ID ATF4_MOUSE Reviewed; 349 AA. AC Q06507; Q5U4B2; Q61906; DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot. DT 27-JUL-2011, sequence version 2. DT 27-MAR-2024, entry version 176. 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:11018027}; DE AltName: Full=C/EBP-related ATF {ECO:0000303|PubMed:8506317}; DE Short=C/ATF {ECO:0000303|PubMed:8506317}; DE AltName: Full=Cyclic AMP-responsive element-binding protein 2 {ECO:0000303|PubMed:10885750}; DE Short=CREB-2 {ECO:0000303|PubMed:10885750}; DE Short=cAMP-responsive element-binding protein 2 {ECO:0000303|PubMed:10885750}; GN Name=Atf4 {ECO:0000303|PubMed:10096021, ECO:0000312|MGI:MGI:88096}; GN Synonyms=Creb2 {ECO:0000303|PubMed:10885750}; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBUNIT, AND SUBCELLULAR LOCATION. RC TISSUE=Adipocyte; RX PubMed=8506317; DOI=10.1073/pnas.90.10.4679; RA Vallejo M., Ron D., Miller C.P., Habener J.F.; RT "C/ATF, a member of the activating transcription factor family of DNA- RT binding proteins, dimerizes with CAAT/enhancer-binding proteins and directs RT their binding to cAMP response elements."; RL Proc. Natl. Acad. Sci. U.S.A. 90:4679-4683(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC STRAIN=CD-1; TISSUE=Embryo; RX PubMed=1631061; DOI=10.1073/pnas.89.13.5789; RA Chevray P.M., Nathans D.; RT "Protein interaction cloning in yeast: identification of mammalian proteins RT that react with the leucine zipper of Jun."; RL Proc. Natl. Acad. Sci. U.S.A. 89:5789-5793(1992). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=BALB/cJ, C57BL/6J, and NOD; RC TISSUE=Lung, Spinal cord, and Spleen; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J; TISSUE=Eye; 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 [6] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=10096021; DOI=10.1046/j.1365-2443.1998.00230.x; RA Tanaka T., Tsujimura T., Takeda K., Sugihara A., Maekawa A., Terada N., RA Yoshida N., Akira S.; RT "Targeted disruption of ATF4 discloses its essential role in the formation RT of eye lens fibres."; RL Genes Cells 3:801-810(1998). RN [7] RP FUNCTION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND DISRUPTION RP PHENOTYPE. RX PubMed=10885750; DOI=10.1006/dbio.2000.9699; RA Hettmann T., Barton K., Leiden J.M.; RT "Microphthalmia due to p53-mediated apoptosis of anterior lens epithelial RT cells in mice lacking the CREB-2 transcription factor."; RL Dev. Biol. 222:110-123(2000). RN [8] RP FUNCTION, AND INDUCTION. RX PubMed=11106749; DOI=10.1016/s1097-2765(00)00108-8; RA Harding H.P., Novoa I., Zhang Y., Zeng H., Wek R., Schapira M., Ron D.; RT "Regulated translation initiation controls stress-induced gene expression RT in mammalian cells."; RL Mol. Cell 6:1099-1108(2000). RN [9] RP 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). RN [10] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=11806972; DOI=10.1182/blood.v99.3.736; RA Masuoka H.C., Townes T.M.; RT "Targeted disruption of the activating transcription factor 4 gene results RT in severe fetal anemia in mice."; RL Blood 99:736-745(2002). RN [11] RP FUNCTION, AND INDUCTION. RX PubMed=12667446; DOI=10.1016/s1097-2765(03)00105-9; RA Harding H.P., Zhang Y., Zeng H., Novoa I., Lu P.D., Calfon M., Sadri N., RA Yun C., Popko B., Paules R., Stojdl D.F., Bell J.C., Hettmann T., RA Leiden J.M., Ron D.; RT "An integrated stress response regulates amino acid metabolism and RT resistance to oxidative stress."; RL Mol. Cell 11:619-633(2003). RN [12] RP FUNCTION. RX PubMed=12925279; DOI=10.1016/s0896-6273(03)00501-4; RA Chen A., Muzzio I.A., Malleret G., Bartsch D., Verbitsky M., Pavlidis P., RA Yonan A.L., Vronskaya S., Grody M.B., Cepeda I., Gilliam T.C., Kandel E.R.; RT "Inducible enhancement of memory storage and synaptic plasticity in RT transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP RT proteins."; RL Neuron 39:655-669(2003). RN [13] RP FUNCTION, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, PHOSPHORYLATION AT RP SER-251, AND MUTAGENESIS OF SER-247; SER-251 AND SER-254. 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 [14] RP INDUCTION. RX PubMed=15277680; DOI=10.1073/pnas.0400541101; RA Vattem K.M., Wek R.C.; RT "Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in RT mammalian cells."; RL Proc. Natl. Acad. Sci. U.S.A. 101:11269-11274(2004). RN [15] 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 [16] 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 [17] RP INTERACTION WITH SATB2. RX PubMed=16751105; DOI=10.1016/j.cell.2006.05.012; RA Dobreva G., Chahrour M., Dautzenberg M., Chirivella L., Kanzler B., RA Farinas I., Karsenty G., Grosschedl R.; RT "SATB2 is a multifunctional determinant of craniofacial patterning and RT osteoblast differentiation."; RL Cell 125:971-986(2006). RN [18] RP FUNCTION, AND INTERACTION WITH TRIB3. RX PubMed=17369260; DOI=10.1074/jbc.m611723200; RA Jousse C., Deval C., Maurin A.C., Parry L., Cherasse Y., Chaveroux C., RA Lefloch R., Lenormand P., Bruhat A., Fafournoux P.; RT "TRB3 inhibits the transcriptional activation of stress-regulated genes by RT a negative feedback on the ATF4 pathway."; RL J. Biol. Chem. 282:15851-15861(2007). RN [19] RP DEVELOPMENTAL STAGE, AND SUBCELLULAR LOCATION. RX PubMed=19232401; DOI=10.1016/j.gep.2009.02.002; RA Yu V.W., Akhouayri O., St-Arnaud R.; RT "FIAT is co-expressed with its dimerization target ATF4 in early RT osteoblasts, but not in osteocytes."; RL Gene Expr. Patterns 9:335-340(2009). RN [20] RP FUNCTION, AND INDUCTION. RX PubMed=21159964; DOI=10.1523/jneurosci.1598-10.2010; RA Galehdar Z., Swan P., Fuerth B., Callaghan S.M., Park D.S., Cregan S.P.; RT "Neuronal apoptosis induced by endoplasmic reticulum stress is regulated by RT ATF4-CHOP-mediated induction of the Bcl-2 homology 3-only member PUMA."; RL J. Neurosci. 30:16938-16948(2010). RN [21] RP FUNCTION, AND INDUCTION. RX PubMed=21768648; DOI=10.1074/jbc.m111.258970; RA Koyanagi S., Hamdan A.M., Horiguchi M., Kusunose N., Okamoto A., RA Matsunaga N., Ohdo S.; RT "cAMP-response element (CRE)-mediated transcription by activating RT transcription factor-4 (ATF4) is essential for circadian expression of the RT Period2 gene."; RL J. Biol. Chem. 286:32416-32423(2011). RN [22] 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 [23] RP DISRUPTION PHENOTYPE, SUBCELLULAR LOCATION, INTERACTION WITH FOXO1, AND RP FUNCTION. RX PubMed=22298775; DOI=10.1074/jbc.m111.282897; RA Kode A., Mosialou I., Silva B.C., Joshi S., Ferron M., Rached M.T., RA Kousteni S.; RT "FoxO1 protein cooperates with ATF4 protein in osteoblasts to control RT glucose homeostasis."; RL J. Biol. Chem. 287:8757-8768(2012). RN [24] RP FUNCTION, AND INDUCTION. RX PubMed=22572884; DOI=10.1124/mol.112.079079; RA Ushijima K., Koyanagi S., Sato Y., Ogata T., Matsunaga N., Fujimura A., RA Ohdo S.; RT "Role of activating transcription factor-4 in 24-hour rhythm of serotonin RT transporter expression in the mouse midbrain."; RL Mol. Pharmacol. 82:264-270(2012). RN [25] RP FUNCTION, UBIQUITINATION, PHOSPHORYLATION AT THR-212; SER-218; SER-223; RP SER-230; SER-234 AND SER-247, AND MUTAGENESIS OF THR-212; SER-218; SER-223; RP SER-230; SER-234 AND SER-247. RX PubMed=23663782; DOI=10.1016/j.cell.2013.04.023; RA Csibi A., Fendt S.M., Li C., Poulogiannis G., Choo A.Y., Chapski D.J., RA Jeong S.M., Dempsey J.M., Parkhitko A., Morrison T., Henske E.P., RA Haigis M.C., Cantley L.C., Stephanopoulos G., Yu J., Blenis J.; RT "The mTORC1 pathway stimulates glutamine metabolism and cell proliferation RT by repressing SIRT4."; RL Cell 153:840-854(2013). RN [26] RP FUNCTION, DNA-BINDING, AND INTERACTION WITH DDIT3. RX PubMed=23624402; DOI=10.1038/ncb2738; RA Han J., Back S.H., Hur J., Lin Y.H., Gildersleeve R., Shan J., Yuan C.L., RA Krokowski D., Wang S., Hatzoglou M., Kilberg M.S., Sartor M.A., RA Kaufman R.J.; RT "ER-stress-induced transcriptional regulation increases protein synthesis RT leading to cell death."; RL Nat. Cell Biol. 15:481-490(2013). RN [27] RP HYDROXYLATION AT PRO-60 AND PRO-235. RX PubMed=24809345; DOI=10.1371/journal.pgen.1004348; RA Scortegagna M., Kim H., Li J.L., Yao H., Brill L.M., Han J., Lau E., RA Bowtell D., Haddad G., Kaufman R.J., Ronai Z.A.; RT "Fine tuning of the UPR by the ubiquitin ligases Siah1/2."; RL PLoS Genet. 10:e1004348-e1004348(2014). RN [28] {ECO:0007744|PDB:6IRR} RP STRUCTURE BY NMR OF 314-349 IN COMPLEX WITH DISC1, INTERACTION WITH DISC1, RP AND FUNCTION. 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). 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:8506317, PubMed:11106749, CC PubMed:12667446, PubMed:23624402). Binds to asymmetric CRE's as a CC heterodimer and to palindromic CRE's as a homodimer (PubMed:8506317, CC PubMed:23624402). Core effector of the ISR, which is required for CC adaptation to various stress such as endoplasmic reticulum (ER) stress, CC amino acid starvation, mitochondrial stress or oxidative stress CC (PubMed:11106749, PubMed:12667446). During ISR, ATF4 translation is CC induced via an alternative ribosome translation re-initiation mechanism CC in response to EIF2S1/eIF-2-alpha phosphorylation, and stress-induced CC ATF4 acts as a master transcription factor of stress-responsive genes CC in order to promote cell recovery (PubMed:11106749, PubMed:12667446). CC Promotes the transcription of genes linked to amino acid sufficiency CC and resistance to oxidative stress to protect cells against metabolic CC consequences of ER oxidation (PubMed:12667446). Activates the CC transcription of NLRP1, possibly in concert with other factors in CC response to ER stress (By similarity). Activates the transcription of CC asparagine synthetase (ASNS) in response to amino acid deprivation or CC ER stress (PubMed:15775988, PubMed:21159964). However, when associated CC with DDIT3/CHOP, the transcriptional activation of the ASNS gene is CC inhibited in response to amino acid deprivation (By similarity). CC Together with DDIT3/CHOP, mediates programmed cell death by promoting CC the expression of genes involved in cellular amino acid metabolic CC processes, mRNA translation and the terminal unfolded protein response CC (terminal UPR), a cellular response that elicits programmed cell death CC when ER stress is prolonged and unresolved (PubMed:23624402). Together CC with DDIT3/CHOP, activates the transcription of the IRS-regulator TRIB3 CC and promotes ER stress-induced neuronal cell death by regulating the CC expression of BBC3/PUMA in response to ER stress (PubMed:15775988, CC PubMed:17369260, PubMed:21159964). May cooperate with the UPR CC transcriptional regulator QRICH1 to regulate ER protein homeostasis CC which is critical for cell viability in response to ER stress (By CC similarity). In the absence of stress, ATF4 translation is at low CC levels and it is required for normal metabolic processes such as CC embryonic lens formation, fetal liver hematopoiesis, bone development CC and synaptic plasticity (PubMed:10096021, PubMed:10885750, CC PubMed:11806972, PubMed:12925279, PubMed:15109498, PubMed:22298775). CC Acts as a regulator of osteoblast differentiation in response to CC phosphorylation by RPS6KA3/RSK2: phosphorylation in osteoblasts CC enhances transactivation activity and promotes expression of CC 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 (PubMed:22298775). Activates CC transcription of SIRT4 (PubMed:23663782). Regulates the circadian CC expression of the core clock component PER2 and the serotonin CC transporter SLC6A4 (PubMed:21768648, PubMed:22572884). Binds in a CC circadian time-dependent manner to the cAMP response elements (CRE) in CC the SLC6A4 and PER2 promoters and periodically activates the CC transcription of these genes (PubMed:21768648, PubMed:22572884). Mainly CC acts as a transcriptional activator in cellular stress adaptation, but CC it can also act as a transcriptional repressor: acts as a regulator of CC synaptic plasticity by repressing transcription, thereby inhibiting CC induction and maintenance of long-term memory (PubMed:12925279). CC Regulates synaptic functions via interaction with DISC1 in neurons, CC which inhibits ATF4 transcription factor activity by disrupting ATF4 CC dimerization and DNA-binding (PubMed:31444471). CC {ECO:0000250|UniProtKB:P18848, ECO:0000269|PubMed:10096021, CC ECO:0000269|PubMed:10885750, ECO:0000269|PubMed:11106749, CC ECO:0000269|PubMed:11806972, ECO:0000269|PubMed:12667446, CC ECO:0000269|PubMed:12925279, ECO:0000269|PubMed:15109498, CC ECO:0000269|PubMed:15775988, ECO:0000269|PubMed:17369260, CC ECO:0000269|PubMed:21159964, ECO:0000269|PubMed:21768648, CC ECO:0000269|PubMed:22298775, ECO:0000269|PubMed:22572884, CC ECO:0000269|PubMed:23624402, ECO:0000269|PubMed:23663782, CC ECO:0000269|PubMed:31444471, ECO:0000269|PubMed:8506317}. CC -!- SUBUNIT: Binds DNA as a homodimer and as a heterodimer CC (PubMed:23624402). Heterodimer; heterodimerizes with CEBPB CC (PubMed:11018027). Heterodimer; heterodimerizes with DDIT3/CHOP CC (PubMed:23624402). Interacts with CEP290 (via an N-terminal region) (By CC similarity). Interacts with NEK6, DAPK2 (isoform 2) and ZIPK/DAPK3 (By CC similarity). Interacts (via its leucine zipper domain) with GABBR1 and CC GABBR2 (via their C-termini) (By similarity). Forms a heterodimer with CC TXLNG in osteoblasts (PubMed:15911876). Interacts (via its DNA binding CC domain) with FOXO1 (C-terminal half); the interaction occurs in CC osteoblasts and regulates glucose homeostasis through suppression of CC beta-cell proliferation and a decrease in insulin production CC (PubMed:22298775). Interacts with SATB2; the interaction results in CC enhanced DNA binding and transactivation by these transcription factors CC (PubMed:16751105). Interacts with ABRAXAS2 (PubMed:22974638). Interacts CC with TRIB3, inhibiting the transactivation activity of ATF4 CC (PubMed:17369260). Interacts with DISC1; which inhibits ATF4 CC transcription factor activity by disrupting ATF4 dimerization and DNA- CC binding (PubMed:31444471). 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 (By similarity). {ECO:0000250|UniProtKB:P18848, CC ECO:0000250|UniProtKB:Q9ES19, ECO:0000269|PubMed:11018027, CC ECO:0000269|PubMed:15911876, ECO:0000269|PubMed:16751105, CC ECO:0000269|PubMed:17369260, ECO:0000269|PubMed:22298775, CC ECO:0000269|PubMed:22974638, ECO:0000269|PubMed:23624402, CC ECO:0000269|PubMed:31444471}. CC -!- INTERACTION: CC Q06507; O54784: Dapk3; NbExp=3; IntAct=EBI-77383, EBI-77359; CC Q06507; P35639: Ddit3; NbExp=3; IntAct=EBI-77383, EBI-10636142; CC Q06507; Q8K4K2: Trib3; NbExp=3; IntAct=EBI-77383, EBI-448962; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:15109498, CC ECO:0000269|PubMed:19232401, ECO:0000269|PubMed:22974638}. Nucleus CC speckle {ECO:0000250|UniProtKB:P18848}. Cytoplasm CC {ECO:0000269|PubMed:19232401}. Cell membrane CC {ECO:0000250|UniProtKB:Q9ES19}. Cytoplasm, cytoskeleton, microtubule CC organizing center, centrosome {ECO:0000250|UniProtKB:P18848}. CC Note=Colocalizes with GABBR1 in hippocampal neuron dendritic membranes. CC Colocalizes with NEK6 in the centrosome (By similarity). Recruited to CC nuclear speckles following interaction with EP300/p300 (By similarity). CC {ECO:0000250|UniProtKB:P18848, ECO:0000250|UniProtKB:Q9ES19}. CC -!- TISSUE SPECIFICITY: Ubiquitously expressed in adults. CC {ECO:0000305|PubMed:10885750}. CC -!- DEVELOPMENTAL STAGE: During embryonic development, expressed at high CC levels in anterior epithelial lens cells at 14.5 dpc (PubMed:10885750). CC At 16.5 dpc, expressed in osteoblasts surrounding newly formed CC trabecular bone (PubMed:19232401). At postnatal day 2, detected in most CC osteoblasts and lining cells (PubMed:19232401). By postnatal week 4, is CC detected in fewer osteoblasts, but remains present in lining cells (at CC protein level) (PubMed:19232401). {ECO:0000269|PubMed:10885750, CC ECO:0000269|PubMed:19232401}. 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:11106749, PubMed:12667446, PubMed:15277680, CC PubMed:21159964). In the absence of stress, ribosomes re-initiate CC translation at an inhibitory open reading frame (uORF) upstream of the CC ATF4 transcript, which precludes AFT4 translation (PubMed:11106749, CC PubMed:15277680). In response to stress and subsequent EIF2S1/eIF-2- CC alpha phosphorylation, ribosomes bypass the inhibitory uORF and re- CC initiate translation at the AFT4 coding sequence (PubMed:15277680). CC Expressed in a circadian manner in the midbrain with an increased CC expression seen during the dark phase (at protein level) CC (PubMed:21768648, PubMed:22572884). Expressed in a circadian manner CC also in the suprachiasmatic nucleus (SCN) of the brain, cerebral CC cortex, kidney and small intestine (PubMed:21768648, PubMed:22572884). CC {ECO:0000269|PubMed:11106749, ECO:0000269|PubMed:12667446, CC ECO:0000269|PubMed:15277680, ECO:0000269|PubMed:21159964, CC ECO:0000269|PubMed:21768648, ECO:0000269|PubMed:22572884}. CC -!- DOMAIN: The BetaTrCP degron motif promotes binding to BTRC when CC phosphorylated. {ECO:0000269|PubMed:23663782}. 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:23663782). Interaction with EP300/p300 inhibits CC ubiquitination by SCF(BTRC) (By similarity). CC {ECO:0000250|UniProtKB:P18848, ECO:0000269|PubMed:23663782}. CC -!- PTM: Phosphorylation at Ser-251 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 218, followed by phosphorylation at Thr-212, Ser-223, Ser-230, Ser-234 CC and Ser-247, promoting interaction with BTRC and ubiquitination CC (PubMed:23663782). Phosphorylation is promoted by mTORC1 CC (PubMed:23663782). Phosphorylation at Ser-214 by CK2 decreases its CC stability (By similarity). Phosphorylated by NEK6 (By similarity). CC {ECO:0000250|UniProtKB:P18848, ECO:0000269|PubMed:15109498, CC ECO:0000269|PubMed:23663782}. CC -!- PTM: Hydroxylated by PHD3, leading to decreased protein stability. CC {ECO:0000269|PubMed:24809345}. CC -!- DISRUPTION PHENOTYPE: Mice were born at a much lower rate than CC predicted by the Mendelian ratio (PubMed:10096021, PubMed:10885750). CC Homozygous pups generally die during the first hour after birth, CC although excess mortality occurrs throughout the first 3 weeks of life CC (PubMed:10096021, PubMed:11806972). Embryos are severely anemic during CC fetal development, due to an impairment in definitive hematopoiesis CC (PubMed:11806972). Surviving mice display defects in embryonic lens CC formation leading to severe microphthalmia in adults (PubMed:10096021, CC PubMed:10885750). Embryos show delayed bone formation and surviving CC mice display low bone mass throughout postnatal life (PubMed:15109498). CC Surviving null mice exhibit an increase in serum insulin levels and low CC blood glucose levels (PubMed:22298775). There is a decrease in total CC fat content, gonadal fat, lean mass and body weight (PubMed:22298775). CC Serum levels of osteocalcin/BGLAP are decreased (PubMed:22298775). CC PBK/AKT1-mediated phosphorylation of FOXO1 at 'Ser-258' is increased CC with a subsequent decrease of FOXO1-mediated transcriptional activity CC (PubMed:22298775). {ECO:0000269|PubMed:10096021, CC ECO:0000269|PubMed:10885750, ECO:0000269|PubMed:11806972, CC ECO:0000269|PubMed:15109498, ECO:0000269|PubMed:22298775}. CC -!- SIMILARITY: Belongs to the bZIP family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA53043.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; 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; L13791; AAA40476.1; -; mRNA. DR EMBL; M94087; AAA53043.1; ALT_INIT; mRNA. DR EMBL; AK138657; BAE23736.1; -; mRNA. DR EMBL; AK144777; BAE26060.1; -; mRNA. DR EMBL; AK146193; BAE26967.1; -; mRNA. DR EMBL; AK156298; BAE33662.1; -; mRNA. DR EMBL; CH466550; EDL04604.1; -; Genomic_DNA. DR EMBL; CH466550; EDL04605.1; -; Genomic_DNA. DR EMBL; BC085169; AAH85169.1; -; mRNA. DR CCDS; CCDS37145.1; -. DR RefSeq; NP_001274109.1; NM_001287180.1. DR RefSeq; NP_033846.2; NM_009716.3. DR PDB; 6IRR; NMR; -; A=314-349. DR PDBsum; 6IRR; -. DR AlphaFoldDB; Q06507; -. DR SMR; Q06507; -. DR BioGRID; 198235; 12. DR ComplexPortal; CPX-6; bZIP transcription factor complex, Atf4-Creb1. DR ComplexPortal; CPX-7; bZIP transcription factor complex, Atf1-Atf4. DR CORUM; Q06507; -. DR DIP; DIP-30969N; -. DR IntAct; Q06507; 10. DR STRING; 10090.ENSMUSP00000105234; -. DR iPTMnet; Q06507; -. DR PhosphoSitePlus; Q06507; -. DR PaxDb; 10090-ENSMUSP00000105234; -. DR ProteomicsDB; 265159; -. DR Antibodypedia; 12687; 1290 antibodies from 47 providers. DR DNASU; 11911; -. DR Ensembl; ENSMUST00000109605.5; ENSMUSP00000105234.4; ENSMUSG00000042406.9. DR GeneID; 11911; -. DR KEGG; mmu:11911; -. DR UCSC; uc007wvl.2; mouse. DR AGR; MGI:88096; -. DR CTD; 468; -. DR MGI; MGI:88096; Atf4. DR VEuPathDB; HostDB:ENSMUSG00000042406; -. DR eggNOG; KOG4571; Eukaryota. DR GeneTree; ENSGT00530000063801; -. DR HOGENOM; CLU_055748_1_0_1; -. DR InParanoid; Q06507; -. DR OMA; WMTEKID; -. DR OrthoDB; 4843682at2759; -. DR TreeFam; TF316136; -. DR BioGRID-ORCS; 11911; 20 hits in 85 CRISPR screens. DR ChiTaRS; Atf4; mouse. DR PRO; PR:Q06507; -. DR Proteomes; UP000000589; Chromosome 15. DR RNAct; Q06507; Protein. DR Bgee; ENSMUSG00000042406; Expressed in ankle joint and 288 other cell types or tissues. DR ExpressionAtlas; Q06507; 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; ISO:MGI. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0032590; C:dendrite membrane; ISO:MGI. DR GO; GO:1990037; C:Lewy body core; ISO:MGI. DR GO; GO:0043005; C:neuron projection; ISO:MGI. DR GO; GO:0034399; C:nuclear periphery; ISO:MGI. DR GO; GO:0016607; C:nuclear speck; IEA:UniProtKB-SubCell. DR GO; GO:0005654; C:nucleoplasm; ISO:MGI. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0032991; C:protein-containing complex; ISO:MGI. DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; IDA:MGI. DR GO; GO:0005667; C:transcription regulator complex; IDA:MGI. DR GO; GO:0008140; F:cAMP response element binding protein binding; IDA:UniProtKB. DR GO; GO:0003677; F:DNA binding; IGI:MGI. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IMP:NTNU_SB. 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; ISO:MGI. DR GO; GO:0140297; F:DNA-binding transcription factor binding; ISO:MGI. DR GO; GO:0140296; F:general transcription initiation factor binding; ISO:MGI. DR GO; GO:0042802; F:identical protein binding; ISO:MGI. DR GO; GO:0043522; F:leucine zipper domain binding; ISO:MGI. DR GO; GO:1990841; F:promoter-specific chromatin binding; IDA:MGI. DR GO; GO:0046982; F:protein heterodimerization activity; IDA:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; ISO:MGI. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA: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; ISO:MGI. DR GO; GO:0043565; F:sequence-specific DNA binding; ISO:MGI. DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI. DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISO:MGI. DR GO; GO:0030282; P:bone mineralization; IMP:UniProtKB. DR GO; GO:0034198; P:cellular response to amino acid starvation; IDA:UniProtKB. DR GO; GO:0042149; P:cellular response to glucose starvation; ISO:MGI. 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:UniProtKB. DR GO; GO:0032922; P:circadian regulation of gene expression; IMP:UniProtKB. DR GO; GO:0007623; P:circadian rhythm; IEP:UniProtKB. DR GO; GO:0035162; P:embryonic hemopoiesis; IMP:UniProtKB. DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IDA:UniProtKB. DR GO; GO:0007214; P:gamma-aminobutyric acid signaling pathway; ISO:MGI. DR GO; GO:0006094; P:gluconeogenesis; IDA:MGI. DR GO; GO:0140468; P:HRI-mediated signaling; ISS:UniProtKB. DR GO; GO:0140467; P:integrated stress response signaling; IMP:UniProtKB. DR GO; GO:0006874; P:intracellular calcium ion homeostasis; IMP:MGI. DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; IDA:UniProtKB. DR GO; GO:0070982; P:L-asparagine metabolic process; ISO:MGI. DR GO; GO:0070309; P:lens fiber cell morphogenesis; IMP:UniProtKB. DR GO; GO:0042789; P:mRNA transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; IMP:YuBioLab. DR GO; GO:1903377; P:negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; ISO:MGI. DR GO; GO:0043267; P:negative regulation of potassium ion transport; ISO:MGI. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:UniProtKB. DR GO; GO:0030182; P:neuron differentiation; IEA:Ensembl. DR GO; GO:0036499; P:PERK-mediated unfolded protein response; IDA:UniProtKB. DR GO; GO:0070169; P:positive regulation of biomineral tissue development; IMP:MGI. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ParkinsonsUK-UCL. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IMP:UniProtKB. DR GO; GO:2000120; P:positive regulation of sodium-dependent phosphate transport; IMP:MGI. DR GO; GO:0045943; P:positive regulation of transcription by RNA polymerase I; ISO:MGI. 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; IMP:MGI. DR GO; GO:0010575; P:positive regulation of vascular endothelial growth factor production; ISO:MGI. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IDA:MGI. DR GO; GO:0045667; P:regulation of osteoblast differentiation; IMP:UniProtKB. DR GO; GO:0048167; P:regulation of synaptic plasticity; IMP:UniProtKB. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:MGI. 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; ISO:MGI. DR GO; GO:0009636; P:response to toxic substance; IEA:Ensembl. DR GO; GO:0006366; P:transcription by RNA polymerase II; IGI:MGI. 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; Q06507; MM. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Activator; Biological rhythms; Cell membrane; KW Cytoplasm; Cytoskeleton; DNA-binding; Hydroxylation; Isopeptide bond; KW Membrane; Nucleus; Phosphoprotein; Reference proteome; Repressor; KW Transcription; Transcription regulation; Ubl conjugation. FT CHAIN 1..349 FT /note="Cyclic AMP-dependent transcription factor ATF-4" FT /id="PRO_0000076585" FT DOMAIN 276..339 FT /note="bZIP" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978" FT REGION 49..75 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 204..271 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 278..298 FT /note="Basic motif" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978" FT REGION 279..298 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 303..339 FT /note="Interaction with GABBR1" FT /evidence="ECO:0000250" FT REGION 304..332 FT /note="Leucine-zipper" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978" FT MOTIF 214..223 FT /note="BetaTrCP degron motif" FT /evidence="ECO:0000269|PubMed:23663782" FT COMPBIAS 216..244 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 60 FT /note="4-hydroxyproline" FT /evidence="ECO:0000269|PubMed:24809345" FT MOD_RES 212 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:23663782" FT MOD_RES 214 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P18848" FT MOD_RES 218 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:23663782" FT MOD_RES 223 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:23663782" FT MOD_RES 230 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:23663782" FT MOD_RES 234 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:23663782" FT MOD_RES 235 FT /note="4-hydroxyproline" FT /evidence="ECO:0000269|PubMed:24809345" FT MOD_RES 247 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:23663782" FT MOD_RES 251 FT /note="Phosphoserine; by RPS6KA3" FT /evidence="ECO:0000269|PubMed:15109498" FT MOD_RES 309 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P18848" FT CROSSLNK 258 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0000250|UniProtKB:P18848" FT CROSSLNK 270 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0000250|UniProtKB:P18848" FT MUTAGEN 212 FT /note="T->A: Promotes stabilization due to impaired FT ubiquitination; when associated with A-223; A-230; A-234 FT and A-247." FT /evidence="ECO:0000269|PubMed:23663782" FT MUTAGEN 218 FT /note="S->A: Promotes stabilization due to impaired FT ubiquitination." FT /evidence="ECO:0000269|PubMed:23663782" FT MUTAGEN 223 FT /note="S->A: Promotes stabilization due to impaired FT ubiquitination; when associated with A-212; A-230; A-234 FT and A-247." FT /evidence="ECO:0000269|PubMed:23663782" FT MUTAGEN 230 FT /note="S->A: Promotes stabilization due to impaired FT ubiquitination; when associated with A-212; A-223; A-234 FT and A-247." FT /evidence="ECO:0000269|PubMed:23663782" FT MUTAGEN 234 FT /note="S->A: Promotes stabilization due to impaired FT ubiquitination; when associated with A-212; A-223; A-230 FT and A-247." FT /evidence="ECO:0000269|PubMed:23663782" FT MUTAGEN 247 FT /note="S->A: Promotes stabilization due to impaired FT ubiquitination; when associated with A-212; A-223; A-230 FT and A-234. Does not affect phosphorylation by FT RPS6KA3/RSK2." FT /evidence="ECO:0000269|PubMed:15109498, FT ECO:0000269|PubMed:23663782" FT MUTAGEN 251 FT /note="S->A,R,D: Abolished phosphorylation by FT RPS6KA3/RSK2." FT /evidence="ECO:0000269|PubMed:15109498" FT MUTAGEN 254 FT /note="S->A: Does not affect phosphorylation by FT RPS6KA3/RSK2." FT /evidence="ECO:0000269|PubMed:15109498" FT CONFLICT 345 FT /note="K -> Q (in Ref. 1; AAA40476)" FT /evidence="ECO:0000305" FT HELIX 317..342 FT /evidence="ECO:0007829|PDB:6IRR" SQ SEQUENCE 349 AA; 38355 MW; 0C3F895755B1C7B9 CRC64; MTEMSFLNSE VLAGDLMSPF DQSGLGAEES LGLLDDYLEV AKHLKPHGFS SDKAGSSEWP AMDDGLASAS DTGKEDAFSG TDWMLEKMDL KEFDFDALFR MDDLETMPDE LLTTLDDTCD LFAPLVQETN KEPPQTVNPI GHLPESLIKV DQVAPFTFLQ PFPCSPGVLS STPEHSFSLE LGSEVDISEG DRKPDSAAYI TLIPPCVKEE DTPSDNDSGI CMSPESYLGS PQHSPSTSRA PPDNLPSPGG SRGSPRPKPY DPPGVSLTAK VKTEKLDKKL KKMEQNKTAA TRYRQKKRAE QEALTGECKE LEKKNEALKE KADSLAKEIQ YLKDLIEEVR KARGKKRVP //