Search results for EIF2S1

Showing 15 results out of 19

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Protein (2 results from a total of 2)

Identifier: R-HSA-72510
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: P05198
Identifier: R-HSA-381060
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: EIF2S1: P05198

Reaction (6 results from a total of 10)

Identifier: R-HSA-9648888
Species: Homo sapiens
Compartment: cytosol
Phosphorylated EIF2AK1 phosphorylates EIF2S1 (eIF2-alpha) on serine-52 (homologous to serine-51 of the rabbit homologue) (inferred from rabbit and mouse homologs). Phosphothreonine 488 (homologous to phosphothreonine-485 of the mouse homolog) of EIF2AK1 is required for kinase activity of EIF2AK1 acting on EIF2S1 (inferred from mouse homologs). Phosphorylated EIF2S1 in the EIF2alpha complex causes the complex to bind more tightly to the GTP exchange factor EIF2B, which inhibits exchange of GDP for GTP, and hence inhibits recycling of EIF2alpha to the active (GTP-bound) state. The result is a general decrease of translation in the cell, with a few mRNAs, such as ATF4, that possess upstream ORFs exhibiting increased translation. The decrease in translation of globin mRNAs in particular helps to maintain a 1:1 balance of heme and globin in erythropoiesis during heme deficiency.
Identifier: R-HSA-381111
Species: Homo sapiens
Compartment: cytosol, endoplasmic reticulum membrane
The C-terminal domain of PERK (EIF2AK3) has kinase activity when PERK homodimerizes. PERK kinase specifically phosphorylates Ser52 of eIF2-alpha, causing an arrest in translation. The result is that translation of ER-targeted proteins is halted on ribosomes in the vicinity of activated PERK. The general arrest of translation results in the loss of short-lived proteins such as Cyclin D1, causing an arrest of the cell cycle in G1.
Identifier: R-HSA-9648883
Species: Homo sapiens
Compartment: cytosol
During heme deficiency, EIF2AK1 (HRI) autophosphorylates, notably on threonine residues in the activation loop (inferred from the mouse homolog). EIF2AK1 also has many phosphorylated residues prior to activation in response to heme deficiency (inferred from the mouse homolog). Autophosphorylation of threonine-488 (threonine-485 in the mouse homolog) is essential for kinase activity of EIF2AK1 acting on EIF2S1 (eIF2-alpha) in response to heme deficiency and oxidative stress by arsenite (inferred from the mouse homolog).
Identifier: R-HSA-9650722
Species: Homo sapiens
Compartment: cytosol, nucleoplasm
The DDIT3 mRNA is translated to yield DDIT3 (CHOP) protein (Jousse et al. 2001, and inferred from the mouse homolog), which is then imported into the nucleus. The mRNA of DDIT3 contains an upstream ORF (uORF) which has a start codon in an unfavorable context (Jousse et al. 2001, and inferred from the mouse homolog), resulting in low expression of the downstream DDIT3 coding region. When EIF2S1 (eIF2-alpha) is phosphorylated in response to stress, translation of the uORF is suppressed and translation of DDIT3 is increased (inferred from the mouse homolog).
Identifier: R-HSA-9633008
Species: Homo sapiens
Compartment: cytosol
After binding uncharged tRNA and autophosphorylating, EIF2AK4 (GCN2) phosphorylates EIF2S1 (eIF2 alpha subunit) on serine-52 (serine-51 in the rabbit homolog, inferred from mouse homologs and yeast homologs), which inhibits the guanine nucleotide exchange factor eIF2B, impairs exchange of GDP for GTP, and reduces recycling of EIF2 for initiation of translation. This causes downregulation of translation of most mRNAs, however translation of certain mRNAs possessing upstream ORFs, such as ATF4, is upregulated (inferred from mouse homologs and yeast homologs).
Identifier: R-HSA-9650710
Species: Homo sapiens
Compartment: cytosol
The PPP1R15A (GADD34) mRNA is translated to yield PPP1R15A protein which then associates with the cytosolic faces of the endoplasmic reticulum membrane and the mitochondrial outer membrane (inferred from the mouse homolog). The PPP1R15A mRNA contains 2 upstream ORFs (uORFs) that limit translation of the downstream PPP1R15A coding region (inferred from the mouse homolog). During certain stresses, EIF2S1 (eIF2-alpha) is phosphorylated, causing a reduction in initiation at the uORFs and increased translation of the PPP1R15A coding region (inferred from mouse homologs).

Complex (3 results from a total of 3)

Identifier: R-HSA-5226905
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-9633006
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-72515
Species: Homo sapiens
Compartment: cytosol

Pathway (3 results from a total of 3)

Identifier: R-HSA-9633012
Species: Homo sapiens
EIF2AK4 (GCN2) senses amino acid deficiency by binding uncharged tRNAs near the ribosome and responds by phosphorylating EIF2S1, the alpha subunit of the translation initiation factor EIF2 (inferred from yeast homologs and mouse homologs, reviewed in Chaveroux et al. 2010, Castilho et al. 2014, Gallinetti et al. 2013, Bröer and Bröer 2017, Wek 2018). Phosphorylated EIF2S1 reduces translation of most mRNAs but increases translation of downstream ORFs in mRNAs such as ATF4 that contain upstream ORFs (inferred from mouse homologs in Vattem and Wek 2004, reviewed in Hinnebusch et al. 2016, Sonenberg and Hinnebusch 2009). ATF4, in turn, activates expression of genes involved in responding to amino acid deficiency such as DDIT3 (CHOP), ASNS (asparagine synthetase), CEBPB, and ATF3 (reviewed in Kilberg et al. 2012, Wortel et al. 2017). In mice, EIF2AK4 in the brain may responsible for avoidance of diets lacking essential amino acids (Hao et al. 2005, Maurin et al. 2005, see also Leib and Knight 2015, Gietzen et al. 2016, reviewed in Dever and Hinnebusch 2005).
EIF2AK4 is bound to both the ribosome and GCN1, which is required for activation of EIF2AK4 and may act by shuttling uncharged tRNAs from the A site of the ribosome to EIF2AK4. Upon binding tRNA, EIF2AK4 trans-autophosphorylates. Phosphorylated EIF2AK4 then phosphorylates EIF2S1 on serine-52, the same serine residue phosphorylated by other kinases of the integrated stress response: EIF2AK1 (HRI, activated by heme deficiency and other stresses), EIF2AK2 (PKR, activated by double-stranded RNA), and EIF2AK3 (PERK, activated by unfolded proteins) (reviewed in Hinnebusch 1994, Wek et al. 2006, Donnelly et al. 2013, Pakos-Zebrucka et al. 2016, Wek 2018),
Identifier: R-HSA-9711097
Species: Homo sapiens
Deprivation of nutrients triggers diverse short- and long terms adaptations in cells. Here we have annotated two aspects of cellular responses to amino acid deprivation, ones mediated by EIF2AK4 and ones mediated by mTORC.

EIF2AK4 (GCN2) senses amino acid deficiency by binding uncharged tRNAs near the ribosome, and phosphorylating EIF2S1 (reviewed in Chaveroux et al. 2010, Castilho et al. 2014, Gallinetti et al. 2013, Bröer and Bröer 2017, Wek 2018). This reduces translation of most mRNAs but increases translation of mRNAs, notably ATF4, that mediate stress responses (reviewed in Kilberg et al. 2012, Wortel et al. 2017; Dever and Hinnebusch 2005).

The mTORC1 complex acts as an integrator that regulates translation, lipid synthesis, autophagy, and cell growth in response to multiple inputs, notably glucose, oxygen, amino acids, and growth factors such as insulin (reviewed in Sabatini 2017, Meng et al. 2018, Kim and Guan 2019).

MTOR, the kinase subunit of mTORC1, is activated by interaction with RHEB:GTP at the cytosolic face of lysosomal membrane (Long et al. 2005, Tee et al. 2005, Long et al. 2007, Yang et al. 2017). This process is regulated by various individual amino acids (reviewed in Zhuang et al. 2019, Wolfson and Sabatini 2017, Yao et al. 2017) and is reversed in response to the removal of amino acids, through the action of TSC1 (Demetriades et al. 2014).
Identifier: R-HSA-9648895
Species: Homo sapiens
The kinases of the integrated stress response phosphorylate EIF2S1 (eIF2-alpha) to regulate cellular translation. The kinases comprise PERK (also called EIF2AK3), which responds to unfolded protein in the endoplasmic reticulum; EIF2AK2 (also called PKR), which responds to cytosolic double-stranded RNA; EIF2AK4 (also called GCN2), which responds to amino acid deficiency; and EIF2AK1 (also called heme-regulated inhibitor, HRI, and heme-controlled repressor, HCR), which responds to heme deficiency and cytosolic unfolded protein. Each molecule of EIF2AK1 binds two molecules of heme, one bound near the N-terminus and one bound at the kinase insert (KI) domain that inhibits the kinase activity of EIF2AK1 (inferred from the rabbit homolog in Chefalo et al. 1998, Rafie-Kolpin et al. 2000, inferred from the mouse homolog in Misanova et al. 2006, Hirai et al. 2007, Igarashi et al. 2008). Dissociation of heme from the KI domain activates the kinase activity of EIF2AK1, which autophosphorylates (inferred from the mouse homolog in Bauer et al. 2001, Rafie-Kolpin et al. 2003, Igarashi et al. 2011) and then phosphorylates EIF2S1 (Bhavnani et al. 2018, inferred from the rabbit homologs in Chefalo et al. 1998, Rafie-Kolpin et al. 2000, inferred from the mouse homologs in Lu et al. 2001, Rafie-Kolpin et al. 2003, Igarashi et al. 2011).
Phosphorylated EIFS1 causes a reduction in general cellular translation and thereby coordinates globin synthesis with heme availability during erythropoiesis (inferred from mouse knockout in Han et al. 2001, reviewed in Chen et al. 2014). Translation of mitochondrial and cytosolic ribosomal proteins is most severely reduced, causing a decrease in cellular protein synthesis (inferred from mouse homologs in Zhang et al. 2019). Lack of EIF2AK1 causes accumulation of unfolded globins devoid of heme and consequent anemia in iron-deficient mice (inferred from mouse knockout in Han et al. 2001). Activation of the cytoplasmic unfolded protein response and impaired mitochondrial respiration are also observed in HRI deficiency (inferred from mouse homologs in Zhang et al. 2019).
Phosphorylation of EIFS1 activates translation of certain mRNAs such as ATF4, ATF5, and DDIT3 (CHOP) that have upstream ORFs (inferred from mouse homologs in Harding et al. 2000). ATF4 in turn activates programs of gene expression that ameliorate effects of the stress to maintain mitochondrial function, redox homeostasis, and erythroid differentiation (inferred from mouse homologs in Zhang et al. 2019). Unresolved stress, however, can eventually lead to apoptosis regulated by DDIT3. EIF2AK1 also represses mTORC1 (mechanistic target of mechanistic target of rapamycin complex 1) signaling via ATF4-mediated induction of GRB10 as a feedback mechanism to attenuate erythropoietin-mTORC1-stimulated ineffective erythropoiesis in iron deficiency anemia (inferred from mouse homologs in Zhang et al. 2018 and Zhang et. al. 2019).
EIF2AK1 is also activated by heat shock, arsenite (oxidative stress), and osmotic stress (inferred from mouse homologs in Lu et al. 2001). The mechanisms by which these stresses act on EIF2AK1 are independent of heme but are not yet fully elucidated. Furthermore, EIF2AK1 is involved in the production of human fetal hemoglobin, and EIF2AK1-mediated stress response has emerged as a potential therapeutic target for hemoglobinopathies (reviewed in Chen and Zhang 2019).
In addition to regulation of erythropoiesis, EIF2AK1 shows effects outside of the erythroid lineage, including requirement for the maturation and functions of macrophages (inferred from mouse homologs in Liu et al. 2007), reduction in endoplasmic reticulum stress in hepatocytes, activation of hepatic expression of fibroblast growth factor, and mediation of translation of GRIN2B (GluN2B. a subunit of the NMDA receptor) and BACE1 in the nervous system (reviewed in Burwick and Aktas 2017). HRI-integrated stress response is activated in human cancer cell lines and primary multiple myeloma cells, and has emerged as a molecular target of anticancer agents (reviewed in Burwick and Aktas 2017; reviewed in Chen and Zhang 2019).

Icon (1 results from a total of 1)

Species: Homo sapiens
Curator: Bruce May
Designer: Cristoffer Sevilla
EIF2S1 icon
Eukaryotic translation initiation factor 2 subunit 1
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