Last update: February 24, 2008
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EIF2 alpha kinases, ATF4 and EIF2B See this page for pathway

Backround information for :-

Carter C.J. Multiple genes and factors associated with bipolar disorder converge on growth factor and stress activated kinase pathways controlling translation initiation: Implications for oligodendrocyte viability. Neurochem Int 50, 461-490

...EIF2B and oligodendrocyte vulnerability: Where nature and nurture meet in Bipolar disorder and schizophrenia ? Schiz Bull.33,1343-1353. 2007

Enhanced links to genes are provided by

Diverse stressors activate a series of eif2-alpha kinases (EIF2AK 1-4; commonly known as HRI, PKR, PERK and GCN2). Phosphorylated eif2-alpha has two effects. It shuts down protein synthesis by inhibiting the translation initiation factor eif2b (see Biocarta EIF2 pathway) see Biocarta Terms and conditions) and Disclaimer and activates the transcription factor ATF4 Rutkowski and Kaufman, 2003, Wek et al, 2006. ATF4 activates nrf1(NFE2L1) nrf2 (NFE2L2) , herp (HERPUD1) and chop/gadd153 (DDIT3). Endoplasmic reticulum stress activates PERK, ATF6 and XBP1. The outputs of these pathways control the Unfolded Protein Response, or Integrated Stress Response Harding et al, 2003 Ma and Hendershot, 2003. The activators, partners and major downstream effects of these genes/proteins are summarised below, with particular reference to genes associated with Bipolar disorder or schizophrenia. These are highlighted in bold and superscripted B(bipolar) or S (schizophrenia). Entrez gene and OMIM links are provided.

These pathways are activated by the environmental risk factors associated with Schizophrenia or Bipolar disorder (famine (GCN2), viruses (PKR)). Toxoplasmosis, also a risk factor in schizophrenia (see Schizophrenia Forum ) activates Toll-like receptors Pubmed which input into this network via PKR Horng et al, 2001 (Biocarta Toll-like receptor pathway).


Activators and partners (Binding interactions are from Entrez gene data, unless specified)

Downstream effects

EIF2AK1 (HRI) eukaryotic translation initiation factor 2-alpha kinase 1

Activated by heme deficiency (cf HMBSS , nitric oxide (NOS1BS, NOS3 B) oxidative stress, arsenite and lead: inhibited by carbon monoxide (Yun et al. 2005;Sarkar et al. 2005) .

Phosphorylates EIF2alpha (EIF2S1,2 or3).

Important in alpha and beta globin protein synthesis in erythroid cells (Han et al. 2001).

EIF2AK2 (PKR) eukaryotic translation initiation factor 2-alpha kinase 2 OMIM


Activated by viral double-stranded DNA (measles, mumps, rubella, influenza, etc) (Russell 2002).  Activated by IL1B BS and TNF BS (Kaempfer 2003) (Williams 2001)and by interferons (Williams 1999). Binds to and phosphorylates TP53S (Cuddihy et al. 1999)

Phosphorylates EIF2alpha (EIF2S1,2 or3).

PKR activation leads to the production of inflammatory cytokines (IL1B BS and TNF BS ) (Williams 2001).

Interferon use is associated with bipolar symptoms and psychiatric disturbances (Greenberg et al. 2000;Constant et al. 2005) 

EIF2AK3 (PERK) eukaryotic translation initiation factor 2-alpha kinase 3 OMIM

Activated by endoplasmic reticulum stress which is promoted by problems in protein glycosylation, sorting folding, or degradation (Cullinan and Diehl 2006).  Binds to HSPA5B.  Activated by Herpes simplex(Cheng et al. 2005): Inhibited by Hepatitis C envelope protein (Pavio et al. 2003)

Phosphorylates EIF2alpha (EIF2S1,2 or3).

Phosphorylates and activates NFE2L2(Cullinan and Diehl 2005).

EIF2AK4 (GCN2) eukaryotic translation initiation factor 2-alpha kinase 4 OMIM

Activated by amino acid starvation (Hinnebusch 1994).

Phosphorylates EIF2alpha (EIF2S1,2 or3).

LTP is impaired in GCN2 knockout mice (Costa-Mattioli et al. 2005)

ATF4 Sactivating transcription factor 4 (CREB-2) OMIM

Downstream target of EIF2alpha kinase activation (Rutkowski and Kaufman 2003).  Binds to DISC1 BS, GABBR1 S, PTGS2 S and to NFE2L1, NFE2L2, inter alia.

Effects on oxidative defence, apoptosis, and chaperones are mediated via interactions with DDIT3, NFE2L1,2,  and HERPUD1.  Controls GCHI B expression.

ATF5 activating transcription factor 5 OMIM

Binds to DISC1 BS  and GABBR1 S

ATF5 plays an important role in the differentiation of neurones, astrocytes and oligodendrocytes (Angelastro et al. 2003;Angelastro et al. 2005;Mason et al. 2005).

NFE2L1 nuclear factor (erythroid-derived 2)-like 1 OMIM

 Binds to ATF4S

Overexpression increases cellular glutathione levels and transactivates the gamma-glutamylcysteine synthetase (GCS) heavy subunit promoter (Myhrstad et al. 2001). Controls TNF BS expression Novotny et al, 1998

NFE2L2 nuclear factor (erythroid-derived 2)-like 2 OMIM

Binds to ATF4: Phosphorylated and inhibited by GSK3B B (Salazar et al. 2006).  Phosphorylated and activated by perk (EIF2AK3) (Cullinan and Diehl 2005) . Effects suppressed by TP53S Faraonio et al, 2006

Controls the expression of glutathione and quinone-related genes (Lee et al. 2003b) and: -

Bipolar genes

BDNF BS, G6PD B (Lee et al. 2003b;Lee et al. 2003c)

Schizophrenia genes

BDNF BS, CHGB S, GABBR1 S, GCLM S,GSTM1 S,NQO2 S, (Lee et al. 2003b;Lee et al. 2003c) HMBS S (Johnsen et al. 1996)

DDIT3 DNA-damage-inducible transcript 3 (alias CEBPZ, CHOP, CHOP10, GADD153) OMIM

Activated by ATF4S (Wek et al. 2006)TP53 S binds to promoter.  Activated by NRG1 BS in epithelial cells and by NMDA receptorBS activation during hippocampal LTP (Matsuo et al. 2000).

Increased DDIT3 expression results in glutathione depletion, increased production of reactive oxygen species and downregulation of bcl2.(McCullough et al. 2001) Controls the expression of genes related to apoptosis, cell proliferation, adhesion, protein processing (proteasome), and SOD2 S expression (You et al. 2003)

HERPUD1 (Alias Herp, mif1) homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 OMIM

Activated by endoplasmic reticulum stress and other stressors (Ma and Hendershot 2004)

.Forms a complex with elements of the endoplasmic reticulum associated protein degradation pathway (ERAD) (see Biocarta) with a proposed role in ubiquitinylation and export of proteins from the endoplasmic reticulum ; These steps are necessary for the degradation of proteins by the proteasomal complex  (Schulze et al. 2005) .

Induced by homocysteine (Kokame et al. 2000), high levels of which have been associated with both biplar disorder and schizophrenia (Levine et al. 2005;Osher et al. 2004). (cf MTHFR BS).  Interacts with presenilins (Sai et al. 2002)which cleave the NRG1 BS receptor ERBB4 S (Sardi et al. 2006).

PPP1R15A(alias Gadd34) protein phosphatase 1, regulatory (inhibitor) subunit 15A

Activated by apoptotic stimuli including TNF BS. Inhibited by herpes simplex virus (Hollander et al. 2001)

Dephosphorylates EIF2alpha, a prerequisite for recovery from translational repression (Novoa et al. 2003)

ATF6 activating transcription factor 6 OMIM Activated by endoplasmic reticulum stress: released from the endoplasmic reticulum by HSPA5 B (Xu et al. 2005). Controls the expression of proteins concerned with protein folding, and molecular chaperones including HSPA5 B Okada et al, 2002

XBP1 BSX-box binding protein 1 OMIM

Activated by endoplasmic reticulum stress via ATF6, which is released from  the endoplasmic reticulum by HSPA5 B (Xu et al. 2005).

Controls the expression of ER resident proteins that regulate heat shock protein and chaperone activity and the endoplasmic reticulum associated degradation pathway (Lee et al. 2003a).

eIF2alpha and eIF2beta

 eIF2-alpha(3 subunits)

 Binding partners and other effects (from Entrez Gene Interaction summaries unless indicated)  Diseases
EIF2S1 eukaryotic translation initiation factor 2, subunit 1 alpha, 35kDa - Mutant mice become diabetic and obese on a high fat diet Scheuner et al, 2005: No Human disease OMIM
EIF2S2 eukaryotic translation initiation factor 2, subunit 2 beta, 38kDa Interacts with casein kinase 2 alpha (CSNK2A1) and beta (CSNK2B) and NCK1. No Human disease OMIM
EIF2S3 eukaryotic translation initiation factor 2, subunit 3 gamma, 52kDa Interacts with CTCF, H3F3A and METAP2METAP2 No Human disease OMIM

eIFf2beta (5 subunits form a multicomplex)

EIF2B1 eukaryotic translation initiation factor 2B, subunit 1 alpha, 26kDa

Binds to carboxy terminus of alpha (ADRA2A, ADRA2B, ADRA2C) and beta (ADRB2) adrenoceptors Klein et al, 1997

Vanishing White matter disease (OMIM) Mutations in any of these 5 subunits can provoke white matter lesions





EIF2B2 eukaryotic translation initiation factor 2B, subunit 2 beta, 39kDa Binds to NCK1 which is able to affect protein translation Kebache et al, 2002. NCK1 is an adaptor protein for growth factor signalling and aids in eIF2alpha dephosphorylation Latreille and Larose,2006
 EIF2B3 eukaryotic translation initiation factor 2B, subunit 3 gamma, 58kDa  EIF2B1-5 form a multicomplex
 EIF2B4 eukaryotic translation initiation factor 2B, subunit 4 delta, 67kDa  " "
EIF2B5 eukaryotic translation initiation factor 2B, subunit 5 epsilon, 82kDa

Phosphorylated by GSK3B B casein kinase 1 and casein kinase 2 Wang et al, 2001


Reference List

Angelastro J. M., Ignatova T. N., Kukekov V. G., Steindler D. A., Stengren G. B., Mendelsohn C., and Greene L. A. (2003) Regulated expression of ATF5 is required for the progression of neural progenitor cells to neurons. J Neurosci 23, 4590-4600.

Angelastro J. M., Mason J. L., Ignatova T. N., Kukekov V. G., Stengren G. B., Goldman J. E., and Greene L. A. (2005) Downregulation of activating transcription factor 5 is required for differentiation of neural progenitor cells into astrocytes. J Neurosci 25, 3889-3899.

Cheng G., Feng Z., and He B. (2005) Herpes simplex virus 1 infection activates the endoplasmic reticulum resident kinase PERK and mediates eIF-2alpha dephosphorylation by the gamma(1)34.5 protein. J Virol  79, 1379-1388.

Constant A., Castera L., Dantzer R., Couzigou P., de L., V, Demotes-Mainard J., and Henry C. (2005) Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. J Clin Psychiatry 66, 1050-1057.

Costa-Mattioli M., Gobert D., Harding H., Herdy B., Azzi M., Bruno M., Bidinosti M., Ben Mamou C., Marcinkiewicz E., Yoshida M., Imataka H., Cuello A. C., Seidah N., Sossin W., Lacaille J. C., Ron D., Nader K., and Sonenberg N. (2005) Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature 436, 1166-1173.

Cuddihy A. R., Wong A. H., Tam N. W., Li S., and Koromilas A. E. (1999) The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro. Oncogene 18, 2690-2702.

Cullinan S. B. and Diehl J. A. (2005) Coordination of ER and oxidative stress signaling: The PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol.

Cullinan S. B. and Diehl J. A. (2006) Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol 38, 317-332.

Greenberg D. B., Jonasch E., Gadd M. A., Ryan B. F., Everett J. R., Sober A. J., Mihm M. A., Tanabe K. K., Ott M., and Haluska F. G. (2000) Adjuvant therapy of melanoma with interferon-alpha-2b is associated with mania and bipolar syndromes. Cancer 89, 356-362.

Han A. P., Yu C., Lu L., Fujiwara Y., Browne C., Chin G., Fleming M., Leboulch P., Orkin S. H., and Chen J. J. (2001) Heme-regulated eIF2alpha kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency. EMBO J 20, 6909-6918.

Hinnebusch A. G. (1994) The eIF-2 alpha kinases: regulators of protein synthesis in starvation and stress. Semin Cell Biol 5, 417-426.

Hollander M. C., Sheikh M. S., Yu K., Zhan Q., Iglesias M., Woodworth C., and Fornace A. J., Jr. (2001) Activation of Gadd34 by diverse apoptotic signals and suppression of its growth inhibitory effects by apoptotic inhibitors. Int J Cancer 96, 22-31.

Johnsen O., Skammelsrud N., Luna L., Nishizawa M., Prydz H., and Kolsto A. B. (1996) Small Maf proteins interact with the human transcription factor TCF11/Nrf1/LCR-F1. Nucleic Acids Res 24, 4289-4297.

Kaempfer R. (2003) RNA sensors: novel regulators of gene expression. EMBO Rep 4, 1043-1047.

Kokame K., Agarwala K. L., Kato H., and Miyata T. (2000) Herp, a new ubiquitin-like membrane protein induced by endoplasmic reticulum stress. J Biol Chem 275, 32846-32853.

Lee A. H., Iwakoshi N. N., and Glimcher L. H. (2003a) XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 23, 7448-7459.

Lee J. M., Calkins M. J., Chan K., Kan Y. W., and Johnson J. A. (2003b) Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol Chem 278, 12029-12038.

Lee J. M., Shih A. Y., Murphy T. H., and Johnson J. A. (2003c) NF-E2-related factor-2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons. J Biol Chem 278, 37948-37956.

Levine J., Sela B. A., Osher Y., and Belmaker R. H. (2005) High homocysteine serum levels in young male schizophrenia and bipolar patients and in an animal model. Prog Neuropsychopharmacol Biol Psychiatry  29, 1181-1191.

Ma Y. and Hendershot L. M. (2004) Herp is dually regulated by both the endoplasmic reticulum stress-specific branch of the unfolded protein response and a branch that is shared with other cellular stress pathways. J Biol Chem 279, 13792-13799.

Mason J. L., Angelastro J. M., Ignatova T. N., Kukekov V. G., Lin G., Greene L. A., and Goldman J. E. (2005) ATF5 regulates the proliferation and differentiation of oligodendrocytes. Mol Cell Neurosci 29, 372-380.

Matsuo R., Murayama A., Saitoh Y., Sakaki Y., and Inokuchi K. (2000) Identification and cataloging of genes induced by long-lasting long-term potentiation in awake rats. J Neurochem 74, 2239-2249.

McCullough K. D., Martindale J. L., Klotz L. O., Aw T. Y., and Holbrook N. J. (2001) Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21, 1249-1259.

Myhrstad M. C., Husberg C., Murphy P., Nordstrom O., Blomhoff R., Moskaug J. O., and Kolsto A. B. (2001) TCF11/Nrf1 overexpression increases the intracellular glutathione level and can transactivate the gamma-glutamylcysteine synthetase (GCS) heavy subunit promoter. Biochim Biophys Acta 1517, 212-219.

Novoa I., Zhang Y., Zeng H., Jungreis R., Harding H. P., and Ron D. (2003) Stress-induced gene expression requires programmed recovery from translational repression. EMBO J 22, 1180-1187.

Osher Y., Sela B. A., Levine J., and Belmaker R. H. (2004) Elevated homocysteine levels in euthymic bipolar disorder patients showing functional deterioration. Bipolar Disord 6, 82-86.

Pavio N., Romano P. R., Graczyk T. M., Feinstone S. M., and Taylor D. R. (2003) Protein synthesis and endoplasmic reticulum stress can be modulated by the hepatitis C virus envelope protein E2 through the eukaryotic initiation factor 2alpha kinase PERK. J Virol 77, 3578-3585.

Russell S. J. (2002) RNA viruses as virotherapy agents.  Cancer Gene Ther 9, 961-966.

Rutkowski D. T. and Kaufman R. J. (2003) All roads lead to ATF4. Dev Cell 4, 442-444.

Sai X., Kawamura Y., Kokame K., Yamaguchi H., Shiraishi H., Suzuki R., Suzuki T., Kawaichi M., Miyata T., Kitamura T., De Strooper B., Yanagisawa K., and Komano H. (2002) Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid beta-protein. J Biol Chem 277, 12915-12920.

Salazar M., Rojo A. I., Velasco D., de Sagarra R. M., and Cuadrado A. (2006) Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2. J Biol Chem 281, 14841-14851.

Sardi S. P., Murtie J., Koirala S., Patten B. A., and Corfas G. (2006) Presenilin-Dependent ErbB4 Nuclear Signaling Regulates the Timing of Astrogenesis in the Developing Brain. Cell 127, 185-197.

Sarkar A., Kulkarni A., Chattopadhyay S., Mogare D., Sharma K. K., Singh K., and Pal J. K. (2005) Lead-induced upregulation of the heme-regulated eukaryotic initiation factor 2alpha kinase is compromised by hemin in human K562 cells. Biochim Biophys Acta 1732, 15-22.

Schulze A., Standera S., Buerger E., Kikkert M., van Voorden S., Wiertz E., Koning F., Kloetzel P. M., and Seeger M. (2005) The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway. J Mol Biol 354, 1021-1027.

Wek R. C., Jiang H. Y., and Anthony T. G. (2006) Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans 34, 7-11.

Williams B. R. (1999) PKR; a sentinel kinase for cellular stress. Oncogene 18, 6112-6120.

Williams B. R. (2001) Signal integration via PKR. Sci STKE 2001, RE2.

Xu C., Bailly-Maitre B., and Reed J. C. (2005) Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 115, 2656-2664.

You K. R., Liu M. J., Han X. J., Lee Z. W., and Kim D. G. (2003) Transcriptional regulation of the human transferrin gene by GADD153 in hepatoma cells. Hepatology 38, 745-755.

Yun B. G., Matts J. A., and Matts R. L. (2005) Interdomain interactions regulate the activation of the heme-regulated eIF 2 alpha kinase. Biochim Biophys Acta 1725, 174-181.

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