Response of EIF2AK4 (GCN2) to amino acid deficiency (Homo sapiens)

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1, 3, 4, 8, 9, 14...1812, 4313, 467, 10, 13, 22, 292, 5, 7, 29, 30, 36...7, 29, 404113, 21, 24, 277, 11, 13, 21, 24...45, 49402, 16, 25, 36, 397, 29, 32, 45, 49nucleoplasmcytosolRPL21 CEBPB geneRPL9 RPS23 RPLP0 RPL3L RPL22L1 RPL10 RPL10 RPL3L RPS20 DDIT3 geneRPS15 RPS16 TRIB3RPL7A RPL40 EIF2S1:EIF2S2:EIF2S3RPL23A RPS27L RPS26 RPL26 RPL14 RPL34 RPLP1 RPL32 RPL37 mRNA RPL18 RPS28 RPS17 RPSA RPS4Y1 RPL10A EIF2AK4 IMPACT RPS4Y1 RPL22L1 RPS5 RPS9 RPS27A(77-156) RPL19 RPS14 RPL34 RPL30 CEBPB RPL35A 5S rRNA RPL15 GCN1:80Sribosome:mRNARPS5 RPS7 RPL21 RPS21 RPS13 RPS15 5.8S rRNA RPS28 RPL27 RPL4 RPLP2 RPL13A RPL14 mRNA RPL15 RPL38 RPL4 ATF4:CEBPB,CEBPG,DDIT3:TRIB3 geneRPS4Y2 RPS5 RPS6 RPS19 RPL29 RPS4Y2 RPL6 RPL35 RPL13 RPL17 RPL6 RPS27L RPL31 RPL36AL RPL36A RPL36 RPL8 18S rRNA DDIT3 gene GCN1 TRIB3 geneDDIT3 28S rRNA RPLP1 RPL36AL ATF4 RPL14 CEBPG RPL34 RPS15A RPS29 RPL7A RPL26 RPL13A RPS3A RPS11 EIF2S2 p-T899-EIF2AK4 RPL24 RPS23 RPL26 RPL37 RPL10L RPS16 RPL37A RPLP2 RPL12 RPS15A RPL15 RPL28 RPS27A(77-156) RPL38 FAU RPS9 CEBPB RPL34 RPL10A RPL19 RPS20 RPL13 RPLP0 RPS2 RPL4 RPS21 RPSA RPL11 RPL37A RPS17 GCN1 RPL17 RPL39L RPS27 RPL40 RPS4Y2 RPS26 RPL35 RPL39 RPL8 RPL30 RPS3A RPL27A RPL36 RPL13 RPL27A RPL13A 28S rRNA 5.8S rRNA CEBPB gene RPL27 RPS8 RPL3L CEBPB,CEBPGRPS10 FAU p-T69,T71-ATF2RPS23 RPS4X RPS16 ADPRPL5 RPL26L1 RPL11 RPS25 IMPACT:GCN1:80Sribosome:mRNARPS25 RPS14 RPS9 RPS28 RPS24 RPL26 RPS8 RPL26L1 RPL18 RPS15A DDIT3 RPS27A(77-156) EIF2S3 RPL7A RPS16 RPL18A ADPRPL23A RPS4Y1 RPL30 RPS19 EIF2AK4:GCN1:80Sribosome:mRNARPL24 RPS15 28S rRNA RPL26L1 RPS29 RPL21 ATF4 RPS10 RPS9 RPL27A RPS20 28S rRNA RPL15 RPS17 CEBPG RPL37 RPL3L RPLP1 RPL27 RPL13 RPS14 RPL11 RPS21 RPL31 RPL12 tRNARPS27 RPL29 RPL28 5S rRNA RPS27L RPL24 RPL10L RPL8 CEBPBRPL10L RPL9 RPL7A 18S rRNA CEBPB p-S52-EIF2S1:EIF2S2:EIF2S3RPS8 RPS28 5S rRNA RPS2 RPL5 RPL14 RPS3 RPS4Y2 RPL10A RPS26 RPL10A RPL23 RPL37 p-S52-EIF2S1 RPL31 RPS6 IMPACTRPS19 RPS25 RPL39 RPS27 RPL38 RPS4X RPL36A EIF2AK4 RPS15 RPS11 RPL37A RPS20 5.8S rRNA RPL39L RPS3 RPL27A RPL36A RPL10 RPS15 RPL17 RPL32 RPS4X RPS16 RPL3 RPL9 RPS3 RPL12 RPS3A RPS26 RPS13 RPL24 tRNA RPS11 RPS18 RPS21 RPL7 RPL19 RPS4X 5S rRNA RPL35A RPL18A RPL35A RPS3 ATPRPL19 5.8S rRNA RPS12 RPL28 tRNA:EIF2AK4:GCN1:80S Ribosome:mRNARPS10 RPS5 RPL26L1 RPS12 RPL9 RPLP1 RPS24 18S rRNA RPLP2 RPL41 RPL21 RPS18 RPS7 RPS17 ATF3 geneATF3RPS27 RPL23A mRNA RPL26 RPL23 RPL27A mRNA RPL39 FAU RPL7 RPLP2 RPLP0 RPL27 RPS24 RPL41 RPS6 CEBPG RPL36AL RPL3 ATF4 mRNARPS25 RPL34 RPS12 GCN1 RPL36AL CEBPB RPL5 RPL22L1 RPL23 RPL37A RPL3 RPS24 ATF4 RPL22 RPL35A RPL31 EIF2S1 ASNS gene RPS12 RPS29 RPS19 RPL12 RPL22 5S rRNA RPL27 RPL11 RPL6 RPL35 RPL35 RPL7 RPL13A RPL8 RPS7 RPL23A RPL7A RPL36A RPL29 RPLP0 RPS14 FAU RPL22L1 RPS6 5.8S rRNA RPS2 RPL39L RPL41 RPS2 ATF4:CEBPB,CEBPG:ASNS geneRPL40 RPL3 RPL37A RPL32 RPL23A RPL6 RPS5 RPS4Y2 RPS13 RPL12 RPS21 RPS18 RPSA RPL4 RPL32 ATF4RPS4Y1 RPL5 tRNA ASNSRPL10L RPS13 ASNS geneRPL29 RPS8 RPL36AL RPS28 RPS7 RPS26 RPL17 RPL39L RPL10A RPL40 DDIT3 mRNA18S rRNA RPL18 RPS15A CEBPG RPS3 ATF4 RPL28 RPS12 RPL10 EIF2S2 RPL41 18S rRNA RPS7 RPL26L1 RPL29 28S rRNA RPS27L RPL18 RPL22L1 RPL15 RPS23 DDIT3RPL36 EIF2S3 RPL39 RPL37 RPL19 RPL23 RPS29 RPL21 RPL39 GCN1 RPS9 RPS18 ATF4:CEBPB geneRPL18A RPL22 ATF4dimer:p-T69,T71-ATF2 dimer:DDIT3 geneRPL30 RPL23 RPL11 RPS18 RPL36 RPL32 ATPRPS11 RPL36A RPL41 RPL39L RPS11 RPL13A RPSA RPS4X RPL22 RPSA ATF4 RPL14 RPL3L RPL18A RPL10 p-T69,T71-ATF2 RPLP0 RPS19 RPL5 RPS15A RPS8 RPLP1 RPL7 RPL36 RPL35A RPL4 RPS27L RPL8 RPS2 RPL35 RPL31 RPL38 RPS3A RPS23 RPS3A RPS4Y1 GCN1 RPS27 RPS14 RPS10 RPL9 RPS27A(77-156) RPL24 CEBPB,CEBPG,DDIT3RPS13 RPL38 RPL13 RPS10 RPS29 RPS24 RPLP2 FAU RPS27A(77-156) RPL3 RPL30 RPS25 RPS17 RPL28 RPS20 RPL18 RPS6 RPL17 RPL6 RPL40 RPL10L TRIB3 gene RPL18A RPL22 mRNA tRNA:p-T899-EIF2AK4:GCN1:80S Ribosome:mRNARPL7 ATF3 gene ATF4:ATF3 gene3631, 45, 496, 23, 4440


Description

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), View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 9633012
Reactome-version 
Reactome version: 74
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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History

CompareRevisionActionTimeUserComment
114695view16:17, 25 January 2021ReactomeTeamReactome version 75
113140view11:20, 2 November 2020ReactomeTeamReactome version 74
112785view17:41, 9 October 2020DeSlOntology Term : 'pathway pertinent to DNA replication and repair, cell cycle, maintenance of genomic integrity, RNA and protein biosynthesis' added !
112741view16:14, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
18S rRNA ProteinX03205 (EMBL)
28S rRNA ProteinM11167 (EMBL)
5.8S rRNA ProteinJ01866 (EMBL)
5S rRNA ProteinV00589 (EMBL)
ADPMetaboliteCHEBI:456216 (ChEBI)
ASNS gene ProteinENSG00000070669 (Ensembl)
ASNS geneGeneProductENSG00000070669 (Ensembl)
ASNSProteinP08243 (Uniprot-TrEMBL)
ATF3 gene ProteinENSG00000162772 (Ensembl)
ATF3 geneGeneProductENSG00000162772 (Ensembl)
ATF3ProteinP18847 (Uniprot-TrEMBL)
ATF4 dimer:p-T69,T71-ATF2 dimer:DDIT3 geneComplexR-HSA-9635843 (Reactome)
ATF4 ProteinP18848 (Uniprot-TrEMBL)
ATF4 mRNARnaENST00000404241 (Ensembl)
ATF4:ATF3 geneComplexR-HSA-9635905 (Reactome)
ATF4:CEBPB geneComplexR-HSA-9635875 (Reactome)
ATF4:CEBPB,CEBPG,DDIT3:TRIB3 geneComplexR-HSA-9635876 (Reactome)
ATF4:CEBPB,CEBPG:ASNS geneComplexR-HSA-9635898 (Reactome)
ATF4ProteinP18848 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:30616 (ChEBI)
CEBPB ProteinP17676 (Uniprot-TrEMBL)
CEBPB gene ProteinENSG00000172216 (Ensembl)
CEBPB geneGeneProductENSG00000172216 (Ensembl)
CEBPB,CEBPG,DDIT3ComplexR-HSA-9654226 (Reactome)
CEBPB,CEBPGComplexR-HSA-9658331 (Reactome)
CEBPBProteinP17676 (Uniprot-TrEMBL)
CEBPG ProteinP53567 (Uniprot-TrEMBL)
DDIT3 ProteinP35638 (Uniprot-TrEMBL)
DDIT3 gene ProteinENSG00000175197 (Ensembl)
DDIT3 geneGeneProductENSG00000175197 (Ensembl)
DDIT3 mRNARnaENST00000346473 (Ensembl)
DDIT3ProteinP35638 (Uniprot-TrEMBL)
EIF2AK4 ProteinQ9P2K8 (Uniprot-TrEMBL)
EIF2AK4:GCN1:80S ribosome:mRNAComplexR-HSA-9633014 (Reactome)
EIF2S1 ProteinP05198 (Uniprot-TrEMBL)
EIF2S1:EIF2S2:EIF2S3ComplexR-HSA-72515 (Reactome)
EIF2S2 ProteinP20042 (Uniprot-TrEMBL)
EIF2S3 ProteinP41091 (Uniprot-TrEMBL)
FAU ProteinP62861 (Uniprot-TrEMBL)
GCN1 ProteinQ92616 (Uniprot-TrEMBL)
GCN1:80S ribosome:mRNAComplexR-HSA-9634679 (Reactome)
IMPACT ProteinQ9P2X3 (Uniprot-TrEMBL)
IMPACT:GCN1:80S ribosome:mRNAComplexR-HSA-9634665 (Reactome)
IMPACTProteinQ9P2X3 (Uniprot-TrEMBL)
RPL10 ProteinP27635 (Uniprot-TrEMBL)
RPL10A ProteinP62906 (Uniprot-TrEMBL)
RPL10L ProteinQ96L21 (Uniprot-TrEMBL)
RPL11 ProteinP62913 (Uniprot-TrEMBL)
RPL12 ProteinP30050 (Uniprot-TrEMBL)
RPL13 ProteinP26373 (Uniprot-TrEMBL)
RPL13A ProteinP40429 (Uniprot-TrEMBL)
RPL14 ProteinP50914 (Uniprot-TrEMBL)
RPL15 ProteinP61313 (Uniprot-TrEMBL)
RPL17 ProteinP18621 (Uniprot-TrEMBL)
RPL18 ProteinQ07020 (Uniprot-TrEMBL)
RPL18A ProteinQ02543 (Uniprot-TrEMBL)
RPL19 ProteinP84098 (Uniprot-TrEMBL)
RPL21 ProteinP46778 (Uniprot-TrEMBL)
RPL22 ProteinP35268 (Uniprot-TrEMBL)
RPL22L1 ProteinQ6P5R6 (Uniprot-TrEMBL)
RPL23 ProteinP62829 (Uniprot-TrEMBL)
RPL23A ProteinP62750 (Uniprot-TrEMBL)
RPL24 ProteinP83731 (Uniprot-TrEMBL)
RPL26 ProteinP61254 (Uniprot-TrEMBL)
RPL26L1 ProteinQ9UNX3 (Uniprot-TrEMBL)
RPL27 ProteinP61353 (Uniprot-TrEMBL)
RPL27A ProteinP46776 (Uniprot-TrEMBL)
RPL28 ProteinP46779 (Uniprot-TrEMBL)
RPL29 ProteinP47914 (Uniprot-TrEMBL)
RPL3 ProteinP39023 (Uniprot-TrEMBL)
RPL30 ProteinP62888 (Uniprot-TrEMBL)
RPL31 ProteinP62899 (Uniprot-TrEMBL)
RPL32 ProteinP62910 (Uniprot-TrEMBL)
RPL34 ProteinP49207 (Uniprot-TrEMBL)
RPL35 ProteinP42766 (Uniprot-TrEMBL)
RPL35A ProteinP18077 (Uniprot-TrEMBL)
RPL36 ProteinQ9Y3U8 (Uniprot-TrEMBL)
RPL36A ProteinP83881 (Uniprot-TrEMBL)
RPL36AL ProteinQ969Q0 (Uniprot-TrEMBL)
RPL37 ProteinP61927 (Uniprot-TrEMBL)
RPL37A ProteinP61513 (Uniprot-TrEMBL)
RPL38 ProteinP63173 (Uniprot-TrEMBL)
RPL39 ProteinP62891 (Uniprot-TrEMBL)
RPL39L ProteinQ96EH5 (Uniprot-TrEMBL)
RPL3L ProteinQ92901 (Uniprot-TrEMBL)
RPL4 ProteinP36578 (Uniprot-TrEMBL)
RPL40 ProteinP62987 (Uniprot-TrEMBL)
RPL41 ProteinP62945 (Uniprot-TrEMBL)
RPL5 ProteinP46777 (Uniprot-TrEMBL)
RPL6 ProteinQ02878 (Uniprot-TrEMBL)
RPL7 ProteinP18124 (Uniprot-TrEMBL)
RPL7A ProteinP62424 (Uniprot-TrEMBL)
RPL8 ProteinP62917 (Uniprot-TrEMBL)
RPL9 ProteinP32969 (Uniprot-TrEMBL)
RPLP0 ProteinP05388 (Uniprot-TrEMBL)
RPLP1 ProteinP05386 (Uniprot-TrEMBL)
RPLP2 ProteinP05387 (Uniprot-TrEMBL)
RPS10 ProteinP46783 (Uniprot-TrEMBL)
RPS11 ProteinP62280 (Uniprot-TrEMBL)
RPS12 ProteinP25398 (Uniprot-TrEMBL)
RPS13 ProteinP62277 (Uniprot-TrEMBL)
RPS14 ProteinP62263 (Uniprot-TrEMBL)
RPS15 ProteinP62841 (Uniprot-TrEMBL)
RPS15A ProteinP62244 (Uniprot-TrEMBL)
RPS16 ProteinP62249 (Uniprot-TrEMBL)
RPS17 ProteinP08708 (Uniprot-TrEMBL)
RPS18 ProteinP62269 (Uniprot-TrEMBL)
RPS19 ProteinP39019 (Uniprot-TrEMBL)
RPS2 ProteinP15880 (Uniprot-TrEMBL)
RPS20 ProteinP60866 (Uniprot-TrEMBL)
RPS21 ProteinP63220 (Uniprot-TrEMBL)
RPS23 ProteinP62266 (Uniprot-TrEMBL)
RPS24 ProteinP62847 (Uniprot-TrEMBL)
RPS25 ProteinP62851 (Uniprot-TrEMBL)
RPS26 ProteinP62854 (Uniprot-TrEMBL)
RPS27 ProteinP42677 (Uniprot-TrEMBL)
RPS27A(77-156) ProteinP62979 (Uniprot-TrEMBL)
RPS27L ProteinQ71UM5 (Uniprot-TrEMBL)
RPS28 ProteinP62857 (Uniprot-TrEMBL)
RPS29 ProteinP62273 (Uniprot-TrEMBL)
RPS3 ProteinP23396 (Uniprot-TrEMBL)
RPS3A ProteinP61247 (Uniprot-TrEMBL)
RPS4X ProteinP62701 (Uniprot-TrEMBL)
RPS4Y1 ProteinP22090 (Uniprot-TrEMBL)
RPS4Y2 ProteinQ8TD47 (Uniprot-TrEMBL)
RPS5 ProteinP46782 (Uniprot-TrEMBL)
RPS6 ProteinP62753 (Uniprot-TrEMBL)
RPS7 ProteinP62081 (Uniprot-TrEMBL)
RPS8 ProteinP62241 (Uniprot-TrEMBL)
RPS9 ProteinP46781 (Uniprot-TrEMBL)
RPSA ProteinP08865 (Uniprot-TrEMBL)
TRIB3 gene ProteinENSG00000101255 (Ensembl)
TRIB3 geneGeneProductENSG00000101255 (Ensembl)
TRIB3ProteinQ96RU7 (Uniprot-TrEMBL)
mRNA R-HSA-72323 (Reactome)
p-S52-EIF2S1 ProteinP05198 (Uniprot-TrEMBL)
p-S52-EIF2S1:EIF2S2:EIF2S3ComplexR-HSA-9633006 (Reactome)
p-T69,T71-ATF2 ProteinP15336 (Uniprot-TrEMBL)
p-T69,T71-ATF2ProteinP15336 (Uniprot-TrEMBL)
p-T899-EIF2AK4 ProteinQ9P2K8 (Uniprot-TrEMBL)
tRNA R-HSA-141679 (Reactome)
tRNA:EIF2AK4:GCN1:80S Ribosome:mRNAComplexR-HSA-9633013 (Reactome)
tRNA:p-T899-EIF2AK4:GCN1:80S Ribosome:mRNAComplexR-HSA-9633821 (Reactome)
tRNAR-HSA-141679 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-9633008 (Reactome)
ADPArrowR-HSA-9633742 (Reactome)
ASNS geneR-HSA-1791118 (Reactome)
ASNS geneR-HSA-9635915 (Reactome)
ASNSArrowR-HSA-1791118 (Reactome)
ATF3 geneR-HSA-1791173 (Reactome)
ATF3 geneR-HSA-9635892 (Reactome)
ATF3ArrowR-HSA-1791173 (Reactome)
ATF4 dimer:p-T69,T71-ATF2 dimer:DDIT3 geneArrowR-HSA-9635804 (Reactome)
ATF4 dimer:p-T69,T71-ATF2 dimer:DDIT3 geneArrowR-HSA-9644926 (Reactome)
ATF4 mRNAR-HSA-381128 (Reactome)
ATF4:ATF3 geneArrowR-HSA-1791173 (Reactome)
ATF4:ATF3 geneArrowR-HSA-9635892 (Reactome)
ATF4:CEBPB geneArrowR-HSA-9635918 (Reactome)
ATF4:CEBPB geneArrowR-HSA-9635936 (Reactome)
ATF4:CEBPB,CEBPG,DDIT3:TRIB3 geneArrowR-HSA-9635912 (Reactome)
ATF4:CEBPB,CEBPG,DDIT3:TRIB3 geneArrowR-HSA-9635927 (Reactome)
ATF4:CEBPB,CEBPG:ASNS geneArrowR-HSA-1791118 (Reactome)
ATF4:CEBPB,CEBPG:ASNS geneArrowR-HSA-9635915 (Reactome)
ATF4ArrowR-HSA-381128 (Reactome)
ATF4R-HSA-9635804 (Reactome)
ATF4R-HSA-9635892 (Reactome)
ATF4R-HSA-9635915 (Reactome)
ATF4R-HSA-9635927 (Reactome)
ATF4R-HSA-9635936 (Reactome)
ATPR-HSA-9633008 (Reactome)
ATPR-HSA-9633742 (Reactome)
CEBPB geneR-HSA-9635918 (Reactome)
CEBPB geneR-HSA-9635936 (Reactome)
CEBPB,CEBPG,DDIT3R-HSA-9635927 (Reactome)
CEBPB,CEBPGR-HSA-9635915 (Reactome)
CEBPBArrowR-HSA-9635918 (Reactome)
DDIT3 geneR-HSA-9635804 (Reactome)
DDIT3 geneR-HSA-9644926 (Reactome)
DDIT3 mRNAArrowR-HSA-9644926 (Reactome)
DDIT3 mRNAR-HSA-9650722 (Reactome)
DDIT3ArrowR-HSA-9650722 (Reactome)
EIF2AK4:GCN1:80S ribosome:mRNAR-HSA-9633005 (Reactome)
EIF2S1:EIF2S2:EIF2S3R-HSA-9633008 (Reactome)
GCN1:80S ribosome:mRNAR-HSA-9634669 (Reactome)
IMPACT:GCN1:80S ribosome:mRNAArrowR-HSA-9634669 (Reactome)
IMPACTR-HSA-9634669 (Reactome)
R-HSA-1791118 (Reactome) The Asparagine Synthetase (ASNS) gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Chen et al. 2004, Lee et al. 2008, Gjymishka et al. 2009, Sikalidis et al. 2011, Balasubramanian et al. 2013, inferred from the mouse homolog). Transcription of ASNS is activated by the unfolded protein response (Gjymishka et al. 2009), amino acid deficiency (Chen et al. 2004, Lee et al. 2008, Sikalidis et al. 2011, Balasubramanian et al. 2013, inferred from the mouse homolog), and heme deficiency (inferred from the mouse homolog).
R-HSA-1791173 (Reactome) The ATF3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Chen et al. 2004, Pan et al. 2007, Lee et al. 2008, Armstrong et al. 2010, Sikalidis et al. 2011, Fu and Kilberg 2013, Lee et al. 2013, Hayner et al. 2018). Transcription of ATF3 is enhanced in response to amino acid deficiency (Chen et al. 2004, Pan et al. 2007, Lee et al. 2008, Sikaldis et al. 2011, Fu and Kilberg 2013, Hayner et al. 2018). ATF4 binds a CEBP-ATF response element (CARE) and an additional upstream element in the promoter of the ATF3 gene, resulting in enhanced transcription (Pan et al. 2007, Armstrong et al. 2010, Fu and Kilberg 2013, Lee et al. 2013, Hayner et al. 2018, and inferred from mouse homologs). CEBPB and ATF3 bind later and correlate with reduced expression of ATF4 (Pan et al. 2007)
R-HSA-381128 (Reactome) ATF4 mRNA is translated to yield ATF4 protein, which then transits to the nucleus (Blais et al. 2004, Ross et al. 2018). The mRNA of ATF4 contains 2 upstream ORFs (uORFs) (Ross et al. 2018 and inferred from the mouse homolog). The second uORF overlaps the ORF encoding ATF4 and thus prevents translation of ATF4. When EIF2S1 (eIF2-alpha) is phosphorylated, translation initiation is decreased overall, translation of the uORFs is suppressed, and translation of the ORF encoding ATF4 is increased (Blais et al. 2004, Ross et al. 2018, and inferred from mouse homologs).
R-HSA-9633005 (Reactome) The histidyl-tRNA synthetase-like domain of EIF2AK4 (GCN2) binds uncharged tRNA, resulting in activation of the protein kinase domain of EIF2AK4 (Inglis et al. 2019 and inferred from yeast homologs and mouse homologs). In the absence of tRNA, EIF2AK4 appears to exist in an equilibrium between antiparallel and parallel dimers. Upon binding tRNA, the parallel dimer is stabilized and the C-terminal domain shifts away from the protein kinase domain, resulting in activation of the kinase activity of EIF2AK4 (inferred from GCN2, the yeast homolog).
EIF2AK4 interacts with GCN1 and the P-stalk of ribosomes (Inglis et al. 2019), though the interaction between mammalian EIF2AK4 and ribosomes is not as stable as the interaction between yeast GCN2 and ribosomes (inferred from yeast homologs and mouse homologs). By such transient interactions, a population of EIF2AK4 may sample a larger population of ribosomes for uncharged tRNAs. The interaction between EIF2AK4 and GCN1 is required for efficient phosphorylation of EIF2S1 by EIF2AK4 and GCN1 may act to transfer uncharged tRNAs from the A site of the ribosome to EIF2AK4 (inferred from yeast homologs and mouse homologs).
R-HSA-9633008 (Reactome) 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).
R-HSA-9633742 (Reactome) After binding uncharged tRNA, the EIF2AK4 (GCN2) dimer trans-autophosphorylates on threonine-899, resulting in activation of the kinase domain of EIF2AK4 (Harding et al. 2000, Deng et al. 2002, Cambiaghi et al. 2014, and inferred from mouse homologs and yeast homologs).
R-HSA-9634669 (Reactome) IMPACT, a mammalian homolog of yeast YIH1, competes with EIF2AK4 (GCN2) for binding to GCN1, which is required for activation of EIF2AK4 and may act by transferring unacylated tRNAs from the ribosome to EIF2AK4 (inferred from mouse homologs). IMPACT thereby inhibits phosphorylation of EIF2A by EIF2AK4 in response to amino acid deficiency (inferred from mouse homologs). IMPACT is preferentially expressed in neurons, associates with translating ribosomes, enhances translation initiation, and promotes neuritogenesis (inferred from mouse homologs).
R-HSA-9635804 (Reactome) The promoter of the DDIT3 (CHOP) gene contains an Amino Acid Response Element (AARE) that binds ATF4 and ATF2. ATF2 and ATF4 are required for full activation of gene transcription in response to amino acid deprivation (Bruhat et al. 2000, Averous et al. 2004). Phospho-ATF2 is essential in the acetylation of histone H4 and H2B (Bruhat et al. 2007). ATF4 recruits PCAF to enhance transcription (Chérasse et al. 2007). ATF4 appears to be a monomer in the absence of DNA and a dimer after binding DNA (Podust et al. 2001).
R-HSA-9635892 (Reactome) ATF4 binds an amino acid response element (AARE) in the promoter of the ATF3 gene (Chen et al. 2004, Pan et al. 2007, Fu and Kilberg 2013, Hayner et al. 2018). ATF4 initially binds the ATF3 promoter with phosphorylated ATF2, then with JUN (c-Jun), then with CEBPB (Fu and Kilberg 2013, Hayner et al. 2018). ATF3 and CEBPB bind later and correlate with reduced expression of ATF3 (Pan et al. 2007, Fu and Kilberg 2013, Hayner et al. 2018).
R-HSA-9635912 (Reactome) The TRIB3 (TRB3, NIPK) gene is transcribed to yield mRNA and the mRNA is translated to yield TRIB3 protein (Ohoka et al. 2005, Ord and Ord 2005, Lee et al. 2008, Sikalidis et al. 2011, Ord et al. 2016, and inferred from the mouse homolog). Transcription of TRIB3 is enhanced in response to amino acid deficiency (Lee et al. 2008, Sikalidis et al. 2011, and inferred from mouse homologs), endoplasmic reticulum stress (Ohoka et al. 2005, Ord and Ord 2005), oxidative stress (Ord and Ord 2005, Ord et al. 2016) and heme deficiency (inferred from mouse homologs). ATF4 bound with a CEBP family protein to the promoter of TRIB3 (NIPK, TRB3) enhances transcription of TRIB3 (Ohoka et al. 2005, Ord and Ord 2005, Lee et al. 2008, Sikalidis et al. 2011, Ord et al. 2016, and inferred from mouse homologs).
R-HSA-9635915 (Reactome) ATF4 and CEBPB or CEBPG bind a CEBP-ATF regulatory element (CARE) in the promoter of the ASNS gene (Siu et al 2001, Chen et al. 2004, inferred from mouse homologs). ATF4 binds rapidly during the first 2 hours after amino acid deprivation (Chen et al. 2004). ATF3 and CEBPB accumulate on the ASNS promoter more slowly and appear to correlate with decreasing transcription of ASNS (Chen et al. 2004). EIF2AK1 acts via ATF4 to activate transcription of ASNS in response to heme deficiency (inferred from mouse homologs).
R-HSA-9635918 (Reactome) The CEBPB gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Chen et al. 2005, Lee et al. 2008, Sikalidis et al. 2011). Transcription of CEBPB is activated in response to amino acid deficiency (Chen et al. 2005, Lee et al. 2008, Sikalidis et al. 2011). ATF4 bound to an enhancer downstream of the CEBPB coding region (Chen et al. 2005) increases transcription of CEBPB approximately 4-fold (Chen et al. 2005, Lee et al. 2008, Sikalidis et al. 2011).
R-HSA-9635927 (Reactome) ATF4 binds composite CEBP-ATF elements located in three 33-bp tandem repeats in the promoter of the TRIB3 (TRB3, NIPK) gene (Ohoka et al. 2005, Ord and Ord 2005). ATF4 cooperates with DDIT3 to activate TRIB3 promoter activity (Ohoka et al. 2005). ATF4 also appears to bind as a heterodimer with CEBPB or CEBPG, which is required for full response to amino acid deficiency (inferred from mouse homologs).
R-HSA-9635936 (Reactome) ATF4 binds an enhancer downstream of the protein coding region of the CEBPB gene (Chen et al. 2005). The binding site resembles a composite CEBP-ATF element. Therefore ATF4 may form a heterodimer with a CEBP protein at the element (Chen et al. 2005).
R-HSA-9644926 (Reactome) The DDIT3 (CHOP) gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Bartlett et al. 1992, Carlson et al. 1993, Bruhat et al. 1997, Yoshida et al. 2000, Lee et al. 2008, Sikalidis et al. 2011). In response to amino acid starvation, transcription of DDIT3 s enhanced by ATF4 and phosphorylated ATF2 (Bruhat et al. 2000, Averous et al. 2004, Bruhat et al. 2007)
R-HSA-9650722 (Reactome) 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).
TRIB3 geneR-HSA-9635912 (Reactome)
TRIB3 geneR-HSA-9635927 (Reactome)
TRIB3ArrowR-HSA-9635912 (Reactome)
p-S52-EIF2S1:EIF2S2:EIF2S3ArrowR-HSA-381128 (Reactome)
p-S52-EIF2S1:EIF2S2:EIF2S3ArrowR-HSA-9633008 (Reactome)
p-S52-EIF2S1:EIF2S2:EIF2S3ArrowR-HSA-9650722 (Reactome)
p-T69,T71-ATF2R-HSA-9635804 (Reactome)
tRNA:EIF2AK4:GCN1:80S Ribosome:mRNAArrowR-HSA-9633005 (Reactome)
tRNA:EIF2AK4:GCN1:80S Ribosome:mRNAR-HSA-9633742 (Reactome)
tRNA:EIF2AK4:GCN1:80S Ribosome:mRNAmim-catalysisR-HSA-9633742 (Reactome)
tRNA:p-T899-EIF2AK4:GCN1:80S Ribosome:mRNAArrowR-HSA-9633742 (Reactome)
tRNA:p-T899-EIF2AK4:GCN1:80S Ribosome:mRNAmim-catalysisR-HSA-9633008 (Reactome)
tRNAR-HSA-9633005 (Reactome)
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