eukaryotic initiation factor 2b

Summary

Summary: A guanine nucleotide exchange factor that acts to restore EUKARYOTIC INITIATION FACTOR-2 to its GTP bound form.

Top Publications

  1. Boesen T, Mohammad S, Pavitt G, Andersen G. Structure of the catalytic fragment of translation initiation factor 2B and identification of a critically important catalytic residue. J Biol Chem. 2004;279:10584-92 pubmed
  2. Fogli A, Schiffmann R, Hugendubler L, Combes P, Bertini E, Rodriguez D, et al. Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients. Eur J Hum Genet. 2004;12:561-6 pubmed
    ..This relevant cellular model may also be used to test the functional impact of different molecules on the GEF activity for future therapeutic strategies. ..
  3. Fogli A, Wong K, Eymard Pierre E, Wenger J, Bouffard J, Goldin E, et al. Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus. Ann Neurol. 2002;52:506-10 pubmed
    ..In three patients of two Cree families, we found a homozygous missense mutation resulting in a histidine substitution at arginine 195 of epsilon-eIF2B. ..
  4. Fogli A, Schiffmann R, Bertini E, Ughetto S, Combes P, Eymard Pierre E, et al. The effect of genotype on the natural history of eIF2B-related leukodystrophies. Neurology. 2004;62:1509-17 pubmed
    ..The degree of eIF2B dysfunction, which is involved in the regulation of protein synthesis during cellular stress, may play a role in the clinical expression of eIF2B-related disorders. ..
  5. Leegwater P, Vermeulen G, Könst A, Naidu S, Mulders J, Visser A, et al. Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat Genet. 2001;29:383-8 pubmed
    ..Mutant translation initiation factors have not previously been implicated in disease. ..
  6. Wang X, Paulin F, Campbell L, Gomez E, O brien K, Morrice N, et al. Eukaryotic initiation factor 2B: identification of multiple phosphorylation sites in the epsilon-subunit and their functions in vivo. EMBO J. 2001;20:4349-59 pubmed
    ..The fifth site, which lies outside the catalytic domain of eIF2Bepsilon, can be phosphorylated by casein kinase 1. All five sites are phosphorylated in the eIF2B complex in vivo. ..
  7. Kimball S, Heinzinger N, Horetsky R, Jefferson L. Identification of interprotein interactions between the subunits of eukaryotic initiation factors eIF2 and eIF2B. J Biol Chem. 1998;273:3039-44 pubmed
  8. Miyamoto S, Kimball S, Safer B. Signal transduction pathways that contribute to increased protein synthesis during T-cell activation. Biochim Biophys Acta. 2000;1494:28-42 pubmed
  9. Ashe M, Slaven J, De Long S, Ibrahimo S, Sachs A. A novel eIF2B-dependent mechanism of translational control in yeast as a response to fusel alcohols. EMBO J. 2001;20:6464-74 pubmed
    ..This represents one of the key limiting steps of translation initiation and we provide evidence that fusel alcohols target eIF2B in order to bring about translational regulation...

More Information

Publications62

  1. Schiffmann R, Elroy Stein O. Childhood ataxia with CNS hypomyelination/vanishing white matter disease--a common leukodystrophy caused by abnormal control of protein synthesis. Mol Genet Metab. 2006;88:7-15 pubmed
    Mutations in eukaryotic initiation factor 2B (eIF2B) cause one of the most common leukodystrophies, childhood ataxia with CNS hypomyelination/vanishing white matter disease or CACH/VWM...
  2. Webb B, Proud C. Eukaryotic initiation factor 2B (eIF2B). Int J Biochem Cell Biol. 1997;29:1127-31 pubmed
    b>Eukaryotic initiation factor 2B (eIF2B) is a guanine nucleotide-exchange factor which mediates the exchange of GDP (bound to initiation factor eIF2) for GTP, thus regenerating the active [eIF2...
  3. Mohammad Qureshi S, Haddad R, Hemingway E, Richardson J, Pavitt G. Critical contacts between the eukaryotic initiation factor 2B (eIF2B) catalytic domain and both eIF2beta and -2gamma mediate guanine nucleotide exchange. Mol Cell Biol. 2007;27:5225-34 pubmed
    ..One of the most complicated pairs is eukaryotic initiation factor 2B (eIF2B) and eIF2, which function during protein synthesis initiation in eukaryotes...
  4. Jefferson L, Fabian J, Kimball S. Glycogen synthase kinase-3 is the predominant insulin-regulated eukaryotic initiation factor 2B kinase in skeletal muscle. Int J Biochem Cell Biol. 1999;31:191-200 pubmed
    ..Thus, insulin-mediated changes in eIF2B activity are likely to involve GSK-3. ..
  5. Hardt S, Tomita H, Katus H, Sadoshima J. Phosphorylation of eukaryotic translation initiation factor 2Bepsilon by glycogen synthase kinase-3beta regulates beta-adrenergic cardiac myocyte hypertrophy. Circ Res. 2004;94:926-35 pubmed
  6. Smirnova J, Selley J, Sanchez Cabo F, Carroll K, Eddy A, McCarthy J, et al. Global gene expression profiling reveals widespread yet distinctive translational responses to different eukaryotic translation initiation factor 2B-targeting stress pathways. Mol Cell Biol. 2005;25:9340-9 pubmed
    ..The transcriptional regulation of these genes has recently been connected to the regulation of cellular proliferation, and on the basis of our results, the translational control of these mRNAs should be factored into this equation. ..
  7. Dever T, Chen J, Barber G, Cigan A, Feng L, Donahue T, et al. Mammalian eukaryotic initiation factor 2 alpha kinases functionally substitute for GCN2 protein kinase in the GCN4 translational control mechanism of yeast. Proc Natl Acad Sci U S A. 1993;90:4616-20 pubmed
    ..These results also suggest that GCN4 translational control will be a good model system to study how mammalian eIF-2 alpha kinases are modulated by environmental signals and viral regulatory factors. ..
  8. Kantor L, Harding H, Ron D, Schiffmann R, Kaneski C, Kimball S, et al. Heightened stress response in primary fibroblasts expressing mutant eIF2B genes from CACH/VWM leukodystrophy patients. Hum Genet. 2005;118:99-106 pubmed
    ..vanishing white matter (VWM) leukoencephalopathy, is a fatal genetic disease caused by mutations in eukaryotic initiation factor 2B (eIF2B) genes...
  9. Palmer L, Shoemaker J, Baptiste B, Wolfe D, Keil R. Inhibition of translation initiation by volatile anesthetics involves nutrient-sensitive GCN-independent and -dependent processes in yeast. Mol Biol Cell. 2005;16:3727-39 pubmed
    ..The maintenance phase is GCN-dependent and requires inhibition of general translation imparted by enhanced eIF2alpha phosphorylation. Surprisingly, as shown here, the transcription activator Gcn4p does not affect anesthetic response. ..
  10. Proud C. eIF2 and the control of cell physiology. Semin Cell Dev Biol. 2005;16:3-12 pubmed
  11. Wang X, Proud C. A novel mechanism for the control of translation initiation by amino acids, mediated by phosphorylation of eukaryotic initiation factor 2B. Mol Cell Biol. 2008;28:1429-42 pubmed
    b>Eukaryotic initiation factor 2B (eIF2B) plays a key role in controlling the initiation of mRNA translation. eIF2B is heteropentamer whose catalytic (epsilon) subunit promotes GDP/GTP exchange on eIF2...
  12. Campbell S, Ashe M. Localization of the translational guanine nucleotide exchange factor eIF2B: a common theme for GEFs?. Cell Cycle. 2006;5:678-80 pubmed
    The eukaryotic initiation factor 2B (eIF2B) serves an essential recycling function in protein synthesis...
  13. van der Knaap M, van Berkel C, Herms J, Van Coster R, Baethmann M, Naidu S, et al. eIF2B-related disorders: antenatal onset and involvement of multiple organs. Am J Hum Genet. 2003;73:1199-207 pubmed
  14. Bushman J, Asuru A, Matts R, Hinnebusch A. Evidence that GCD6 and GCD7, translational regulators of GCN4, are subunits of the guanine nucleotide exchange factor for eIF-2 in Saccharomyces cerevisiae. Mol Cell Biol. 1993;13:1920-32 pubmed
    ..Together, our results provide evidence that GCD6 and GCD7 are subunits of eIF-2B in S. cerevisiae and further implicate this GDP-GTP exchange factor in gene-specific translational control. ..
  15. Pap M, Cooper G. Role of translation initiation factor 2B in control of cell survival by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta signaling pathway. Mol Cell Biol. 2002;22:578-86 pubmed
    ..Regulation of translation resulting from phosphorylation of eIF2B by GSK-3beta thus appears to contribute to the control of cell survival by the PI 3-kinase/Akt signaling pathway, acting upstream of mitochondrial cytochrome c release. ..
  16. Scali O, Di Perri C, Federico A. The spectrum of mutations for the diagnosis of vanishing white matter disease. Neurol Sci. 2006;27:271-7 pubmed
    ..In the present paper we summarise the up-to-date knowledge about VWM and include the full list of known mutations. ..
  17. Pavitt G. eIF2B, a mediator of general and gene-specific translational control. Biochem Soc Trans. 2005;33:1487-92 pubmed
    eIF2B (eukaryotic initiation factor 2B) is a multisubunit protein that is required for protein synthesis initiation and its regulation in all eukaryotic cells...
  18. Gomez E, Pavitt G. Identification of domains and residues within the epsilon subunit of eukaryotic translation initiation factor 2B (eIF2Bepsilon) required for guanine nucleotide exchange reveals a novel activation function promoted by eIF2B complex formation. Mol Cell Biol. 2000;20:3965-76 pubmed
    ..This suggests that the N-terminal region of eIF2Bepsilon is an activation domain that responds to eIF2B complex formation. ..
  19. Pavitt G, Ramaiah K, Kimball S, Hinnebusch A. eIF2 independently binds two distinct eIF2B subcomplexes that catalyze and regulate guanine-nucleotide exchange. Genes Dev. 1998;12:514-26 pubmed
  20. Li W, Wang X, van der Knaap M, Proud C. Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways. Mol Cell Biol. 2004;24:3295-306 pubmed
    ..human neurodegenerative disorder that is caused by mutations in the genes for the subunits of eukaryotic initiation factor 2B (eIF2B), a heteropentameric guanine nucleotide exchange factor that regulates both global and mRNA-..
  21. Singh C, Lee B, Udagawa T, Mohammad Qureshi S, Yamamoto Y, Pavitt G, et al. An eIF5/eIF2 complex antagonizes guanine nucleotide exchange by eIF2B during translation initiation. EMBO J. 2006;25:4537-46 pubmed
    ..We propose that the eIF2/eIF5 complex represents a cytoplasmic reservoir for eIF2 that antagonizes eIF2B-promoted guanine nucleotide exchange, enabling coordinated regulation of translation initiation. ..
  22. Horzinski L, Huyghe A, Cardoso M, Gonthier C, Ouchchane L, Schiffmann R, et al. Eukaryotic initiation factor 2B (eIF2B) GEF activity as a diagnostic tool for EIF2B-related disorders. PLoS ONE. 2009;4:e8318 pubmed publisher
    In recent years, the phenotypes of leukodystrophies linked to mutations in the eukaryotic initiation factor 2B genes have been extended, classically called CACH/VWM (Childhood ataxia with cntral hypomyélination/vanishing white matter ..
  23. Richardson J, Mohammad S, Pavitt G. Mutations causing childhood ataxia with central nervous system hypomyelination reduce eukaryotic initiation factor 2B complex formation and activity. Mol Cell Biol. 2004;24:2352-63 pubmed
    ..or vanishing white matter leukoencephalopathy (VWM), is a fatal brain disorder caused by mutations in eukaryotic initiation factor 2B (eIF2B)...
  24. Krishnamoorthy T, Pavitt G, Zhang F, Dever T, Hinnebusch A. Tight binding of the phosphorylated alpha subunit of initiation factor 2 (eIF2alpha) to the regulatory subunits of guanine nucleotide exchange factor eIF2B is required for inhibition of translation initiation. Mol Cell Biol. 2001;21:5018-30 pubmed
    ..We propose that this regulatory interaction prevents association of the eIF2B catalytic subcomplex with the beta and gamma subunits of eIF2 in the manner required for GDP-GTP exchange. ..
  25. Labauge P, Horzinski L, Ayrignac X, Blanc P, Vukusic S, Rodriguez D, et al. Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases. Brain. 2009;132:2161-9 pubmed publisher
    Mutations in one of the five eukaryotic initiation factor 2B genes (EIF2B1-5) were first described in childhood ataxia with cerebral hypomyelination--vanishing white matter syndrome...
  26. van der Knaap M, Pronk J, Scheper G. Vanishing white matter disease. Lancet Neurol. 2006;5:413-23 pubmed
    ..Recently, undue activation of the unfolded-protein response has emerged as important in the pathophysiology of VWM, but the selective vulnerability of glia for defects in eIF2B is poorly understood. ..
  27. Kleijn M, Proud C. Glucose and amino acids modulate translation factor activation by growth factors in PC12 cells. Biochem J. 2000;347:399-406 pubmed
    ..Thus the ERK pathway plays a key role in the regulation of protein synthesis in PC12 cells. ..
  28. Hannig E, Hinnebusch A. Molecular analysis of GCN3, a translational activator of GCN4: evidence for posttranslational control of GCN3 regulatory function. Mol Cell Biol. 1988;8:4808-20 pubmed
  29. Vanderver A, Hathout Y, Maletkovic J, Gordon E, Mintz M, Timmons M, et al. Sensitivity and specificity of decreased CSF asialotransferrin for eIF2B-related disorder. Neurology. 2008;70:2226-32 pubmed publisher
    ..This rapid (<48 hours) and inexpensive diagnostic tool for eIF2B-related disorders has the potential to identify patients with likely eIF2B-related disorder for mutation analysis. ..
  30. Welsh G, Miyamoto S, Price N, Safer B, Proud C. T-cell activation leads to rapid stimulation of translation initiation factor eIF2B and inactivation of glycogen synthase kinase-3. J Biol Chem. 1996;271:11410-3 pubmed
    ..Since phosphorylation of eIF2B by GSK-3 appears to inhibit nucleotide exchange in vitro, this provides a potential mechanism by which eIF2B may be activated. ..
  31. Yang W, Hinnebusch A. Identification of a regulatory subcomplex in the guanine nucleotide exchange factor eIF2B that mediates inhibition by phosphorylated eIF2. Mol Cell Biol. 1996;16:6603-16 pubmed
    ..Together, our results provide strong evidence that GCN3, GCD7, and the C-terminal half of GCD2 comprise the regulatory domain in eIF2B. ..
  32. Pavitt G, Yang W, Hinnebusch A. Homologous segments in three subunits of the guanine nucleotide exchange factor eIF2B mediate translational regulation by phosphorylation of eIF2. Mol Cell Biol. 1997;17:1298-313 pubmed
    ..Most of the eIF2 is phosphorylated in certain mutants, suggesting that these substitutions allow eIF2B to accept phosphorylated eIF2 as a substrate for nucleotide exchange. ..
  33. Nika J, Yang W, Pavitt G, Hinnebusch A, Hannig E. Purification and kinetic analysis of eIF2B from Saccharomyces cerevisiae. J Biol Chem. 2000;275:26011-7 pubmed
    ..In support of this model, our yeast eIF2B preparations bind guanine nucleotides, with an apparent dissociation constant for GTP in the low micromolar range. ..
  34. Kleijn M, Proud C. The activation of eukaryotic initiation factor (eIF)2B by growth factors in PC12 cells requires MEK/ERK signalling. FEBS Lett. 2000;476:262-5 pubmed
    ..Thus, the EGF- and NGF-induced activation of eIF2B in PC12 cells involves regulatory mechanisms distinct from dephosphorylation of the GSK-3 site. ..
  35. van der Knaap M, Leegwater P, Könst A, Visser A, Naidu S, Oudejans C, et al. Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann Neurol. 2002;51:264-70 pubmed
    ..A defect in eIF2B may explain the sensitivity to stress factors in vanishing white matter patients. ..
  36. Campbell S, Hoyle N, Ashe M. Dynamic cycling of eIF2 through a large eIF2B-containing cytoplasmic body: implications for translation control. J Cell Biol. 2005;170:925-34 pubmed
    ..A focused core of eIF2B guanine nucleotide exchange might allow either greater activity or control of this elementary conserved step in the translation pathway. ..
  37. Mohammad Qureshi S, Jennings M, Pavitt G. Clues to the mechanism of action of eIF2B, the guanine-nucleotide-exchange factor for translation initiation. Biochem Soc Trans. 2008;36:658-64 pubmed publisher
  38. Federico A, Scali O, Stromillo M, Di Perri C, Bianchi S, Sicurelli F, et al. Peripheral neuropathy in vanishing white matter disease with a novel EIF2B5 mutation. Neurology. 2006;67:353-5 pubmed
    ..Sequence analysis of EIF2B5 gene showed that the patient was a double heterozygote, with novel missense mutation CGA-->CAA in codon 269 of exon 6, resulting in the replacement of an arginine residue with glutamine. ..
  39. Llorens F, Roher N, Miro F, Sarno S, Ruiz F, Meggio F, et al. Eukaryotic translation-initiation factor eIF2beta binds to protein kinase CK2: effects on CK2alpha activity. Biochem J. 2003;375:623-31 pubmed
    ..The results demonstrate that the ability to associate with CK2 subunits and to serve as a CK2 substrate are confined to different regions in eIF2beta and that it may act as an inhibitor on CK2alpha. ..
  40. Fogli A, Rodriguez D, Eymard Pierre E, Boespflug Tanguy O. [eIF2B and Cree Indian leukodystrophies]. Med Sci (Paris). 2003;19:283-4 pubmed
  41. Hinnebusch A. A hierarchy of trans-acting factors modulates translation of an activator of amino acid biosynthetic genes in Saccharomyces cerevisiae. Mol Cell Biol. 1985;5:2349-60 pubmed
    ..The effects of the trans-acting mutations on the translation of GCN4-lacZ mRNA remained intact even when transcription of the fusion gene was placed under the control of the S. cerevisiae GAL1 transcriptional control element. ..
  42. Gaudiano C, Di Perri C, Scali O, Rufa A, Battisti C, De Stefano N, et al. A case of ovarioleukodystrophy without eIF2B mutations. J Neurol Sci. 2008;268:183-6 pubmed
    ..We describe here a case suggestive of ovarioleukodistrophy carrying no eIF2B mutations. ..
  43. Lang C, Frost R, Nairn A, MacLean D, Vary T. TNF-alpha impairs heart and skeletal muscle protein synthesis by altering translation initiation. Am J Physiol Endocrinol Metab. 2002;282:E336-47 pubmed
  44. Meier K, Deloche O, Kajiwara K, Funato K, Riezman H. Sphingoid base is required for translation initiation during heat stress in Saccharomyces cerevisiae. Mol Biol Cell. 2006;17:1164-75 pubmed
    ..Taken together, we have shown a requirement for sphingoid bases during the recovery from heat shock and suggest that this reflects a direct lipid-dependent signal to the cap-dependent translation initiation apparatus. ..
  45. Bourdelas A, Li H, Boucaut J, Shi D. Identification of distinct genes with restricted expression in the somitic mesoderm in Xenopus embryo. Gene Expr Patterns. 2004;4:695-9 pubmed
    ..This study thus reveals an unexpected dynamic expression pattern for various genes with distinct function in vertebrates. ..
  46. Matsui M, Mizutani K, Ohtake H, Miki Y, Ishizu K, Fukuyama H, et al. Novel mutation in EIF2B gene in a case of adult-onset leukoencephalopathy with vanishing white matter. Eur Neurol. 2007;57:57-8 pubmed
  47. Bosetti F, Seemann R, Rapoport S. Chronic lithium chloride administration to rats decreases brain protein level of epsilon (epsilon) subunit of eukaryotic initiation factor-2B. Neurosci Lett. 2002;327:71-3 pubmed
    ..01) in LiCl-fed rats, 0.86+/-0.06 (SE) compared to 1.2+/-0.07 in control rats. These results suggest that a therapeutic level of lithium may downregulate the synthesis of proteins whose translation depends on eIF-2B. ..
  48. Bush J, Kimball S, O Connor P, Suryawan A, Orellana R, Nguyen H, et al. Translational control of protein synthesis in muscle and liver of growth hormone-treated pigs. Endocrinology. 2003;144:1273-83 pubmed
    ..The results further indicate that the GH-induced protein synthetic response is dependent upon nutritional state and is tissue specific. ..
  49. Mueller P, Grueter P, Hinnebusch A, Trachsel H. A ribosomal protein is required for translational regulation of GCN4 mRNA. Evidence for involvement of the ribosome in eIF2 recycling. J Biol Chem. 1998;273:32870-7 pubmed
  50. Elde N, Child S, Geballe A, Malik H. Protein kinase R reveals an evolutionary model for defeating viral mimicry. Nature. 2009;457:485-9 pubmed publisher
  51. Sprinzak E, Cokus S, Yeates T, Eisenberg D, Pellegrini M. Detecting coordinated regulation of multi-protein complexes using logic analysis of gene expression. BMC Syst Biol. 2009;3:115 pubmed publisher
    ..In this network we find that all multi-protein complexes that belong to the same functional class are regulated in the same direction as a group (either induced or repressed). ..
  52. Davis T, Nguyen H, Suryawan A, Bush J, Jefferson L, Kimball S. Developmental changes in the feeding-induced stimulation of translation initiation in muscle of neonatal pigs. Am J Physiol Endocrinol Metab. 2000;279:E1226-34 pubmed
    ..The results further suggest that the overall developmental decline in skeletal muscle protein synthesis involves regulation by eIF2B...
  53. Salvi M, Sarno S, Marin O, Meggio F, Itarte E, Pinna L. Discrimination between the activity of protein kinase CK2 holoenzyme and its catalytic subunits. FEBS Lett. 2006;580:3948-52 pubmed
    ..Transfection with individual subunits moreover does not give rise to holoenzyme formation unless the catalytic and regulatory subunits are co-transfected together, arguing against the existence of free subunits in CHO cells. ..