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

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6, 9, 11, 14, 15, 20...313, 16, 32, 502, 4, 31, 43, 472, 13, 16, 19, 32...16, 3358, 122, 7, 16, 42, 432, 5, 4310, 30, 38, 40, 494, 472, 17, 21, 27, 30...35nucleoplasmcytosolRPS7 RPL12 RPL27A RPS3A ATF4 RPS15A RPS18 TRIB3 gene RPL10 RPS16 RPL30 DDIT3 RPL5 RPL18 RPL36A 5S rRNA RPS5 RPS6 RPL40 RPL15 RPS24 5S rRNA RPL7A RPL29 RPL26 RPS8 RPS8 RPL7 RPL39L RPL13 RPL19 CEBPG RPS27L DDIT3 mRNACEBPB RPL22 RPS26 RPL21 RPL35A RPL37 RPS4Y2 RPL36AL RPS3A FAU RPLP2 RPS23 RPS29 RPL3 RPSA tRNA:EIF2AK4:GCN1:80S Ribosome:mRNARPS14 RPS10 RPL11 RPL18 ASNS geneRPL39 RPL12 ATF4:CEBPB,CEBPG:ASNS geneRPL29 RPL21 GCN1 RPS7 RPS27A(77-156) CEBPB geneRPL6 RPL24 RPS3A RPS6 RPL3L RPS23 RPL23A RPL4 RPS12 CEBPB RPL7A RPS11 RPS13 RPS4Y1 RPS29 RPL8 RPS3A RPS17 RPL18A ATF4 RPSA RPS10 RPL35A RPS25 RPS27L ATF4:ATF3 geneRPS27 RPS26 RPS15 GCN1:80Sribosome:mRNARPS19 RPL22L1 GCN1 RPS14 RPL36 RPL37 RPL39L RPS2 RPL36A 28S rRNA RPL41 EIF2S3 RPL13 RPS9 RPS25 RPL37 RPS21 RPL26 RPS28 p-T69,T71-ATF2 RPL6 RPS7 RPS6 ATF3RPL30 RPL36A RPS2 RPS27 RPS15 RPS9 18S rRNA RPL39L RPL7 RPL40 RPL22 RPLP1 RPS27A(77-156) RPL32 RPL6 RPLP1 FAU RPS16 RPL17 RPL39L RPS24 RPL27 RPL15 RPL24 RPL7 RPLP0 RPL40 RPS28 RPS8 RPS27L RPL13A RPS21 RPS19 RPS4Y1 RPS28 RPLP1 RPS18 RPL37 RPS24 RPL34 CEBPB gene RPLP2 RPL5 RPS3 RPL14 RPL14 RPL23A RPL23A RPL9 RPL26 DDIT3 gene RPL12 RPL34 RPL35 RPL27 RPS29 RPL3 RPS3 RPL17 RPL22L1 RPL26L1 CEBPB RPLP1 EIF2AK4:GCN1:80Sribosome:mRNAtRNA:p-T899-EIF2AK4:GCN1:80S Ribosome:mRNARPL17 RPL27 ATF4:CEBPB geneRPS15 RPS25 RPL13 RPL10 RPL13 18S rRNA RPL36 DDIT3 RPL9 18S rRNA RPL18 RPLP0 RPL17 RPL31 RPS3 28S rRNA p-S52-EIF2S1:EIF2S2:EIF2S3RPS4Y1 CEBPB RPS12 RPL37A RPL10A RPL37A RPL22 EIF2AK4 RPL4 RPL39 RPL23 RPL12 RPL13A ATPRPL26 RPL34 RPL10A RPL4 RPL3L RPL23 RPS3A RPS12 ATF4 RPL36AL RPL36 TRIB3RPL18A ASNS gene RPS6 RPL38 5S rRNA RPL35A RPS4X IMPACTCEBPBRPL19 RPS27L RPL35 RPL38 RPS5 CEBPB,CEBPGRPL28 RPL11 RPS14 RPL32 RPS26 RPL10 RPL11 RPL35A RPS7 RPL9 RPLP2 EIF2S1:EIF2S2:EIF2S3RPS27A(77-156) RPS18 RPS27 RPL23 TRIB3 geneRPS20 RPS21 p-S52-EIF2S1 RPS17 RPS23 RPL3L RPL31 RPS29 RPS13 RPS20 tRNA GCN1 RPL31 RPL36 RPL18 RPS23 5.8S rRNA RPL22L1 28S rRNA RPS27L RPS13 RPL4 RPL8 ATF4RPS18 RPS16 RPL37A RPS26 5.8S rRNA RPS10 RPL4 RPL5 RPS23 RPL3 5.8S rRNA RPS17 RPS12 RPS15A RPS6 5.8S rRNA RPS27A(77-156) RPS14 RPL14 RPL15 RPS10 RPL3L ADPmRNA RPL39 RPS17 18S rRNA RPS2 RPL10L RPS4X RPS14 DDIT3 geneRPL14 RPS4X RPS27 RPS17 RPL10 5S rRNA RPL30 RPL28 RPS3 CEBPB,CEBPG,DDIT3RPS25 RPL34 RPL36A ATF4dimer:p-T69,T71-ATF2 dimer:DDIT3 geneRPL19 RPL40 RPL22 RPS16 ADPATF3 geneRPL3L RPL28 RPL37A mRNA EIF2S2 RPL23A EIF2S3 RPS13 RPL26 RPL26L1 RPL13A RPSA RPL27A RPS26 IMPACT:GCN1:80Sribosome:mRNARPLP0 RPL24 RPL26L1 RPL18 RPL38 FAU RPS27 RPL36 RPL35 RPL6 RPS3 EIF2S2 RPL8 RPS4Y2 RPS8 RPL21 IMPACT RPS5 RPL24 RPL27 RPS25 RPS11 CEBPG RPS9 RPL41 FAU GCN1 mRNA RPL6 RPL10A RPS20 FAU ATF3 gene RPL27A RPL3 RPL5 RPL21 RPL27A RPS24 28S rRNA RPS15 p-T899-EIF2AK4 RPL23 18S rRNA CEBPG RPL22L1 RPL29 RPL40 RPL18A RPL23A RPS15 RPS24 RPL13A RPL15 RPS28 RPL35 CEBPG RPS19 RPL10L RPS4Y1 RPL15 RPL11 RPL32 RPL41 RPS12 RPS9 RPS11 RPL29 RPL37 RPS21 RPS2 RPL12 RPLP0 RPS13 RPLP0 RPS4X RPL13 RPL21 RPS7 RPL5 RPL10L 5S rRNA ATF4 RPL36AL RPL14 RPL28 RPL35 RPS4Y2 RPL27A ATPRPS15A RPS19 RPL30 RPL7A RPS27A(77-156) RPL26L1 RPL36AL RPL7 RPL27 RPS28 RPL7A 5.8S rRNA RPS11 RPL18A RPL38 RPL10L RPS29 RPS4Y2 ATF4:CEBPB,CEBPG,DDIT3:TRIB3 geneRPS9 RPL31 p-T69,T71-ATF2RPS20 RPL8 RPL39L RPL8 RPS15A RPL23 RPS19 RPL38 RPL41 RPL35A RPSA RPL34 mRNA RPL17 RPL11 DDIT3RPL7 RPLP2 ATF4 RPL9 RPS20 RPS16 RPL22L1 28S rRNA RPS4X RPL3 RPL19 mRNA RPS11 RPS8 RPS2 RPL18A RPL37A RPL36A ATF4 mRNARPL9 RPL28 GCN1 RPL31 RPL13A RPL10 RPS21 tRNA RPL22 RPS5 RPL26L1 RPL10L RPS5 RPL41 RPLP2 RPL10A RPL10A RPS4Y2 RPL29 EIF2AK4 RPLP1 RPL19 RPL39 RPL24 EIF2S1 RPL30 RPL39 tRNARPS18 RPL32 RPS4Y1 ASNSRPL7A RPS15A RPL36AL RPSA RPS10 RPL32 3851, 23, 254, 18, 47


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: 75
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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