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 27-MAR-2024, entry version 238. 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}, TXREB GN {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="https://atlasgeneticsoncology.org/gene/44413/ATF4"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 95. 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; 9606-ENSP00000336790; -. DR PeptideAtlas; P18848; -. DR ProteomicsDB; 53615; -. DR ABCD; P18848; 1 sequenced antibody. DR Antibodypedia; 12687; 1290 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 AGR; HGNC:786; -. 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; 4843682at2759; -. 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-9818027; NFE2L2 regulating anti-oxidant/detoxification enzymes. DR Reactome; R-HSA-9818035; NFE2L2 regulating ER-stress associated genes. DR SignaLink; P18848; -. DR SIGNOR; P18848; -. DR BioGRID-ORCS; 468; 451 hits in 1147 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 98 other cell types or tissues. DR ExpressionAtlas; P18848; baseline and differential. 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:0005813; C:centrosome; IEA:UniProtKB-SubCell. 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:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0032590; C:dendrite membrane; IEA:Ensembl. DR GO; GO:1990037; C:Lewy body core; IDA:ParkinsonsUK-UCL. 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; IDA:HPA. 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: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:0034198; P:cellular response to amino acid starvation; ISS:UniProtKB. DR GO; GO:0042149; P:cellular response to glucose starvation; IMP:ParkinsonsUK-UCL. DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl. DR GO; GO:1990253; P:cellular response to leucine starvation; IDA:MGI. DR GO; GO:0034599; P:cellular response to oxidative stress; IMP:ParkinsonsUK-UCL. 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:0006874; P:intracellular calcium ion homeostasis; IEA:Ensembl. 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:1903377; P:negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; 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:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. 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: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:0006355; P:regulation of DNA-templated transcription; ISS:UniProtKB. 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; ISO:ComplexPortal. 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 CDD; cd14692; bZIP_ATF4; 1. DR Gene3D; 1.20.5.170; -; 1. DR InterPro; IPR004827; bZIP. DR InterPro; IPR046347; bZIP_sf. DR PANTHER; PTHR13044; ACTIVATING TRANSCRIPTION FACTOR ATF 4/5; 1. DR PANTHER; PTHR13044:SF2; CYCLIC AMP-DEPENDENT TRANSCRIPTION FACTOR ATF-4; 1. DR Pfam; PF00170; bZIP_1; 1. DR SMART; SM00338; BRLZ; 1. DR SUPFAM; SSF57959; Leucine zipper domain; 1. DR PROSITE; PS50217; BZIP; 1. DR PROSITE; PS00036; BZIP_BASIC; 1. DR Genevisible; P18848; HS. 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 //