GCN2

Summary

Gene Symbol: GCN2
Description: eukaryotic translation initiation factor 2 alpha kinase 4
Alias: 2610011M03, GCN2, MGCN2, eIF-2-alpha kinase GCN2, GCN2 eIF2alpha kinase, GCN2-like protein
Species: mouse
Products:     GCN2

Top Publications

  1. Hao S, Sharp J, Ross Inta C, McDaniel B, Anthony T, Wek R, et al. Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform cortex. Science. 2005;307:1776-8 pubmed
    ..transfer RNA induces phosphorylation of eukaryotic initiation factor 2 (eIF2) via the GC nonderepressing 2 (GCN2) kinase...
  2. Hamanaka R, Bennett B, Cullinan S, Diehl J. PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway. Mol Biol Cell. 2005;16:5493-501 pubmed
    ..In cells harboring targeted deletion of both PERK and GCN2, cyclin D1 loss is attenuated, suggesting GCN2 functions as the redundant kinase...
  3. Thiaville M, Pan Y, Gjymishka A, Zhong C, Kaufman R, Kilberg M. MEK signaling is required for phosphorylation of eIF2alpha following amino acid limitation of HepG2 human hepatoma cells. J Biol Chem. 2008;283:10848-57 pubmed publisher
    ..This pathway involves detection of uncharged tRNA by the GCN2 kinase, phosphorylation of the translation initiation factor eIF2alpha (eukaryotic initiation factor 2alpha), and, ..
  4. Krishnamoorthy J, Mounir Z, Raven J, Koromilas A. The eIF2alpha kinases inhibit vesicular stomatitis virus replication independently of eIF2alpha phosphorylation. Cell Cycle. 2008;7:2346-51 pubmed
    ..MEFs) from knock-out mice we show that PKR and HRI have no effects on VSV replication as opposed to PERK and GCN2, which exhibit strong inhibitory effects...
  5. Xiao F, Huang Z, Li H, Yu J, Wang C, Chen S, et al. Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways. Diabetes. 2011;60:746-56 pubmed publisher
    ..Furthermore, we demonstrate a novel function for GCN2 in the regulation of insulin sensitivity...
  6. Berlanga J, Ventoso I, Harding H, Deng J, Ron D, Sonenberg N, et al. Antiviral effect of the mammalian translation initiation factor 2alpha kinase GCN2 against RNA viruses. EMBO J. 2006;25:1730-40 pubmed
    ..heme-regulated inhibitor, double-stranded RNA-dependent protein kinase (PKR), general control non-derepressible-2 (GCN2) and PKR-like endoplasmic reticulum kinase, regulate protein synthesis in response to environmental stresses by ..
  7. Maurin A, Jousse C, Averous J, Parry L, Bruhat A, Cherasse Y, et al. The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores. Cell Metab. 2005;1:273-7 pubmed
    ..We report that brain-specific inactivation of GCN2, a ubiquitously expressed protein kinase that phosphorylates translation initiation factor 2 alpha (eIF2alpha) in ..
  8. Guo F, Cavener D. The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metab. 2007;5:103-14 pubmed
    Metabolic adaptation is required to cope with episodes of protein deprivation and malnutrition. GCN2 eIF2alpha kinase, a sensor of amino acid deficiency, plays a key role in yeast and mammals in modulating amino acid metabolism as part ..
  9. Harding H, Zhang Y, Zeng H, Novoa I, Lu P, Calfon M, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003;11:619-33 pubmed
    ..A signaling pathway initiated by eIF2alpha phosphorylation protects cells against metabolic consequences of ER oxidation by promoting the linked processes of amino acid sufficiency and resistance to oxidative stress. ..

More Information

Publications86

  1. Zhang P, McGrath B, Reinert J, Olsen D, Lei L, Gill S, et al. The GCN2 eIF2alpha kinase is required for adaptation to amino acid deprivation in mice. Mol Cell Biol. 2002;22:6681-8 pubmed
    The GCN2 eIF2alpha kinase is essential for activation of the general amino acid control pathway in yeast when one or more amino acids become limiting for growth...
  2. Deng J, Harding H, Raught B, Gingras A, Berlanga J, Scheuner D, et al. Activation of GCN2 in UV-irradiated cells inhibits translation. Curr Biol. 2002;12:1279-86 pubmed
    ..of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) by activating the kinase GCN2 in a manner that does not require SAPK/JNK or p38 MAP kinase...
  3. Dever T, Feng L, Wek R, Cigan A, Donahue T, Hinnebusch A. Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Cell. 1992;68:585-96 pubmed
    ..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...
  4. Harding H, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000;6:1099-108 pubmed
    ..When activated by their cognate upstream stress signals, the mammalian eIF2 kinases PERK and GCN2 repress translation of most mRNAs but selectively increase translation of Activating Transcription Factor 4 (ATF4), ..
  5. Anthony T, McDaniel B, Byerley R, McGrath B, Cavener D, McNurlan M, et al. Preservation of liver protein synthesis during dietary leucine deprivation occurs at the expense of skeletal muscle mass in mice deleted for eIF2 kinase GCN2. J Biol Chem. 2004;279:36553-61 pubmed
    ..Herein we describe that mice lacking the eIF2 kinase, general control nonderepressible 2 (GCN2) fail to alter the phosphorylation of this initiation factor in liver, and are moribund in response to dietary ..
  6. Deval C, Chaveroux C, Maurin A, Cherasse Y, Parry L, Carraro V, et al. Amino acid limitation regulates the expression of genes involved in several specific biological processes through GCN2-dependent and GCN2-independent pathways. FEBS J. 2009;276:707-18 pubmed publisher
    ..Using GCN2-/- cells and rapamycin treatment, we checked for the role of mGCN2 and mTORC1 kinases in this regulation...
  7. Costa Mattioli M, Gobert D, Harding H, Herdy B, Azzi M, Bruno M, et al. Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature. 2005;436:1166-73 pubmed
    ..The new mRNAs are either translated in the soma or transported to synapses before translation. GCN2, a key protein kinase, regulates the initiation of translation...
  8. Jasperson L, Bucher C, Panoskaltsis Mortari A, Mellor A, Munn D, Blazar B. Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. Blood. 2009;114:5062-70 pubmed publisher
    ..IDO induces GCN2 kinase, up-regulating a T-cell stress response implicated in IDO immunosuppression...
  9. Van De Velde L, Guo X, Barbaric L, Smith A, Oguin T, Thomas P, et al. Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing. Cell Rep. 2016;17:2247-2258 pubmed publisher
    b>GCN2 is one of four "stress kinases" that block translation by phosphorylating eIF2?. GCN2 is thought to bind uncharged tRNAs to "sense" amino acid availability...
  10. Carraro V, Maurin A, Lambert Langlais S, Averous J, Chaveroux C, Parry L, et al. Amino acid availability controls TRB3 transcription in liver through the GCN2/eIF2?/ATF4 pathway. PLoS ONE. 2010;5:e15716 pubmed publisher
    ..In mouse liver, we demonstrate that the GCN2/eIF2?/ATF4 pathway is essential for the induction of the TRB3 gene transcription in response to a leucine-deficient ..
  11. Wilson G, Bunpo P, Cundiff J, Wek R, Anthony T. The eukaryotic initiation factor 2 kinase GCN2 protects against hepatotoxicity during asparaginase treatment. Am J Physiol Endocrinol Metab. 2013;305:E1124-33 pubmed publisher
    ..involving phosphorylation of eukaryotic initiation factor 2 (eIF2) by general control nonderepressible kinase 2 (GCN2). We hypothesized that GCN2 functions to mitigate hepatic stress during asparaginase therapy by activating the AAR...
  12. Xu X, Hu J, McGrath B, Cavener D. GCN2 regulates the CCAAT enhancer binding protein beta and hepatic gluconeogenesis. Am J Physiol Endocrinol Metab. 2013;305:E1007-17 pubmed publisher
    Mice deficient for general control nondepressible-2 (Gcn2) either globally or specifically in the liver display reduced capacity to maintain glucose homeostasis during fasting, suggesting the hypothesis that GCN2 may regulate ..
  13. Lehman S, Cerniglia G, Johannes G, Ye J, Ryeom S, Koumenis C. Translational Upregulation of an Individual p21Cip1 Transcript Variant by GCN2 Regulates Cell Proliferation and Survival under Nutrient Stress. PLoS Genet. 2015;11:e1005212 pubmed publisher
    ..reporter assays, and polysome transcript profiling that activation of the Integrated Stress Response (ISR) kinase GCN2 selectively upregulates the translation of a p21 transcript variant containing 5' upstream open reading frames (..
  14. Kardos G, Wastyk H, Robertson G. Disruption of Proline Synthesis in Melanoma Inhibits Protein Production Mediated by the GCN2 Pathway. Mol Cancer Res. 2015;13:1408-20 pubmed publisher
    ..Mechanistically, targeting ALDH18A1 activated the serine/threonine protein kinase GCN2 (general control nonderepressible 2) to inhibit protein synthesis, which could be reversed with proline ..
  15. Sharma M, Hou D, Baban B, Koni P, He Y, Chandler P, et al. Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity. 2010;33:942-54 pubmed publisher
    ..Reprogrammed Treg cells can thus participate as previously unrecognized drivers of certain early CD8(+) T cell responses. ..
  16. Jack S, Chan S. The role of PERK and GCN2 in basal and hydrogen peroxide-regulated translation from the hepatitis C virus internal ribosome entry site. Virus Genes. 2011;43:208-14 pubmed publisher
    ..wild type and 'knockout' mouse embryonic fibroblasts (MEFs), we showed that two of the eIF2? kinases, PERK and GCN2, were not responsible for translational regulation under physiological and a higher apoptotic doses of H(2)O(2) (..
  17. He H, Singh I, Wek S, Dey S, Baird T, Wek R, et al. Crystal structures of GCN2 protein kinase C-terminal domains suggest regulatory differences in yeast and mammals. J Biol Chem. 2014;289:15023-34 pubmed publisher
    In response to amino acid starvation, GCN2 phosphorylation of eIF2 leads to repression of general translation and initiation of gene reprogramming that facilitates adaptation to nutrient stress...
  18. D Aniello C, Fico A, Casalino L, Guardiola O, Di Napoli G, Cermola F, et al. A novel autoregulatory loop between the Gcn2-Atf4 pathway and (L)-Proline [corrected] metabolism controls stem cell identity. Cell Death Differ. 2015;22:1094-105 pubmed publisher
    ..relies on a feedback loop that involves the non-essential amino acid L-Proline (L-Pro) in the modulation of the Gcn2-Eif2α-Atf4 amino acid starvation response (AAR) pathway that in turn regulates L-Pro biosynthesis...
  19. Yu J, Xiao F, Zhang Q, Liu B, Guo Y, Lv Z, et al. PRLR regulates hepatic insulin sensitivity in mice via STAT5. Diabetes. 2013;62:3103-13 pubmed publisher
    ..These results demonstrate a novel function for hepatic PRLR in the regulation of insulin sensitivity and provide important insights concerning the nutritional regulation of PRLR expression. ..
  20. Liu H, Huang L, Bradley J, Liu K, Bardhan K, Ron D, et al. GCN2-dependent metabolic stress is essential for endotoxemic cytokine induction and pathology. Mol Cell Biol. 2014;34:428-38 pubmed publisher
    ..In this report, we demonstrate that the stress response kinase GCN2 promotes macrophage inflammation and mortality in a mouse model of septicemia...
  21. Laeger T, Albarado D, Burke S, Trosclair L, Hedgepeth J, Berthoud H, et al. Metabolic Responses to Dietary Protein Restriction Require an Increase in FGF21 that Is Delayed by the Absence of GCN2. Cell Rep. 2016;16:707-16 pubmed publisher
    FGF21 contributes to the metabolic response to dietary protein restriction, and prior data implicate GCN2 as the amino acid sensor linking protein restriction to FGF21 induction...
  22. Ravindran R, Khan N, Nakaya H, Li S, Loebbermann J, Maddur M, et al. Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation. Science. 2014;343:313-317 pubmed publisher
    ..in humans have revealed that YF-17D-induced early expression of general control nonderepressible 2 kinase (GCN2) in the blood strongly correlates with the magnitude of the later CD8(+) T cell response...
  23. Cambiaghi T, Pereira C, Shanmugam R, Bolech M, Wek R, Sattlegger E, et al. Evolutionarily conserved IMPACT impairs various stress responses that require GCN1 for activating the eIF2 kinase GCN2. Biochem Biophys Res Commun. 2014;443:592-7 pubmed publisher
    ..The eIF2? kinase GCN2 is activated by amino acid starvation by a mechanism involving GCN2 binding to an activator protein GCN1, along ..
  24. Maurin A, Benani A, Lorsignol A, Brenachot X, Parry L, Carraro V, et al. Hypothalamic eIF2α signaling regulates food intake. Cell Rep. 2014;6:438-44 pubmed publisher
    ..In response to dietary amino acid deficiency, the brain-specific activation of the eIF2α kinase GCN2 leads to food intake inhibition...
  25. Devi L, Ohno M. Deletion of the eIF2? Kinase GCN2 fails to rescue the memory decline associated with Alzheimer's disease. PLoS ONE. 2013;8:e77335 pubmed publisher
    ..However, the underlying mechanisms remain unclear. Here, we crossed knockout mice for an eIF2? kinase (GCN2: general control nonderepressible-2 kinase) with 5XFAD transgenic mice, and investigated whether GCN2 deletion ..
  26. She P, Bunpo P, Cundiff J, Wek R, Harris R, Anthony T. General control nonderepressible 2 (GCN2) kinase protects oligodendrocytes and white matter during branched-chain amino acid deficiency in mice. J Biol Chem. 2013;288:31250-60 pubmed publisher
    ..acid deficiency, phosphorylation of eukaryotic initiation factor 2? (eIF2?P) by general control nonderepressible 2 (GCN2) activates the amino acid stress response...
  27. Muaddi H, Majumder M, Peidis P, Papadakis A, Holcik M, Scheuner D, et al. Phosphorylation of eIF2? at serine 51 is an important determinant of cell survival and adaptation to glucose deficiency. Mol Biol Cell. 2010;21:3220-31 pubmed publisher
    ..We also show that among the eIF2? kinases GCN2 plays a proapoptotic role whereas PERK and PKR play a cytoprotective one in response to glucose deficiency...
  28. Mazroui R, Di Marco S, Kaufman R, Gallouzi I. Inhibition of the ubiquitin-proteasome system induces stress granule formation. Mol Biol Cell. 2007;18:2603-18 pubmed
    ..the phosphorylation of the translation initiation factor eIF2alpha by a mechanism involving the stress kinase GCN2. On prolonged UPS inhibition and despite the maintenance of eIF2alpha phosphorylation, SGs disassemble and ..
  29. Peidis P, Papadakis A, Rajesh K, Koromilas A. HDAC pharmacological inhibition promotes cell death through the eIF2? kinases PKR and GCN2. Aging (Albany NY). 2010;2:669-77 pubmed
    ..our data indicate that eIF2? phosphorylation acts in a cytoprotective manner, whereas the eIF2? kinases PKR and GCN2 promote vorinostat-induced apoptosis...
  30. Vinay D, Kim C, Choi B, Kwon B. Origins and functional basis of regulatory CD11c+CD8+ T cells. Eur J Immunol. 2009;39:1552-63 pubmed publisher
    ..Thus, our data uncover, for the first time, the origin, development, and basis of the suppressive function of this novel CD11c(+)CD8(+) T-cell subpopulation that has many signature features of Treg. ..
  31. Peng W, Robertson L, Gallinetti J, Mejia P, Vose S, Charlip A, et al. Surgical stress resistance induced by single amino acid deprivation requires Gcn2 in mice. Sci Transl Med. 2012;4:118ra11 pubmed publisher
    ..interventions required the amino acid sensor and eIF2? (eukaryotic translation initiation factor 2?) kinase Gcn2 (general control nonderepressible 2), implicating the amino acid starvation response and translational control in ..
  32. Souza Fonseca Guimaraes F, Parlato M, de Oliveira R, Golenbock D, Fitzgerald K, Shalova I, et al. Interferon-? and granulocyte/monocyte colony-stimulating factor production by natural killer cells involves different signaling pathways and the adaptor stimulator of interferon genes (STING). J Biol Chem. 2013;288:10715-21 pubmed publisher
    ..Our study thereby allows us to gain insight into the mechanisms of synergy between accessory cytokines and CpG-ODN in NK cells. It also identifies a new and alternative signaling pathway for CpG-ODN in murine NK cells. ..
  33. Furuya S, Yoshida K, Kawakami Y, Yang J, Sayano T, Azuma N, et al. Inactivation of the 3-phosphoglycerate dehydrogenase gene in mice: changes in gene expression and associated regulatory networks resulting from serine deficiency. Funct Integr Genomics. 2008;8:235-49 pubmed publisher
    ..These observations suggest that Phgdh inactivation alters transcriptional programs in several regulatory networks. ..
  34. Won S, Eidenschenk C, Arnold C, Siggs O, Sun L, Brandl K, et al. Increased susceptibility to DNA virus infection in mice with a GCN2 mutation. J Virol. 2012;86:1802-8 pubmed publisher
    ..eIF2? phosphorylation is a cellular response to diverse stresses, including viral infection, and is mediated by the GCN2 kinase, protein kinase R (PKR), protein kinase-like endoplasmic reticulum kinase (PERK), and heme-regulated ..
  35. Lu W, László C, Miao Z, Chen H, Wu S. The role of nitric-oxide synthase in the regulation of UVB light-induced phosphorylation of the alpha subunit of eukaryotic initiation factor 2. J Biol Chem. 2009;284:24281-8 pubmed publisher
    ..protein kinase-like endoplasmic reticulum kinase (PERK) and general control of nonderepressible protein kinase 2 (GCN2), have been shown to phosphorylate eIF2alpha in response to UV irradiation...
  36. Loch D, Heidel C, Breer H, Strotmann J. Adiponectin enhances the responsiveness of the olfactory system. PLoS ONE. 2013;8:e75716 pubmed publisher
    ..The results of this study indicate that adiponectin increases the responsiveness of the olfactory system, probably due to a higher responsiveness of olfactory sensory neurons. ..
  37. Khoutorsky A, Sorge R, Prager Khoutorsky M, Pawlowski S, Longo G, Jafarnejad S, et al. eIF2? phosphorylation controls thermal nociception. Proc Natl Acad Sci U S A. 2016;113:11949-11954 pubmed
    ..Our results demonstrate that the cellular stress response pathway, mediated via p-eIF2?, represents a mechanism that could be used to alleviate pathological heat sensation. ..
  38. Keil M, Sonner J, Lanz T, Oezen I, Bunse T, Bittner S, et al. General control non-derepressible 2 (GCN2) in T cells controls disease progression of autoimmune neuroinflammation. J Neuroimmunol. 2016;297:117-26 pubmed publisher
    ..In an MS mouse model we show that the stress kinase general control non-derepressible 2 (GCN2),(4) expressed in T cells, contributes to the resolution of autoimmune neuroinflammation...
  39. Sharma M, Hou D, Liu Y, Koni P, Metz R, Chandler P, et al. Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood. 2009;113:6102-11 pubmed publisher
    ..IDO regulated this conversion by dominantly suppressing production of IL-6 in pDCs, in a GCN2-kinase dependent fashion...
  40. Ravindran R, Loebbermann J, Nakaya H, Khan N, Ma H, Gama L, et al. The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation. Nature. 2016;531:523-527 pubmed publisher
    ..General controlled non-repressed (GCN2) kinase is a key orchestrator of the ISR, and modulates protein synthesis in response to amino acid starvation...
  41. Leib D, Knight Z. Re-examination of Dietary Amino Acid Sensing Reveals a GCN2-Independent Mechanism. Cell Rep. 2015;13:1081-1089 pubmed publisher
    ..remarkable phenomenon is proposed to involve post-ingestive sensing of amino acid imbalance by the protein kinase GCN2 in the brain. Here, we systematically re-examine dietary amino acid sensing in mice...
  42. Sharma M, Baban B, Chandler P, Hou D, Singh N, Yagita H, et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest. 2007;117:2570-82 pubmed
    ..Treg activation by IDO+ pDCs was MHC restricted, required an intact amino acid-responsive GCN2 pathway in the Tregs, and was prevented by CTLA4 blockade...
  43. Roffe M, Hajj G, Azevedo H, Alves V, Castilho B. IMPACT is a developmentally regulated protein in neurons that opposes the eukaryotic initiation factor 2? kinase GCN2 in the modulation of neurite outgrowth. J Biol Chem. 2013;288:10860-9 pubmed publisher
    ..We have previously shown that IMPACT overexpression inhibits the activation of the protein kinase GCN2, which signals amino acid starvation...
  44. Cai Q, Brooks H. Phosphorylation of eIF2? via the general control kinase, GCN2, modulates the ability of renal medullary cells to survive high urea stress. Am J Physiol Renal Physiol. 2011;301:F1202-7 pubmed publisher
    ..occurs under many stress conditions in mammalian cells and is mediated by one of four eIF2? kinases: PERK, PKR, GCN2, and HRI...
  45. Li C, Wang L, Huang K, Zheng L. Endoplasmic reticulum stress in retinal vascular degeneration: protective role of resveratrol. Invest Ophthalmol Vis Sci. 2012;53:3241-9 pubmed publisher
    ..ER stress is an important contributor to vascular degeneration in retina. Resveratrol suppresses I/R injury and tunicamycin-induced vascular degeneration by inhibiting ER stress. ..
  46. Dang Do A, Kimball S, Cavener D, Jefferson L. eIF2alpha kinases GCN2 and PERK modulate transcription and translation of distinct sets of mRNAs in mouse liver. Physiol Genomics. 2009;38:328-41 pubmed publisher
    ..While there is only one known eIF2alpha kinase in yeast, general control nonderepressible 2 (GCN2), mammals have evolved to express at least four: GCN2, heme-regulated inhibitor kinase (HRI), double-stranded RNA-..
  47. Phillipson Weiner L, Mirek E, Wang Y, McAuliffe W, Wek R, Anthony T. General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice. Am J Physiol Gastrointest Liver Physiol. 2016;310:G1061-70 pubmed publisher
    ..In the liver of mice, eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2) is essential for mitigating metabolic stress caused by asparaginase...
  48. Cobbold S, Adams E, Farquhar C, Nolan K, Howie D, Lui K, et al. Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci U S A. 2009;106:12055-60 pubmed publisher
    ..Inhibition of the mTOR pathway by limiting EAAs, or by specific inhibitors, induces the Treg-specific transcription factor forkhead box P3, which depends on both T cell receptor activation and synergy with TGF-beta. ..
  49. Wilson G, Lennox B, She P, Mirek E, Al Baghdadi R, Fusakio M, et al. GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment. Am J Physiol Endocrinol Metab. 2015;308:E283-93 pubmed publisher
    ..in the liver by activating the eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2)...
  50. Fletcher M, Ramirez M, Sierra R, Raber P, Thevenot P, Al Khami A, et al. l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells. Cancer Res. 2015;75:275-83 pubmed publisher
    ..Taken together, our results highlight the risks of the l-Arg-depleting therapy for cancer treatment and suggest a need for cotargeting MDSC in such therapeutic settings. ..
  51. Munn D, Sharma M, Baban B, Harding H, Zhang Y, Ron D, et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity. 2005;22:633-42 pubmed
    ..We now show that IDO-expressing plasmacytoid DCs activate the GCN2 kinase pathway in responding T cells...
  52. Jiang H, Wek S, McGrath B, Lu D, Hai T, Harding H, et al. Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Mol Cell Biol. 2004;24:1365-77 pubmed
    ..reticulum (ER) stress or amino acid starvation by a mechanism requiring eIF2 kinases PEK (Perk or EIF2AK3) and GCN2 (EIF2AK4), respectively...
  53. Harputlugil E, Hine C, Vargas D, Robertson L, Manning B, Mitchell J. The TSC complex is required for the benefits of dietary protein restriction on stress resistance in vivo. Cell Rep. 2014;8:1160-70 pubmed publisher
    ..hepatic ischemia reperfusion injury to probe genetic requirements for the evolutionarily conserved nutrient sensors GCN2 and mTORC1 in stress resistance...
  54. Kraushar M, Thompson K, Wijeratne H, Viljetić B, Sakers K, Marson J, et al. Temporally defined neocortical translation and polysome assembly are determined by the RNA-binding protein Hu antigen R. Proc Natl Acad Sci U S A. 2014;111:E3815-24 pubmed publisher
    ..Our study identifies a crucial role for HuR in neocortical development as a translational gatekeeper for functionally related mRNA subgroups and polysomal protein specificity. ..
  55. Liu Y, László C, Liu Y, Liu W, Chen X, Evans S, et al. Regulation of G(1) arrest and apoptosis in hypoxia by PERK and GCN2-mediated eIF2alpha phosphorylation. Neoplasia. 2010;12:61-8 pubmed
    ..that another eIF2AK, the amino acid starvation-dependent general control of amino acid biosynthesis kinase (GCN2), is also involved in hypoxia-induced eIF2alpha phosphorylation...
  56. Manlapat A, Kahler D, Chandler P, Munn D, Mellor A. Cell-autonomous control of interferon type I expression by indoleamine 2,3-dioxygenase in regulatory CD19+ dendritic cells. Eur J Immunol. 2007;37:1064-71 pubmed
    ..Consistent with this, DC from mice deficient in general control of non-derepressible-2 (GCN2)-kinase, a component of the cellular stress response to amino acid withdrawal, did not produce IFN-alpha following ..
  57. Silva R, Sattlegger E, Castilho B. Perturbations in actin dynamics reconfigure protein complexes that modulate GCN2 activity and promote an eIF2 response. J Cell Sci. 2016;129:4521-4533 pubmed
    ..Here, we show that disruption of F-actin in mammalian cells inhibits translation in a GCN2-dependent manner, correlating with increased levels of uncharged tRNA...
  58. Sood R, Porter A, Olsen D, Cavener D, Wek R. A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2alpha. Genetics. 2000;154:787-801 pubmed
    ..Additionally, lysates prepared from yeast expressing mGCN2 were found to phosphorylate recombinant eIF-2alpha substrate...
  59. Nikonorova I, Al Baghdadi R, Mirek E, Wang Y, Goudie M, Wetstein B, et al. Obesity challenges the hepatoprotective function of the integrated stress response to asparaginase exposure in mice. J Biol Chem. 2017;292:6786-6798 pubmed publisher
    ..stress response (ISR) via sensing amino acid depletion by the eukaryotic initiation factor 2 (eIF2) kinase GCN2. The goal of this work was to discern the impact of obesity, alone versus alongside genetic disruption of ..
  60. Orsini H, Araujo L, Maricato J, Guereschi M, Mariano M, Castilho B, et al. GCN2 kinase plays an important role triggering the remission phase of experimental autoimmune encephalomyelitis (EAE) in mice. Brain Behav Immun. 2014;37:177-86 pubmed publisher
    ..Here we verified an important participation of the general control nonrepressible 2 (GCN2), a key regulator kinase of the amino-acid starvation response, in the development of the remission phase of EAE in ..
  61. Elefteriou F, Benson M, Sowa H, Starbuck M, Liu X, Ron D, et al. ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab. 2006;4:441-51 pubmed
    ..By showing that ATF4-dependent skeletal dysplasiae are treatable by dietary manipulations, this study reveals a molecular connection between nutrition and skeletal development...
  62. Ye J, Kumanova M, Hart L, Sloane K, Zhang H, De Panis D, et al. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J. 2010;29:2082-96 pubmed publisher
    ..stresses found in solid tumours, activated the upstream eukaryotic initiation factor 2alpha (eIF2alpha) kinase GCN2 to upregulate ATF4 target genes involved in amino acid synthesis and transport...
  63. Bunpo P, Cundiff J, Reinert R, Wek R, Aldrich C, Anthony T. The eIF2 kinase GCN2 is essential for the murine immune system to adapt to amino acid deprivation by asparaginase. J Nutr. 2010;140:2020-7 pubmed publisher
    ..ASNase) enhances phosphorylation of eukaryotic initiation factor 2 (eIF2) by general control nonderepressible 2 (GCN2) kinase, leading to reduced global mRNA translation rates...
  64. Nameki N, Yoneyama M, Koshiba S, Tochio N, Inoue M, Seki E, et al. Solution structure of the RWD domain of the mouse GCN2 protein. Protein Sci. 2004;13:2089-100 pubmed
    b>GCN2 is the alpha-subunit of the only translation initiation factor (eIF2alpha) kinase that appears in all eukaryotes...
  65. Baban B, Chandler P, Sharma M, Pihkala J, Koni P, Munn D, et al. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol. 2009;183:2475-83 pubmed publisher
    ..These findings support the hypothesis that IDO dominantly controls the functional status of Tregs in response to inflammatory stimuli in physiological settings. ..
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    ..and LP-induced serum FGF21 levels were reduced in mice lacking the eIF2? kinase general control nonderepressible 2 (GCN2)...
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    ..The WNT-induced reduction of glutamine concentration triggered a general control nonderepressible 2-mediated (GCN2-mediated) integrated stress response (ISR) that stimulated expression of genes responsible for amino acid supply, ..
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    ..This is particularly the case for dietary amino acids that are sensed by the protein kinase GCN2. It has been reported that GCN2 is involved in the adaptive response to amino acid imbalanced diets at the level of ..
  69. Ye J, Mancuso A, Tong X, Ward P, Fan J, Rabinowitz J, et al. Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Proc Natl Acad Sci U S A. 2012;109:6904-9 pubmed publisher
    ..of serine depletion depends on general control nonderepressible 2 kinase-activating transcription factor 4 (GCN2-ATF4) pathway activation and results in increased expression of enzymes required for serine synthesis from the ..
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    b>GCN2 is one of the four mammalian kinases that phosphorylate the alpha subunit of the translation initiation factor 2 (eIF2alpha) in a variety of stress situations, resulting in protein synthesis inhibition...
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    ..Furthermore, in myotubes, the GCN2 pathway is not activated by amino-acid starvation due to an amino-acid supply from intracellular proteolysis ..
  72. Iken K, Liu K, Liu H, Bizargity P, Wang L, Hancock W, et al. Indoleamine 2,3-dioxygenase and metabolites protect murine lung allografts and impair the calcium mobilization of T cells. Am J Respir Cell Mol Biol. 2012;47:405-16 pubmed publisher
    ..This work further illustrates the potential role of a high IDO environment in lung transplantation, and that the high IDO environment directly impairs TCR activation via the disruption of calcium signaling. ..
  73. Kumar R, Azam S, Sullivan J, Owen C, Cavener D, Zhang P, et al. Brain ischemia and reperfusion activates the eukaryotic initiation factor 2alpha kinase, PERK. J Neurochem. 2001;77:1418-21 pubmed
    ..in the genes encoding the heme-regulated eIF2alpha kinase (HRI), or the amino acid-regulated eIF2alpha kinase (GCN2). A 10-fold increase in eIF2alpha(P) was observed in reperfused wild-type mice and in the HRI-/- or GCN2-/- mice...
  74. Ravishankar B, Liu H, Shinde R, Chaudhary K, Xiao W, Bradley J, et al. The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity. Proc Natl Acad Sci U S A. 2015;112:10774-9 pubmed publisher
    ..The metabolic-stress sensing protein kinase GCN2 is a primary downstream effector of IDO1; thus, we tested its role in apoptotic cell-driven immune suppression...
  75. Averous J, Lambert Langlais S, Cherasse Y, Carraro V, Parry L, B chir W, et al. Amino acid deprivation regulates the stress-inducible gene p8 via the GCN2/ATF4 pathway. Biochem Biophys Res Commun. 2011;413:24-9 pubmed publisher
    In mammals, the GCN2/ATF4 pathway has been described as the main pathway involved in the regulation of gene expression upon amino acid limitation...
  76. Highfill S, Rodriguez P, Zhou Q, Goetz C, Koehn B, Veenstra R, et al. Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. Blood. 2010;116:5738-47 pubmed publisher
    ..MDSC-IL-13 and pegylated form of human arginase-1 represent novel strategies to prevent GVHD that can be clinically translated. ..
  77. Xu X, Hu J, McGrath B, Cavener D. GCN2 in the brain programs PPAR?2 and triglyceride storage in the liver during perinatal development in response to maternal dietary fat. PLoS ONE. 2013;8:e75917 pubmed publisher
    ..We found that the perinatal programming of adult hepatic triglyceride storage was controlled by the eIF2? kinase GCN2 (EIF2AK4) in the brain of the offspring, which stimulates epigenetic modification of the Ppar?2 gene in the ..