRQFSRYFIEFEELQLLGKGAFGAVIKVQNKLDGCCYAVKRIPINPASRQF 561 - 630 RRIKGEVTLLSRLHHENIVRYYNAWIERHERPAGPGTPPPDSGPLAKDDRAARGQPASDTDGLDSVEAAA 631 - 700 PPPILSSSVEWSTSGERSASARFPATGPGSSDDEDDDEDEHGGVFSQSFLPASDSESDIIFDNEDENSKS 701 - 770 QNQDEDCNEKNGCHESEPSVTTEAVHYLYIQMEYCEKSTLRDTIDQGLYRDTVRLWRLFREILDGLAYIH 771 - 840 EKGMIHRDLKPVNIFLDSDDHVKIGDFGLATDHLAFSADSKQDDQTGDLIKSDPSGHLTGMVGTALYVSP 841 - 910 EVQGSTKSAYNQKVDLFSLGIIFFEMSYHPMVTASERIFVLNQLRDPTSPKFPEDFDDGEHAKQKSVISW 911 - 980 LLNHDPAKRPTATELLKSELLPPPQMEESELHEVLHHTLTNVDGKAYRTMMAQIFSQRISPAIDYTYDSD 981 - 1050 ILKGNFSIRTAKMQQHVCETIIRIFKRHGAVQLCTPLLLPRNRQIYEHNEAALFMDHSGMLVMLPFDLRI 1051 - 1120 PFARYVARNNILNLKRYCIERVFRPRKLDRFHPKELLECAFDIVTSTTNSFLPTAEIIYTIYEIIQEFPA 1121 - 1190 LQERNYSIYLNHTMLLKAILLHCGIPEDKLSQVYIILYDAVTEKLTRREVEAKFCNLSLSSNSLCRLYKF 1191 - 1260 IEQKGDLQDLMPTINSLIKQKTGIAQLVKYGLKDLEEVVGLLKKLGIKLQVLINLGLVYKVQQHNGIIFQ 1261 - 1330 FVAFIKRRQRAVPEILAAGGRYDLLIPQFRGPQALGPVPTAIGVSIAIDKISAAVLNMEESVTISSCDLL 1331 - 1400 VVSVGQMSMSRAINLTQKLWTAGITAEIMYDWSQSQEELQEYCRHHEITYVALVSDKEGSHVKVKSFEKE 1401 - 1470 RQTEKRVLETELVDHVLQKLRTKVTDERNGREASDNLAVQNLKGSFSNASGLFEIHGATVVPIVSVLAPE 1471 - 1540 KLSASTRRRYETQVQTRLQTSLANLHQKSSEIEILAVDLPKETILQFLSLEWDADEQAFNTTVKQLLSRL 1541 - 1610 PKQRYLKLVCDEIYNIKVEKKVSVLFLYSYRDDYYRILF 1611 - 1649 //
| PMID | Year | Title | |
|---|---|---|---|
| 26647830 | 2016 | Indoleamine 2,3?dioxygenase downregulates T?cell receptor complex ??chain and c?Myc, and reduces proliferation, lactate dehydrogenase levels and mitochondrial glutaminase in human T?cells. | |
| 26543160 | 2015 | GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2. | |
| 26541523 | 2015 | Occupational exposure to organic solvents: a risk factor for pulmonary veno-occlusive disease. | |
| 26147366 | 2015 | Indoleamine 2,3-dioxygenase depletes tryptophan, activates general control non-derepressible 2 kinase and down-regulates key enzymes involved in fatty acid synthesis in primary human CD4+ T cells. | |
| 26102367 | 2015 | Translational Upregulation of an Individual p21Cip1 Transcript Variant by GCN2 Regulates Cell Proliferation and Survival under Nutrient Stress. | |
| 26082174 | 2015 | Disruption of Proline Synthesis in Melanoma Inhibits Protein Production Mediated by the GCN2 Pathway. | |
| 25759478 | 2015 | Phosphorylation of eIF2? triggered by mTORC1 inhibition and PP6C activation is required for autophagy and is aberrant in PP6C-mutated melanoma. | |
| 25589675 | 2015 | Involvement of general control nonderepressible kinase 2 in cancer cell apoptosis by posttranslational mechanisms. | |
| 25512148 | 2015 | A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies. | |
| 25329545 | 2015 | p58IPK is an inhibitor of the eIF2? kinase GCN2 and its localization and expression underpin protein synthesis and ER processing capacity. | |
| 25142489 | 2014 | Mechanisms of exertional dyspnoea in pulmonary veno-occlusive disease with EIF2AK4 mutations. | |
| 24827717 | 2014 | Genome wide association study: searching for genes underlying body mass index in the Chinese. | |
| 24751813 | 2014 | Genome-wide association study supports the role of the immunological system and of the neurodevelopmental processes in response to haloperidol treatment. | |
| 24310610 | 2014 | Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation. | |
| 24292273 | 2014 | EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. | |
| 24256275 | 2013 | GCN2, an old dog with new tricks. | |
| 24135949 | 2014 | EIF2AK4 mutations in pulmonary capillary hemangiomatosis. | |
| 24019515 | 2013 | General control nonderepressible 2 (GCN2) kinase protects oligodendrocytes and white matter during branched-chain amino acid deficiency in mice. | |
| 23908598 | 2013 | Amino acid deprivation promotes tumor angiogenesis through the GCN2/ATF4 pathway. | |
| 23417324 | 2013 | Activation of GCN2 upon HIV-1 infection and inhibition of translation. | |
| 23354059 | 2013 | The eIF2? kinases: their structures and functions. | |
| 23216249 | 2013 | Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR. | |
| 23186163 | 2013 | Toward a comprehensive characterization of a human cancer cell phosphoproteome. | |
| 23129244 | 2012 | New functions of protein kinase Gcn2 in yeast and mammals. | |
| 23110064 | 2012 | GCN2 has inhibitory effect on human immunodeficiency virus-1 protein synthesis and is cleaved upon viral infection. | |
| 22969067 | 2012 | Genetic variants near PDGFRA are associated with corneal curvature in Australians. | |
| 22896630 | 2012 | Tryptophan depletion and the kinase GCN2 mediate IFN-?-induced autophagy. | |
| 22435535 | 2012 | AMPK and GCN2-ATF4 signal the repression of mitochondria in colon cancer cells. | |
| 22327514 | 2012 | Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma. | |
| 22301437 | 2013 | Nucleofection induces transient eIF2? phosphorylation by GCN2 and PERK. | |
| 21406692 | 2011 | System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation. | |
| 21269460 | 2011 | Initial characterization of the human central proteome. | |
| 21203563 | 2010 | Amino acid availability controls TRB3 transcription in liver through the GCN2/eIF2?/ATF4 pathway. | |
| 21113813 | 2012 | Effects of essential amino acids or glutamine deprivation on intestinal permeability and protein synthesis in HCT-8 cells: involvement of GCN2 and mTOR pathways. | |
| 21076179 | 2010 | HDAC pharmacological inhibition promotes cell death through the eIF2? kinases PKR and GCN2. | |
| 20551969 | 2010 | How do tumours adapt to nutrient stress? | |
| 20473272 | 2010 | The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. | |
| 20168091 | 2010 | Autophagy impairment stimulates PS1 expression and gamma-secretase activity. | |
| 20068231 | 2010 | Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. | |
| 19608861 | 2009 | Lysine acetylation targets protein complexes and co-regulates major cellular functions. | |
| 19586904 | 2009 | The role of nitric-oxide synthase in the regulation of UVB light-induced phosphorylation of the alpha subunit of eukaryotic initiation factor 2. | |
| 19369195 | 2009 | Large-scale proteomics analysis of the human kinome. | |
| 19029902 | 2009 | Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. | |
| 18691976 | 2008 | Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. | |
| 18669648 | 2008 | A quantitative atlas of mitotic phosphorylation. | |
| 18287093 | 2008 | MEK signaling is required for phosphorylation of eIF2alpha following amino acid limitation of HepG2 human hepatoma cells. | |
| 17974005 | 2007 | The full-ORF clone resource of the German cDNA Consortium. | |
| 17344846 | 2007 | Patterns of somatic mutation in human cancer genomes. | |
| 17276353 | 2007 | The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. | |
| 17202131 | 2007 | Conserved intermolecular salt bridge required for activation of protein kinases PKR, GCN2, and PERK. | |
| 17192257 | 2007 | Proteomics analysis of protein kinases by target class-selective prefractionation and tandem mass spectrometry. | |
| 17081983 | 2006 | Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. | |
| 16601681 | 2006 | Antiviral effect of the mammalian translation initiation factor 2alpha kinase GCN2 against RNA viruses. | |
| 16572171 | 2006 | Analysis of the DNA sequence and duplication history of human chromosome 15. | |
| 16121183 | 2005 | Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. | |
| 15761153 | 2005 | High-throughput mapping of a dynamic signaling network in mammalian cells. | |
| 15489334 | 2004 | The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). | |
| 14702039 | 2004 | Complete sequencing and characterization of 21,243 full-length human cDNAs. | |
| 14671302 | 2003 | Inferring nonneutral evolution from human-chimp-mouse orthologous gene trios. | |
| 12477932 | 2002 | Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. | |
| 12215525 | 2002 | The GCN2 eIF2alpha kinase is required for adaptation to amino acid deprivation in mice. | |
| 10718198 | 2000 | Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. | |
| 10504407 | 1999 | Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase. |
