ATF4_HUMAN
ID ATF4_HUMAN Reviewed; 351 AA.
AC P18848; Q96AQ3; Q9UH31;
DT 01-NOV-1990, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 3.
DT 03-AUG-2022, entry version 229.
DE RecName: Full=Cyclic AMP-dependent transcription factor ATF-4 {ECO:0000305};
DE Short=cAMP-dependent transcription factor ATF-4 {ECO:0000305};
DE AltName: Full=Activating transcription factor 4 {ECO:0000303|PubMed:2516827};
DE AltName: Full=Cyclic AMP-responsive element-binding protein 2 {ECO:0000303|PubMed:1534408};
DE Short=CREB-2 {ECO:0000303|PubMed:1534408};
DE Short=cAMP-responsive element-binding protein 2 {ECO:0000303|PubMed:1534408};
DE AltName: Full=Tax-responsive enhancer element-binding protein 67 {ECO:0000303|PubMed:1847461};
DE Short=TaxREB67 {ECO:0000303|PubMed:1847461};
GN Name=ATF4 {ECO:0000303|PubMed:2516827, ECO:0000312|HGNC:HGNC:786};
GN Synonyms=CREB2 {ECO:0000303|PubMed:1534408},
GN TXREB {ECO:0000303|PubMed:1847461};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND VARIANT PRO-22.
RC TISSUE=Fibroblast;
RX PubMed=1847461; DOI=10.1128/jvi.65.3.1420-1426.1991;
RA Tsujimoto A., Nyunoya H., Morita T., Sato T., Shimotohno K.;
RT "Isolation of cDNAs for DNA-binding proteins which specifically bind to a
RT tax-responsive enhancer element in the long terminal repeat of human T-cell
RT leukemia virus type I.";
RL J. Virol. 65:1420-1426(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT PRO-22.
RC TISSUE=Leukemic T-cell;
RX PubMed=1534408; DOI=10.1073/pnas.89.11.4820;
RA Karpinski B.A., Morle G.D., Huggenvik J., Uhler M.D., Leiden J.M.;
RT "Molecular cloning of human CREB-2: an ATF/CREB transcription factor that
RT can negatively regulate transcription from the cAMP response element.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:4820-4824(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., Clamp M.,
RA Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C.,
RA Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E.,
RA Bridgeman A.M., Buck D., Burgess J., Burrill W.D., Burton J., Carder C.,
RA Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G.,
RA Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V.,
RA Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M.,
RA Ellington A.G., Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., Hunt S.E.,
RA Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F.,
RA Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M.,
RA Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A.,
RA Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D.,
RA Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y.,
RA Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S.,
RA Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E.,
RA Swann R.M., Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., Shintani A.,
RA Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L.,
RA Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P.,
RA Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P.,
RA Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q.,
RA Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J.,
RA Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J.,
RA Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D.,
RA Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T.,
RA Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P.,
RA Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K.,
RA Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L.,
RA McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J.,
RA Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E.,
RA Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P.,
RA Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y.,
RA Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT PRO-22.
RC TISSUE=Colon, Lung, Placenta, and Urinary bladder;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 274-341.
RX PubMed=2516827; DOI=10.1101/gad.3.12b.2083;
RA Hai T., Liu F., Coukos W.J., Green M.R.;
RT "Transcription factor ATF cDNA clones: an extensive family of leucine
RT zipper proteins able to selectively form DNA-binding heterodimers.";
RL Genes Dev. 3:2083-2090(1989).
RN [8]
RP ERRATUM OF PUBMED:2516827.
RA Hai T., Liu F., Coukos W.J., Green M.R.;
RL Genes Dev. 4:682-682(1990).
RN [9]
RP UBIQUITINATION.
RX PubMed=11238952; DOI=10.1128/mcb.21.6.2192-2202.2001;
RA Lassot I., Segeral E., Berlioz-Torrent C., Durand H., Groussin L., Hai T.,
RA Benarous R., Margottin-Goguet F.;
RT "ATF4 degradation relies on a phosphorylation-dependent interaction with
RT the SCF(betaTrCP) ubiquitin ligase.";
RL Mol. Cell. Biol. 21:2192-2202(2001).
RN [10]
RP FUNCTION.
RX PubMed=11960987; DOI=10.1074/jbc.m201959200;
RA Siu F., Bain P.J., LeBlanc-Chaffin R., Chen H., Kilberg M.S.;
RT "ATF4 is a mediator of the nutrient-sensing response pathway that activates
RT the human asparagine synthetase gene.";
RL J. Biol. Chem. 277:24120-24127(2002).
RN [11]
RP FUNCTION, PHOSPHORYLATION AT SER-245, AND MUTAGENESIS OF SER-245.
RX PubMed=15109498; DOI=10.1016/s0092-8674(04)00344-7;
RA Yang X., Matsuda K., Bialek P., Jacquot S., Masuoka H.C., Schinke T.,
RA Li L., Brancorsini S., Sassone-Corsi P., Townes T.M., Hanauer A.,
RA Karsenty G.;
RT "ATF4 is a substrate of RSK2 and an essential regulator of osteoblast
RT biology; implication for Coffin-Lowry Syndrome.";
RL Cell 117:387-398(2004).
RN [12]
RP FUNCTION.
RX PubMed=15775988; DOI=10.1038/sj.emboj.7600596;
RA Ohoka N., Yoshii S., Hattori T., Onozaki K., Hayashi H.;
RT "TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway
RT and is involved in cell death.";
RL EMBO J. 24:1243-1255(2005).
RN [13]
RP ACETYLATION AT LYS-311, UBIQUITINATION, SUBCELLULAR LOCATION, INTERACTION
RP WITH EP300, AND MUTAGENESIS OF SER-219 AND LYS-311.
RX PubMed=16219772; DOI=10.1074/jbc.m505294200;
RA Lassot I., Estrabaud E., Emiliani S., Benkirane M., Benarous R.,
RA Margottin-Goguet F.;
RT "p300 modulates ATF4 stability and transcriptional activity independently
RT of its acetyltransferase domain.";
RL J. Biol. Chem. 280:41537-41545(2005).
RN [14]
RP INTERACTION WITH TXLNG.
RX PubMed=15911876; DOI=10.1083/jcb.200412139;
RA Yu V.W., Ambartsoumian G., Verlinden L., Moir J.M., Prud'homme J.,
RA Gauthier C., Roughley P.J., St-Arnaud R.;
RT "FIAT represses ATF4-mediated transcription to regulate bone mass in
RT transgenic mice.";
RL J. Cell Biol. 169:591-601(2005).
RN [15]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH CEP290.
RX PubMed=16682973; DOI=10.1038/ng1786;
RA Sayer J.A., Otto E.A., O'toole J.F., Nurnberg G., Kennedy M.A., Becker C.,
RA Hennies H.C., Helou J., Attanasio M., Fausett B.V., Utsch B., Khanna H.,
RA Liu Y., Drummond I., Kawakami I., Kusakabe T., Tsuda M., Ma L., Lee H.,
RA Larson R.G., Allen S.J., Wilkinson C.J., Nigg E.A., Shou C., Lillo C.,
RA Williams D.S., Hoppe B., Kemper M.J., Neuhaus T., Parisi M.A., Glass I.A.,
RA Petry M., Kispert A., Gloy J., Ganner A., Walz G., Zhu X., Goldman D.,
RA Nurnberg P., Swaroop A., Leroux M.R., Hildebrandt F.;
RT "The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and
RT activates transcription factor ATF4.";
RL Nat. Genet. 38:674-681(2006).
RN [16]
RP HYDROXYLATION, AND MUTAGENESIS OF PRO-156; PRO-162; PRO-164; PRO-167 AND
RP PRO-174.
RX PubMed=17684156; DOI=10.1182/blood-2007-06-094441;
RA Koeditz J., Nesper J., Wottawa M., Stiehl D.P., Camenisch G., Franke C.,
RA Myllyharju J., Wenger R.H., Katschinski D.M.;
RT "Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor.";
RL Blood 110:3610-3617(2007).
RN [17]
RP FUNCTION, AND INTERACTION WITH DDIT3.
RX PubMed=18940792; DOI=10.1074/jbc.m806874200;
RA Su N., Kilberg M.S.;
RT "C/EBP homology protein (CHOP) interacts with activating transcription
RT factor 4 (ATF4) and negatively regulates the stress-dependent induction of
RT the asparagine synthetase gene.";
RL J. Biol. Chem. 283:35106-35117(2008).
RN [18]
RP SUBCELLULAR LOCATION, INTERACTION WITH NEK6, AND PHOSPHORYLATION.
RX PubMed=20873783; DOI=10.1021/pr100562w;
RA Vaz Meirelles G., Ferreira Lanza D.C., da Silva J.C., Santana Bernachi J.,
RA Paes Leme A.F., Kobarg J.;
RT "Characterization of hNek6 interactome reveals an important role for its
RT short N-terminal domain and colocalization with proteins at the
RT centrosome.";
RL J. Proteome Res. 9:6298-6316(2010).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [20]
RP INTERACTION WITH DAPK2 AND ZIPK/DAPK3.
RX PubMed=21408167; DOI=10.1371/journal.pone.0017344;
RA Shoval Y., Berissi H., Kimchi A., Pietrokovski S.;
RT "New modularity of DAP-kinases: alternative splicing of the DRP-1 gene
RT produces a ZIPk-like isoform.";
RL PLoS ONE 6:E17344-E17344(2011).
RN [21]
RP INTERACTION WITH ABRAXAS2, AND SUBCELLULAR LOCATION.
RX PubMed=22974638; DOI=10.1016/j.bbamcr.2012.08.020;
RA Ambivero C.T., Cilenti L., Zervos A.S.;
RT "ATF4 interacts with Abro1/KIAA0157 scaffold protein and participates in a
RT cytoprotective pathway.";
RL Biochim. Biophys. Acta 1823:2149-2156(2012).
RN [22]
RP PHOSPHORYLATION AT SER-215, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP THR-213 AND SER-215.
RX PubMed=23123191; DOI=10.1016/j.bbamcr.2012.10.025;
RA Ampofo E., Sokolowsky T., Goetz C., Montenarh M.;
RT "Functional interaction of protein kinase CK2 and activating transcription
RT factor 4 (ATF4), a key player in the cellular stress response.";
RL Biochim. Biophys. Acta 1833:439-451(2013).
RN [23]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-267, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25218447; DOI=10.1038/nsmb.2890;
RA Hendriks I.A., D'Souza R.C., Yang B., Verlaan-de Vries M., Mann M.,
RA Vertegaal A.C.;
RT "Uncovering global SUMOylation signaling networks in a site-specific
RT manner.";
RL Nat. Struct. Mol. Biol. 21:927-936(2014).
RN [24]
RP FUNCTION.
RX PubMed=26086088; DOI=10.1371/journal.pone.0130635;
RA D'Osualdo A., Anania V.G., Yu K., Lill J.R., Kaufman R.J., Matsuzawa S.,
RA Reed J.C.;
RT "Transcription factor ATF4 induces NLRP1 inflammasome expression during
RT endoplasmic reticulum stress.";
RL PLoS ONE 10:E0130635-E0130635(2015).
RN [25]
RP REVIEW.
RX PubMed=27629041; DOI=10.15252/embr.201642195;
RA Pakos-Zebrucka K., Koryga I., Mnich K., Ljujic M., Samali A., Gorman A.M.;
RT "The integrated stress response.";
RL EMBO Rep. 17:1374-1395(2016).
RN [26]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-53; LYS-259; LYS-267 AND LYS-272,
RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=28112733; DOI=10.1038/nsmb.3366;
RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA Nielsen M.L.;
RT "Site-specific mapping of the human SUMO proteome reveals co-modification
RT with phosphorylation.";
RL Nat. Struct. Mol. Biol. 24:325-336(2017).
RN [27]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=31444471; DOI=10.1038/s41380-019-0485-2;
RA Wang X., Ye F., Wen Z., Guo Z., Yu C., Huang W.K., Rojas Ringeling F.,
RA Su Y., Zheng W., Zhou G., Christian K.M., Song H., Zhang M., Ming G.L.;
RT "Structural interaction between DISC1 and ATF4 underlying transcriptional
RT and synaptic dysregulation in an iPSC model of mental disorders.";
RL Mol. Psychiatry 26:1346-1360(2021).
RN [28]
RP FUNCTION.
RX PubMed=32132706; DOI=10.1038/s41586-020-2076-4;
RA Fessler E., Eckl E.M., Schmitt S., Mancilla I.A., Meyer-Bender M.F.,
RA Hanf M., Philippou-Massier J., Krebs S., Zischka H., Jae L.T.;
RT "A pathway coordinated by DELE1 relays mitochondrial stress to the
RT cytosol.";
RL Nature 579:433-437(2020).
RN [29]
RP FUNCTION.
RX PubMed=32132707; DOI=10.1038/s41586-020-2078-2;
RA Guo X., Aviles G., Liu Y., Tian R., Unger B.A., Lin Y.T., Wiita A.P.,
RA Xu K., Correia M.A., Kampmann M.;
RT "Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI
RT pathway.";
RL Nature 579:427-432(2020).
RN [30]
RP FUNCTION, AND INDUCTION BY ER STRESS.
RX PubMed=33384352; DOI=10.1126/science.abb6896;
RA You K., Wang L., Chou C.H., Liu K., Nakata T., Jaiswal A., Yao J.,
RA Lefkovith A., Omar A., Perrigoue J.G., Towne J.E., Regev A., Graham D.B.,
RA Xavier R.J.;
RT "QRICH1 dictates the outcome of ER stress through transcriptional control
RT of proteostasis.";
RL Science 371:0-0(2021).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 279-341 IN COMPLEX WITH MOUSE
RP CEBPB, INTERACTION WITH CEBPB, AND DNA-BINDING.
RX PubMed=11018027; DOI=10.1074/jbc.m005594200;
RA Podust L.M., Krezel A.M., Kim Y.;
RT "Crystal structure of the CCAAT box/enhancer-binding protein beta
RT activating transcription factor-4 basic leucine zipper heterodimer in the
RT absence of DNA.";
RL J. Biol. Chem. 276:505-513(2001).
CC -!- FUNCTION: Transcription factor that binds the cAMP response element
CC (CRE) (consensus: 5'-GTGACGT[AC][AG]-3') and displays two biological
CC functions, as regulator of metabolic and redox processes under normal
CC cellular conditions, and as master transcription factor during
CC integrated stress response (ISR) (PubMed:17684156, PubMed:16682973,
CC PubMed:31444471, PubMed:32132707). Binds to asymmetric CRE's as a
CC heterodimer and to palindromic CRE's as a homodimer (By similarity).
CC Core effector of the ISR, which is required for adaptation to various
CC stress such as endoplasmic reticulum (ER) stress, amino acid
CC starvation, mitochondrial stress or oxidative stress (PubMed:32132707).
CC During ISR, ATF4 translation is induced via an alternative ribosome
CC translation re-initiation mechanism in response to EIF2S1/eIF-2-alpha
CC phosphorylation, and stress-induced ATF4 acts as a master transcription
CC factor of stress-responsive genes in order to promote cell recovery
CC (PubMed:32132706, PubMed:32132707). Promotes the transcription of genes
CC linked to amino acid sufficiency and resistance to oxidative stress to
CC protect cells against metabolic consequences of ER oxidation (By
CC similarity). Activates the transcription of NLRP1, possibly in concert
CC with other factors in response to ER stress (PubMed:26086088).
CC Activates the transcription of asparagine synthetase (ASNS) in response
CC to amino acid deprivation or ER stress (PubMed:11960987). However, when
CC associated with DDIT3/CHOP, the transcriptional activation of the ASNS
CC gene is inhibited in response to amino acid deprivation
CC (PubMed:18940792). Together with DDIT3/CHOP, mediates programmed cell
CC death by promoting the expression of genes involved in cellular amino
CC acid metabolic processes, mRNA translation and the terminal unfolded
CC protein response (terminal UPR), a cellular response that elicits
CC programmed cell death when ER stress is prolonged and unresolved (By
CC similarity). Together with DDIT3/CHOP, activates the transcription of
CC the IRS-regulator TRIB3 and promotes ER stress-induced neuronal cell
CC death by regulating the expression of BBC3/PUMA in response to ER
CC stress (PubMed:15775988). May cooperate with the UPR transcriptional
CC regulator QRICH1 to regulate ER protein homeostasis which is critical
CC for cell viability in response to ER stress (PubMed:33384352). In the
CC absence of stress, ATF4 translation is at low levels and it is required
CC for normal metabolic processes such as embryonic lens formation, fetal
CC liver hematopoiesis, bone development and synaptic plasticity (By
CC similarity). Acts as a regulator of osteoblast differentiation in
CC response to phosphorylation by RPS6KA3/RSK2: phosphorylation in
CC osteoblasts enhances transactivation activity and promotes expression
CC of osteoblast-specific genes and post-transcriptionally regulates the
CC synthesis of Type I collagen, the main constituent of the bone matrix
CC (PubMed:15109498). Cooperates with FOXO1 in osteoblasts to regulate
CC glucose homeostasis through suppression of beta-cell production and
CC decrease in insulin production (By similarity). Activates transcription
CC of SIRT4 (By similarity). Regulates the circadian expression of the
CC core clock component PER2 and the serotonin transporter SLC6A4 (By
CC similarity). Binds in a circadian time-dependent manner to the cAMP
CC response elements (CRE) in the SLC6A4 and PER2 promoters and
CC periodically activates the transcription of these genes (By
CC similarity). Mainly acts as a transcriptional activator in cellular
CC stress adaptation, but it can also act as a transcriptional repressor:
CC acts as a regulator of synaptic plasticity by repressing transcription,
CC thereby inhibiting induction and maintenance of long-term memory (By
CC similarity). Regulates synaptic functions via interaction with DISC1 in
CC neurons, which inhibits ATF4 transcription factor activity by
CC disrupting ATF4 dimerization and DNA-binding (PubMed:31444471).
CC {ECO:0000250|UniProtKB:Q06507, ECO:0000269|PubMed:11960987,
CC ECO:0000269|PubMed:15109498, ECO:0000269|PubMed:15775988,
CC ECO:0000269|PubMed:16682973, ECO:0000269|PubMed:17684156,
CC ECO:0000269|PubMed:18940792, ECO:0000269|PubMed:26086088,
CC ECO:0000269|PubMed:31444471, ECO:0000269|PubMed:32132706,
CC ECO:0000269|PubMed:32132707, ECO:0000269|PubMed:33384352}.
CC -!- FUNCTION: (Microbial infection) Binds to a Tax-responsive enhancer
CC element in the long terminal repeat of HTLV-I.
CC {ECO:0000269|PubMed:1847461}.
CC -!- SUBUNIT: Binds DNA as a homodimer and as a heterodimer
CC (PubMed:11018027). Heterodimer; heterodimerizes with CEBPB
CC (PubMed:11018027). Heterodimer; heterodimerizes with DDIT3/CHOP
CC (PubMed:18940792). Interacts with CEP290 (via an N-terminal region)
CC (PubMed:16682973). Interacts with NEK6, DAPK2 (isoform 2) and
CC ZIPK/DAPK3 (PubMed:20873783, PubMed:21408167). Interacts (via its
CC leucine zipper domain) with GABBR1 and GABBR2 (via their C-termini) (By
CC similarity). Forms a heterodimer with TXLNG in osteoblasts
CC (PubMed:15911876). Interacts (via its DNA binding domain) with FOXO1
CC (C-terminal half); the interaction occurs in osteoblasts and regulates
CC glucose homeostasis through suppression of beta-cell proliferation and
CC a decrease in insulin production (By similarity). Interacts with SATB2;
CC the interaction results in enhanced DNA binding and transactivation by
CC these transcription factors (By similarity). Interacts with ABRAXAS2
CC (PubMed:22974638). Interacts with TRIB3, inhibiting the transactivation
CC activity of ATF4 (By similarity). Interacts with DISC1; which inhibits
CC ATF4 transcription factor activity by disrupting ATF4 dimerization and
CC DNA-binding (By similarity). Interacts with EP300/p300; EP300/p300
CC stabilizes ATF4 and increases its transcriptional activity
CC independently of its catalytic activity by preventing its
CC ubiquitination (PubMed:16219772). {ECO:0000250|UniProtKB:Q06507,
CC ECO:0000250|UniProtKB:Q9ES19, ECO:0000269|PubMed:11018027,
CC ECO:0000269|PubMed:15911876, ECO:0000269|PubMed:16219772,
CC ECO:0000269|PubMed:16682973, ECO:0000269|PubMed:18940792,
CC ECO:0000269|PubMed:20873783, ECO:0000269|PubMed:21408167,
CC ECO:0000269|PubMed:22974638}.
CC -!- INTERACTION:
CC P18848; Q9BXS5: AP1M1; NbExp=3; IntAct=EBI-492498, EBI-541426;
CC P18848; P15336: ATF2; NbExp=2; IntAct=EBI-492498, EBI-1170906;
CC P18848; P18847: ATF3; NbExp=9; IntAct=EBI-492498, EBI-712767;
CC P18848; P18848: ATF4; NbExp=2; IntAct=EBI-492498, EBI-492498;
CC P18848; Q16520: BATF; NbExp=3; IntAct=EBI-492498, EBI-749503;
CC P18848; Q9NR55: BATF3; NbExp=2; IntAct=EBI-492498, EBI-10312707;
CC P18848; Q13515: BFSP2; NbExp=11; IntAct=EBI-492498, EBI-10229433;
CC P18848; A0A0S2Z507: BTRC; NbExp=6; IntAct=EBI-492498, EBI-16429247;
CC P18848; B7Z3H4: BTRC; NbExp=3; IntAct=EBI-492498, EBI-16429269;
CC P18848; Q9Y297: BTRC; NbExp=21; IntAct=EBI-492498, EBI-307461;
CC P18848; Q9Y297-2: BTRC; NbExp=5; IntAct=EBI-492498, EBI-8826333;
CC P18848; P55212: CASP6; NbExp=3; IntAct=EBI-492498, EBI-718729;
CC P18848; Q9BWC9: CCDC106; NbExp=14; IntAct=EBI-492498, EBI-711501;
CC P18848; P49715: CEBPA; NbExp=4; IntAct=EBI-492498, EBI-1172054;
CC P18848; P17676: CEBPB; NbExp=2; IntAct=EBI-492498, EBI-969696;
CC P18848; P49716: CEBPD; NbExp=2; IntAct=EBI-492498, EBI-7962058;
CC P18848; Q15744: CEBPE; NbExp=2; IntAct=EBI-492498, EBI-3907048;
CC P18848; P53567: CEBPG; NbExp=16; IntAct=EBI-492498, EBI-740209;
CC P18848; Q9Y592-2: CEP83; NbExp=3; IntAct=EBI-492498, EBI-11123098;
CC P18848; Q9NS37: CREBZF; NbExp=7; IntAct=EBI-492498, EBI-632965;
CC P18848; Q9UIK4-2: DAPK2; NbExp=2; IntAct=EBI-492498, EBI-9693115;
CC P18848; P35638: DDIT3; NbExp=5; IntAct=EBI-492498, EBI-742651;
CC P18848; Q9NRI5: DISC1; NbExp=4; IntAct=EBI-492498, EBI-529989;
CC P18848; Q9NV70: EXOC1; NbExp=3; IntAct=EBI-492498, EBI-1045313;
CC P18848; P01100: FOS; NbExp=4; IntAct=EBI-492498, EBI-852851;
CC P18848; P15407: FOSL1; NbExp=2; IntAct=EBI-492498, EBI-744510;
CC P18848; Q96CN9: GCC1; NbExp=6; IntAct=EBI-492498, EBI-746252;
CC P18848; Q92805: GOLGA1; NbExp=11; IntAct=EBI-492498, EBI-6164177;
CC P18848; Q0D2H9: GOLGA8DP; NbExp=3; IntAct=EBI-492498, EBI-10181276;
CC P18848; Q08AF8: GOLGA8G; NbExp=7; IntAct=EBI-492498, EBI-10181260;
CC P18848; Q13227: GPS2; NbExp=13; IntAct=EBI-492498, EBI-713355;
CC P18848; Q99871: HAUS7; NbExp=3; IntAct=EBI-492498, EBI-395719;
CC P18848; Q8WYK2: JDP2; NbExp=3; IntAct=EBI-492498, EBI-1248415;
CC P18848; P05412: JUN; NbExp=4; IntAct=EBI-492498, EBI-852823;
CC P18848; P17275: JUNB; NbExp=3; IntAct=EBI-492498, EBI-748062;
CC P18848; P13473-2: LAMP2; NbExp=3; IntAct=EBI-492498, EBI-21591415;
CC P18848; O95751: LDOC1; NbExp=10; IntAct=EBI-492498, EBI-740738;
CC P18848; O75444: MAF; NbExp=3; IntAct=EBI-492498, EBI-2805091;
CC P18848; Q96NT1: NAP1L5; NbExp=3; IntAct=EBI-492498, EBI-713627;
CC P18848; O14777: NDC80; NbExp=8; IntAct=EBI-492498, EBI-715849;
CC P18848; Q16236: NFE2L2; NbExp=8; IntAct=EBI-492498, EBI-2007911;
CC P18848; P19387: POLR2C; NbExp=6; IntAct=EBI-492498, EBI-394729;
CC P18848; O75400-2: PRPF40A; NbExp=3; IntAct=EBI-492498, EBI-5280197;
CC P18848; Q86UD0: SAPCD2; NbExp=3; IntAct=EBI-492498, EBI-2561646;
CC P18848; Q9Y371: SH3GLB1; NbExp=3; IntAct=EBI-492498, EBI-2623095;
CC P18848; A2RTX5: TARS3; NbExp=3; IntAct=EBI-492498, EBI-1056629;
CC P18848; Q96RU7: TRIB3; NbExp=16; IntAct=EBI-492498, EBI-492476;
CC P18848; P02766: TTR; NbExp=3; IntAct=EBI-492498, EBI-711909;
CC P18848; O54784: Dapk3; Xeno; NbExp=2; IntAct=EBI-492498, EBI-77359;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16682973,
CC ECO:0000269|PubMed:22974638, ECO:0000269|PubMed:23123191,
CC ECO:0000269|PubMed:31444471}. Nucleus speckle
CC {ECO:0000269|PubMed:16219772}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q9ES19}. Cell membrane
CC {ECO:0000250|UniProtKB:Q9ES19}. Cytoplasm, cytoskeleton, microtubule
CC organizing center, centrosome {ECO:0000269|PubMed:20873783}.
CC Note=Colocalizes with GABBR1 in hippocampal neuron dendritic membranes
CC (By similarity). Colocalizes with NEK6 at the centrosome
CC (PubMed:20873783). Recruited to nuclear speckles following interaction
CC with EP300/p300 (PubMed:16219772). {ECO:0000250|UniProtKB:Q9ES19,
CC ECO:0000269|PubMed:16219772, ECO:0000269|PubMed:20873783}.
CC -!- INDUCTION: Regulated at the translational level in response to various
CC stress such as endoplasmic reticulum stress, amino acid starvation or
CC oxidative stress (PubMed:27629041, PubMed:33384352). In the absence of
CC stress, ribosomes re-initiate translation at an inhibitory open reading
CC frame (uORF) upstream of the ATF4 transcript, which precludes AFT4
CC translation. In response to stress and subsequent EIF2S1/eIF-2-alpha
CC phosphorylation, ribosomes bypass the inhibitory uORF and re-initiate
CC translation at the AFT4 coding sequence (PubMed:27629041).
CC {ECO:0000269|PubMed:33384352, ECO:0000303|PubMed:27629041}.
CC -!- DOMAIN: The BetaTrCP degron motif promotes binding to BTRC when
CC phosphorylated. {ECO:0000269|PubMed:11238952}.
CC -!- PTM: Ubiquitinated by SCF(BTRC) in response to mTORC1 signal, followed
CC by proteasomal degradation and leading to down-regulate expression of
CC SIRT4 (PubMed:11238952). Interaction with EP300/p300 inhibits
CC ubiquitination by SCF(BTRC) (PubMed:16219772).
CC {ECO:0000269|PubMed:11238952, ECO:0000269|PubMed:16219772}.
CC -!- PTM: Phosphorylation at Ser-245 by RPS6KA3/RSK2 in osteoblasts enhances
CC transactivation activity and promotes osteoblast differentiation
CC (PubMed:15109498). Phosphorylated on the betaTrCP degron motif at Ser-
CC 219, followed by phosphorylation at Thr-213, Ser-224, Ser-231, Ser-235
CC and Ser-248, promoting interaction with BTRC and ubiquitination (By
CC similarity). Phosphorylation is promoted by mTORC1 (By similarity).
CC Phosphorylation at Ser-215 by CK2 decreases its stability
CC (PubMed:23123191). Phosphorylated by NEK6 (PubMed:20873783).
CC {ECO:0000250|UniProtKB:Q06507, ECO:0000269|PubMed:15109498,
CC ECO:0000269|PubMed:20873783, ECO:0000269|PubMed:23123191}.
CC -!- PTM: Hydroxylated by PHD3, leading to decreased protein stability.
CC {ECO:0000305|PubMed:17684156}.
CC -!- SIMILARITY: Belongs to the bZIP family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/ATF4ID44413ch22q13.html";
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DR EMBL; D90209; BAA14234.1; -; mRNA.
DR EMBL; M86842; AAA52071.1; -; mRNA.
DR EMBL; CR456384; CAG30270.1; -; mRNA.
DR EMBL; AL022312; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471095; EAW60341.1; -; Genomic_DNA.
DR EMBL; CH471095; EAW60342.1; -; Genomic_DNA.
DR EMBL; BC008090; AAH08090.1; -; mRNA.
DR EMBL; BC011994; AAH11994.1; -; mRNA.
DR EMBL; BC016855; AAH16855.1; -; mRNA.
DR EMBL; BC022088; AAH22088.1; -; mRNA.
DR EMBL; BC024775; AAH24775.1; -; mRNA.
DR EMBL; BC044895; AAH44895.1; -; mRNA.
DR EMBL; BC073754; AAH73754.1; -; mRNA.
DR EMBL; BC073990; AAH73990.1; -; mRNA.
DR CCDS; CCDS13996.1; -.
DR PIR; A45377; A45377.
DR RefSeq; NP_001666.2; NM_001675.4.
DR RefSeq; NP_877962.1; NM_182810.2.
DR RefSeq; XP_016884296.1; XM_017028807.1.
DR PDB; 1CI6; X-ray; 2.60 A; A=280-341.
DR PDBsum; 1CI6; -.
DR AlphaFoldDB; P18848; -.
DR SMR; P18848; -.
DR BioGRID; 106958; 94.
DR ComplexPortal; CPX-6385; bZIP transcription factor complex, ATF3-ATF4.
DR ComplexPortal; CPX-6408; bZIP transcription factor complex, ATF2-ATF4.
DR ComplexPortal; CPX-6521; bZIP transcription factor complex, ATF4-ATF4.
DR ComplexPortal; CPX-6522; bZIP transcription factor complex, ATF4-BATF.
DR ComplexPortal; CPX-6523; bZIP transcription factor complex, ATF4-BATF2.
DR ComplexPortal; CPX-6524; bZIP transcription factor complex, ATF4-BATF3.
DR ComplexPortal; CPX-6525; bZIP transcription factor complex, ATF4-CEBPA.
DR ComplexPortal; CPX-6526; bZIP transcription factor complex, ATF4-CEBPB.
DR ComplexPortal; CPX-6527; bZIP transcription factor complex, ATF4-CEBPG.
DR ComplexPortal; CPX-6528; bZIP transcription factor complex, ATF4-CEBPD.
DR ComplexPortal; CPX-6529; bZIP transcription factor complex, ATF4-CEBPE.
DR ComplexPortal; CPX-6541; bZIP transcription factor complex, ATF4-CREB3.
DR ComplexPortal; CPX-6542; bZIP transcription factor complex, ATF4-CREBZF.
DR ComplexPortal; CPX-6543; bZIP transcription factor complex, ATF4-DDIT3.
DR ComplexPortal; CPX-6562; bZIP transcription factor complex, ATF4-JUN.
DR ComplexPortal; CPX-6563; bZIP transcription factor complex, ATF4-JUNB.
DR ComplexPortal; CPX-6564; bZIP transcription factor complex, ATF4-FOS.
DR ComplexPortal; CPX-6565; bZIP transcription factor complex, ATF4-FOSL1.
DR ComplexPortal; CPX-6566; bZIP transcription factor complex, ATF4-MAF.
DR ComplexPortal; CPX-6567; bZIP transcription factor complex, ATF4-MAFB.
DR ComplexPortal; CPX-6568; bZIP transcription factor complex, ATF4-NFE2.
DR ComplexPortal; CPX-6569; bZIP transcription factor complex, ATF4-NFE2L1.
DR ComplexPortal; CPX-6570; bZIP transcription factor complex, ATF4-NFE2L2.
DR ComplexPortal; CPX-6572; bZIP transcription factor complex, ATF4-NFE2L3.
DR ComplexPortal; CPX-8; bZIP transcription factor complex, ATF4-CREB1.
DR ComplexPortal; CPX-9; bZIP transcription factor complex, ATF1-ATF4.
DR CORUM; P18848; -.
DR DIP; DIP-354N; -.
DR ELM; P18848; -.
DR IntAct; P18848; 80.
DR MINT; P18848; -.
DR STRING; 9606.ENSP00000336790; -.
DR BindingDB; P18848; -.
DR DrugBank; DB00852; Pseudoephedrine.
DR iPTMnet; P18848; -.
DR PhosphoSitePlus; P18848; -.
DR BioMuta; ATF4; -.
DR DMDM; 116241262; -.
DR EPD; P18848; -.
DR jPOST; P18848; -.
DR MassIVE; P18848; -.
DR PaxDb; P18848; -.
DR PeptideAtlas; P18848; -.
DR PRIDE; P18848; -.
DR ProteomicsDB; 53615; -.
DR ABCD; P18848; 1 sequenced antibody.
DR Antibodypedia; 12687; 1140 antibodies from 47 providers.
DR DNASU; 468; -.
DR Ensembl; ENST00000337304.2; ENSP00000336790.2; ENSG00000128272.18.
DR Ensembl; ENST00000396680.3; ENSP00000379912.1; ENSG00000128272.18.
DR Ensembl; ENST00000404241.6; ENSP00000384587.2; ENSG00000128272.18.
DR Ensembl; ENST00000674568.2; ENSP00000501783.2; ENSG00000128272.18.
DR Ensembl; ENST00000674835.2; ENSP00000502610.2; ENSG00000128272.18.
DR Ensembl; ENST00000674920.3; ENSP00000501863.1; ENSG00000128272.18.
DR Ensembl; ENST00000676346.2; ENSP00000502400.2; ENSG00000128272.18.
DR Ensembl; ENST00000679776.1; ENSP00000505360.1; ENSG00000128272.18.
DR GeneID; 468; -.
DR KEGG; hsa:468; -.
DR MANE-Select; ENST00000674920.3; ENSP00000501863.1; NM_182810.3; NP_877962.1.
DR UCSC; uc003axz.4; human.
DR CTD; 468; -.
DR DisGeNET; 468; -.
DR GeneCards; ATF4; -.
DR HGNC; HGNC:786; ATF4.
DR HPA; ENSG00000128272; Low tissue specificity.
DR MIM; 604064; gene.
DR neXtProt; NX_P18848; -.
DR OpenTargets; ENSG00000128272; -.
DR PharmGKB; PA25086; -.
DR VEuPathDB; HostDB:ENSG00000128272; -.
DR eggNOG; KOG4571; Eukaryota.
DR GeneTree; ENSGT00530000063801; -.
DR HOGENOM; CLU_055748_1_0_1; -.
DR InParanoid; P18848; -.
DR OMA; ATIQEFH; -.
DR OrthoDB; 1524842at2759; -.
DR PhylomeDB; P18848; -.
DR TreeFam; TF316136; -.
DR PathwayCommons; P18848; -.
DR Reactome; R-HSA-380994; ATF4 activates genes in response to endoplasmic reticulum stress.
DR Reactome; R-HSA-381042; PERK regulates gene expression.
DR Reactome; R-HSA-381183; ATF6 (ATF6-alpha) activates chaperone genes.
DR Reactome; R-HSA-9633012; Response of EIF2AK4 (GCN2) to amino acid deficiency.
DR Reactome; R-HSA-9648895; Response of EIF2AK1 (HRI) to heme deficiency.
DR Reactome; R-HSA-9759194; Nuclear events mediated by NFE2L2.
DR SignaLink; P18848; -.
DR SIGNOR; P18848; -.
DR BioGRID-ORCS; 468; 447 hits in 1072 CRISPR screens.
DR ChiTaRS; ATF4; human.
DR EvolutionaryTrace; P18848; -.
DR GeneWiki; ATF4; -.
DR GenomeRNAi; 468; -.
DR Pharos; P18848; Tbio.
DR PRO; PR:P18848; -.
DR Proteomes; UP000005640; Chromosome 22.
DR RNAct; P18848; protein.
DR Bgee; ENSG00000128272; Expressed in muscle layer of sigmoid colon and 96 other tissues.
DR ExpressionAtlas; P18848; baseline and differential.
DR Genevisible; P18848; HS.
DR GO; GO:1990590; C:ATF1-ATF4 transcription factor complex; IDA:ParkinsonsUK-UCL.
DR GO; GO:1990589; C:ATF4-CREB1 transcription factor complex; IDA:ParkinsonsUK-UCL.
DR GO; GO:1990617; C:CHOP-ATF4 complex; IDA:ParkinsonsUK-UCL.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005737; C:cytoplasm; IDA:ParkinsonsUK-UCL.
DR GO; GO:0032590; C:dendrite membrane; IEA:Ensembl.
DR GO; GO:1990037; C:Lewy body core; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005815; C:microtubule organizing center; IEA:UniProtKB-SubCell.
DR GO; GO:0043005; C:neuron projection; IDA:ParkinsonsUK-UCL.
DR GO; GO:0034399; C:nuclear periphery; IDA:ParkinsonsUK-UCL.
DR GO; GO:0016607; C:nuclear speck; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; IPI:ComplexPortal.
DR GO; GO:0008140; F:cAMP response element binding protein binding; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:ParkinsonsUK-UCL.
DR GO; GO:0140296; F:general transcription initiation factor binding; IEA:Ensembl.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0043522; F:leucine zipper domain binding; IDA:ParkinsonsUK-UCL.
DR GO; GO:1990841; F:promoter-specific chromatin binding; IDA:MGI.
DR GO; GO:0008022; F:protein C-terminus binding; IEA:Ensembl.
DR GO; GO:0046982; F:protein heterodimerization activity; ISS:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:ParkinsonsUK-UCL.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:ParkinsonsUK-UCL.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:ParkinsonsUK-UCL.
DR GO; GO:0030282; P:bone mineralization; ISS:UniProtKB.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; IEA:Ensembl.
DR GO; GO:0034198; P:cellular response to amino acid starvation; ISS:UniProtKB.
DR GO; GO:1903351; P:cellular response to dopamine; IMP:CAFA.
DR GO; GO:0042149; P:cellular response to glucose starvation; IMP:ParkinsonsUK-UCL.
DR GO; GO:1990253; P:cellular response to leucine starvation; IDA:MGI.
DR GO; GO:0034599; P:cellular response to oxidative stress; ISS:UniProtKB.
DR GO; GO:0090650; P:cellular response to oxygen-glucose deprivation; IEA:Ensembl.
DR GO; GO:0034644; P:cellular response to UV; ISS:UniProtKB.
DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0035162; P:embryonic hemopoiesis; ISS:UniProtKB.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; ISS:UniProtKB.
DR GO; GO:0007214; P:gamma-aminobutyric acid signaling pathway; IEA:Ensembl.
DR GO; GO:0006094; P:gluconeogenesis; ISS:UniProtKB.
DR GO; GO:0140468; P:HRI-mediated signaling; IDA:UniProtKB.
DR GO; GO:0140467; P:integrated stress response signaling; IDA:UniProtKB.
DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; ISS:UniProtKB.
DR GO; GO:0070982; P:L-asparagine metabolic process; IDA:UniProtKB.
DR GO; GO:0070309; P:lens fiber cell morphogenesis; ISS:UniProtKB.
DR GO; GO:0042789; P:mRNA transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:1903204; P:negative regulation of oxidative stress-induced neuron death; IGI:ParkinsonsUK-UCL.
DR GO; GO:0043267; P:negative regulation of potassium ion transport; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0032057; P:negative regulation of translational initiation in response to stress; ISS:UniProtKB.
DR GO; GO:0030182; P:neuron differentiation; IEA:Ensembl.
DR GO; GO:0036499; P:PERK-mediated unfolded protein response; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:ParkinsonsUK-UCL.
DR GO; GO:0070169; P:positive regulation of biomineral tissue development; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ARUK-UCL.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:2000120; P:positive regulation of sodium-dependent phosphate transport; IEA:Ensembl.
DR GO; GO:0045943; P:positive regulation of transcription by RNA polymerase I; IMP:ParkinsonsUK-UCL.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0061395; P:positive regulation of transcription from RNA polymerase II promoter in response to arsenic-containing substance; TAS:ParkinsonsUK-UCL.
DR GO; GO:1990440; P:positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress; IDA:ParkinsonsUK-UCL.
DR GO; GO:0036091; P:positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress; IMP:ParkinsonsUK-UCL.
DR GO; GO:0036003; P:positive regulation of transcription from RNA polymerase II promoter in response to stress; IC:ParkinsonsUK-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:1905461; P:positive regulation of vascular associated smooth muscle cell apoptotic process; IEA:Ensembl.
DR GO; GO:0010575; P:positive regulation of vascular endothelial growth factor production; IMP:ParkinsonsUK-UCL.
DR GO; GO:0045667; P:regulation of osteoblast differentiation; IDA:UniProtKB.
DR GO; GO:0048167; P:regulation of synaptic plasticity; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IDA:UniProtKB.
DR GO; GO:1990737; P:response to manganese-induced endoplasmic reticulum stress; IEA:Ensembl.
DR GO; GO:0031667; P:response to nutrient levels; IDA:UniProtKB.
DR GO; GO:0009636; P:response to toxic substance; IEA:Ensembl.
DR GO; GO:0006366; P:transcription by RNA polymerase II; ISS:UniProtKB.
DR InterPro; IPR029811; ATF4.
DR InterPro; IPR004827; bZIP.
DR InterPro; IPR046347; bZIP_sf.
DR PANTHER; PTHR13044:SF32; PTHR13044:SF32; 1.
DR Pfam; PF00170; bZIP_1; 1.
DR SMART; SM00338; BRLZ; 1.
DR SUPFAM; SSF57959; SSF57959; 1.
DR PROSITE; PS50217; BZIP; 1.
DR PROSITE; PS00036; BZIP_BASIC; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Activator; Biological rhythms; Cell membrane;
KW Coiled coil; Cytoplasm; Cytoskeleton; DNA-binding; Hydroxylation;
KW Isopeptide bond; Membrane; Nucleus; Phosphoprotein; Reference proteome;
KW Repressor; Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1..351
FT /note="Cyclic AMP-dependent transcription factor ATF-4"
FT /id="PRO_0000076584"
FT DOMAIN 278..341
FT /note="bZIP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 210..268
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 280..300
FT /note="Basic motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 305..341
FT /note="Interaction with GABBR1"
FT /evidence="ECO:0000250"
FT REGION 306..334
FT /note="Leucine-zipper"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT COILED 280..340
FT MOTIF 215..224
FT /note="BetaTrCP degron motif"
FT /evidence="ECO:0000269|PubMed:11238952"
FT COMPBIAS 217..245
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 213
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 215
FT /note="Phosphoserine; by CK2"
FT /evidence="ECO:0000269|PubMed:23123191"
FT MOD_RES 219
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 224
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 231
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 235
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 236
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 245
FT /note="Phosphoserine; by RPS6KA3"
FT /evidence="ECO:0000269|PubMed:15109498"
FT MOD_RES 248
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 311
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:16219772"
FT CROSSLNK 53
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT CROSSLNK 259
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT CROSSLNK 267
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:25218447,
FT ECO:0007744|PubMed:28112733"
FT CROSSLNK 272
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT VARIANT 22
FT /note="Q -> P (in dbSNP:rs4894)"
FT /evidence="ECO:0000269|PubMed:1534408,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:1847461"
FT /id="VAR_028253"
FT VARIANT 258
FT /note="P -> A (in dbSNP:rs1803323)"
FT /id="VAR_029259"
FT VARIANT 322
FT /note="E -> D (in dbSNP:rs1803324)"
FT /id="VAR_014768"
FT MUTAGEN 156
FT /note="P->A: Increased stability in low oxygen conditions;
FT when associated with A-162, A-164, A-167 and A-174."
FT /evidence="ECO:0000269|PubMed:17684156"
FT MUTAGEN 162
FT /note="P->A: Increased stability in low oxygen conditions;
FT when associated with A-156, A-164, A-167 and A-174."
FT /evidence="ECO:0000269|PubMed:17684156"
FT MUTAGEN 164
FT /note="P->A: Increased stability in low oxygen conditions;
FT when associated with A-156, A-162, A-167 and A-174."
FT /evidence="ECO:0000269|PubMed:17684156"
FT MUTAGEN 167
FT /note="P->A: Increased stability in low oxygen conditions;
FT when associated with A-156, A-162, A-164 and A-174."
FT /evidence="ECO:0000269|PubMed:17684156"
FT MUTAGEN 174
FT /note="P->A: Increased stability in low oxygen conditions;
FT when associated with A-156, A-162, A-164 and A-167."
FT /evidence="ECO:0000269|PubMed:17684156"
FT MUTAGEN 213
FT /note="T->A: Does not affect phosphorylation by CK2."
FT /evidence="ECO:0000269|PubMed:23123191"
FT MUTAGEN 215
FT /note="S->A: Abolished phosphorylation by CK2 leading to
FT increased stability."
FT /evidence="ECO:0000269|PubMed:23123191"
FT MUTAGEN 219
FT /note="S->N: Abolished phosphorylation on the betaTrCP
FT degron motif, interaction with BTRC and subsequent
FT ubiquitination."
FT /evidence="ECO:0000269|PubMed:16219772"
FT MUTAGEN 245
FT /note="S->A: Abolished phosphorylation by RPS6KA3/RSK2."
FT /evidence="ECO:0000269|PubMed:15109498"
FT MUTAGEN 311
FT /note="K->R: Decreased acetylation without affecting
FT ubiquitination by SCF(BTRC)."
FT /evidence="ECO:0000269|PubMed:16219772"
FT CONFLICT 284
FT /note="K -> R (in Ref. 7; no nucleotide entry)"
FT /evidence="ECO:0000305"
FT CONFLICT 290
FT /note="T -> R (in Ref. 7; no nucleotide entry)"
FT /evidence="ECO:0000305"
FT CONFLICT 329..331
FT /note="KEI -> REK (in Ref. 7; no nucleotide entry)"
FT /evidence="ECO:0000305"
FT CONFLICT 338
FT /note="I -> L (in Ref. 7; no nucleotide entry)"
FT /evidence="ECO:0000305"
FT HELIX 288..340
FT /evidence="ECO:0007829|PDB:1CI6"
SQ SEQUENCE 351 AA; 38590 MW; 3BBB7379DC3B0D07 CRC64;
MTEMSFLSSE VLVGDLMSPF DQSGLGAEES LGLLDDYLEV AKHFKPHGFS SDKAKAGSSE
WLAVDGLVSP SNNSKEDAFS GTDWMLEKMD LKEFDLDALL GIDDLETMPD DLLTTLDDTC
DLFAPLVQET NKQPPQTVNP IGHLPESLTK PDQVAPFTFL QPLPLSPGVL SSTPDHSFSL
ELGSEVDITE GDRKPDYTAY VAMIPQCIKE EDTPSDNDSG ICMSPESYLG SPQHSPSTRG
SPNRSLPSPG VLCGSARPKP YDPPGEKMVA AKVKGEKLDK KLKKMEQNKT AATRYRQKKR
AEQEALTGEC KELEKKNEAL KERADSLAKE IQYLKDLIEE VRKARGKKRV P
