CREB1_HUMAN
ID CREB1_HUMAN Reviewed; 327 AA.
AC P16220; P21934; Q6V963; Q9UMA7;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 07-OCT-2020, sequence version 3.
DT 03-AUG-2022, entry version 246.
DE RecName: Full=Cyclic AMP-responsive element-binding protein 1;
DE Short=CREB-1;
DE Short=cAMP-responsive element-binding protein 1;
GN Name=CREB1;
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] (ISOFORM 2).
RX PubMed=2142528; DOI=10.1073/pnas.87.14.5258;
RA Berkowitz L.A., Gilman M.Z.;
RT "Two distinct forms of active transcription factor CREB (cAMP response
RT element binding protein).";
RL Proc. Natl. Acad. Sci. U.S.A. 87:5258-5262(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=2196176; DOI=10.1002/j.1460-2075.1990.tb07434.x;
RA Yoshimura T., Fujisawa J., Yoshida M.;
RT "Multiple cDNA clones encoding nuclear proteins that bind to the tax-
RT dependent enhancer of HTLV-1: all contain a leucine zipper structure and
RT basic amino acid domain.";
RL EMBO J. 9:2537-2542(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=1966745;
RA Waeber G., Meyer T.E., Hoeffler J.P., Habener J.F.;
RT "Diversification of cyclic AMP-responsive enhancer binding proteins-
RT generated by alternative exon splicing.";
RL Trans. Assoc. Am. Physicians 103:28-37(1990).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2974179; DOI=10.1126/science.2974179;
RA Hoeffler J.P., Meyer T.E., Yun Y., Jameson J.L., Habener J.F.;
RT "Cyclic AMP-responsive DNA-binding protein: structure based on a cloned
RT placental cDNA.";
RL Science 242:1430-1433(1988).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=1831258; DOI=10.1093/nar/19.15.4290;
RA Short M.L., Manohar C.F., Furtado M.R., Ghadge G.D., Wolinsky S.M.,
RA Thimmapaya B., Jungmann R.A.;
RT "Nucleotide and derived amino-acid sequences of the CRE-binding proteins
RT from rat C6 glioma and HeLa cells.";
RL Nucleic Acids Res. 19:4290-4290(1991).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Testis;
RX PubMed=15579595; DOI=10.1530/rep.1.00036;
RA Huang X., Zhang J., Lu L., Yin L., Xu M., Wang Y., Zhou Z., Sha J.;
RT "Cloning and expression of a novel CREB mRNA splice variant in human
RT testis.";
RL Reproduction 128:775-782(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC 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 [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-8.
RX PubMed=8381074; DOI=10.1210/endo.132.2.8381074;
RA Meyer T.E., Waeber G., Lin J., Beckmann W., Habener J.F.;
RT "The promoter of the gene encoding 3',5'-cyclic adenosine monophosphate
RT (cAMP) response element binding protein contains cAMP response elements:
RT evidence for positive autoregulation of gene transcription.";
RL Endocrinology 132:770-780(1993).
RN [9]
RP INTERACTION WITH HBV PROTEIN X (MICROBIAL INFECTION).
RX PubMed=1827531; DOI=10.1126/science.1827531;
RA Maguire H.F., Hoeffler J.P., Siddiqui A.;
RT "HBV X protein alters the DNA binding specificity of CREB and ATF-2 by
RT protein-protein interactions.";
RL Science 252:842-844(1991).
RN [10]
RP INTERACTION WITH HTLV-1 TAX (MICROBIAL INFECTION).
RX PubMed=1386673; DOI=10.1073/pnas.89.15.7070;
RA Zhao L.J., Giam C.-Z.;
RT "Human T-cell lymphotropic virus type I (HTLV-I) transcriptional activator,
RT Tax, enhances CREB binding to HTLV-I 21-base-pair repeats by protein-
RT protein interaction.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:7070-7074(1992).
RN [11]
RP PHOSPHORYLATION AT SER-119, AND MUTAGENESIS OF SER-119.
RX PubMed=8065343; DOI=10.1128/mcb.14.9.6107-6116.1994;
RA Matthews R.P., Guthrie C.R., Wailes L.M., Zhao X., Means A.R.,
RA McKnight G.S.;
RT "Calcium/calmodulin-dependent protein kinase types II and IV differentially
RT regulate CREB-dependent gene expression.";
RL Mol. Cell. Biol. 14:6107-6116(1994).
RN [12]
RP PHOSPHORYLATION AT SER-119.
RX PubMed=7608156; DOI=10.1074/jbc.270.27.16378;
RA Lee H.-J.J., Mignacca R.C., Sakamoto K.M.;
RT "Transcriptional activation of egr-1 by granulocyte-macrophage colony-
RT stimulating factor but not interleukin 3 requires phosphorylation of cAMP
RT response element-binding protein (CREB) on serine 133.";
RL J. Biol. Chem. 270:15979-15983(1995).
RN [13]
RP PHOSPHORYLATION AT SER-119.
RX PubMed=9829964; DOI=10.1074/jbc.273.49.32377;
RA Du K., Montminy M.;
RT "CREB is a regulatory target for the protein kinase Akt/PKB.";
RL J. Biol. Chem. 273:32377-32379(1998).
RN [14]
RP PHOSPHORYLATION AT SER-119.
RX PubMed=9770464; DOI=10.1073/pnas.95.21.12202;
RA De Cesare D., Jacquot S., Hanauer A., Sassone-Corsi P.;
RT "Rsk-2 activity is necessary for epidermal growth factor-induced
RT phosphorylation of CREB protein and transcription of c-fos gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:12202-12207(1998).
RN [15]
RP INTERACTION WITH CRTC1.
RX PubMed=14536081; DOI=10.1016/j.molcel.2003.08.013;
RA Conkright M.D., Canettieri G., Screaton R., Guzman E., Miraglia L.,
RA Hogenesch J.B., Montminy M.;
RT "TORCs: transducers of regulated CREB activity.";
RL Mol. Cell 12:413-423(2003).
RN [16]
RP SUMOYLATION AT LYS-271 AND LYS-290, SUBCELLULAR LOCATION, AND MUTAGENESIS
RP OF LYS-141; LYS-271 AND LYS-290.
RX PubMed=12552083; DOI=10.1073/pnas.0337412100;
RA Comerford K.M., Leonard M.O., Karhausen J., Carey R., Colgan S.P.,
RA Taylor C.T.;
RT "Small ubiquitin-related modifier-1 modification mediates resolution of
RT CREB-dependent responses to hypoxia.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:986-991(2003).
RN [17]
RP INTERACTION WITH CRTC3.
RX PubMed=14506290; DOI=10.1073/pnas.1932773100;
RA Iourgenko V., Zhang W., Mickanin C., Daly I., Jiang C., Hexham J.M.,
RA Orth A.P., Miraglia L., Meltzer J., Garza D., Chirn G.-W., McWhinnie E.,
RA Cohen D., Skelton J., Terry R., Yu Y., Bodian D., Buxton F.P., Zhu J.,
RA Song C., Labow M.A.;
RT "Identification of a family of cAMP response element-binding protein
RT coactivators by genome-scale functional analysis in mammalian cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:12147-12152(2003).
RN [18]
RP INTERACTION WITH CRTC2.
RX PubMed=15454081; DOI=10.1016/j.cell.2004.09.015;
RA Screaton R.A., Conkright M.D., Katoh Y., Best J.L., Canettieri G.,
RA Jeffries S., Guzman E., Niessen S., Yates J.R. III, Takemori H.,
RA Okamoto M., Montminy M.;
RT "The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive
RT coincidence detector.";
RL Cell 119:61-74(2004).
RN [19]
RP INTERACTION WITH TSSK4, PHOSPHORYLATION AT SER-119, AND MUTAGENESIS OF
RP SER-119.
RX PubMed=15964553; DOI=10.1016/j.bbrc.2005.05.157;
RA Chen X., Lin G., Wei Y., Hexige S., Niu Y., Liu L., Yang C., Yu L.;
RT "TSSK5, a novel member of the testis-specific serine/threonine kinase
RT family, phosphorylates CREB at Ser-133, and stimulates the CRE/CREB
RT responsive pathway.";
RL Biochem. Biophys. Res. Commun. 333:742-749(2005).
RN [20]
RP INTERACTION WITH ARRB1.
RX PubMed=16325578; DOI=10.1016/j.cell.2005.09.011;
RA Kang J., Shi Y., Xiang B., Qu B., Su W., Zhu M., Zhang M., Bao G., Wang F.,
RA Zhang X., Yang R., Fan F., Chen X., Pei G., Ma L.;
RT "A nuclear function of beta-arrestin1 in GPCR signaling: regulation of
RT histone acetylation and gene transcription.";
RL Cell 123:833-847(2005).
RN [21]
RP PHOSPHORYLATION AT SER-119 BY SGK1, AND INTERACTION WITH SGK1.
RX PubMed=15733869; DOI=10.1016/j.febslet.2005.01.040;
RA David S., Kalb R.G.;
RT "Serum/glucocorticoid-inducible kinase can phosphorylate the cyclic AMP
RT response element binding protein, CREB.";
RL FEBS Lett. 579:1534-1538(2005).
RN [22]
RP INTERACTION WITH PPRC1.
RX PubMed=16908542; DOI=10.1128/mcb.00585-06;
RA Vercauteren K., Pasko R.A., Gleyzer N., Marino V.M., Scarpulla R.C.;
RT "PGC-1-related coactivator: immediate early expression and characterization
RT of a CREB/NRF-1 binding domain associated with cytochrome c promoter
RT occupancy and respiratory growth.";
RL Mol. Cell. Biol. 26:7409-7419(2006).
RN [23]
RP CHROMOSOMAL TRANSLOCATION WITH EWSR1, AND ASSOCIATION WITH ANGIOMATOID
RP FIBROUS HISTIOCYTOMA.
RX PubMed=17724745; DOI=10.1002/gcc.20491;
RA Antonescu C.R., Dal Cin P., Nafa K., Teot L.A., Surti U., Fletcher C.D.,
RA Ladanyi M.;
RT "EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous
RT histiocytoma.";
RL Genes Chromosomes Cancer 46:1051-1060(2007).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E.,
RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y.,
RA Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [26]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [27]
RP PHOSPHORYLATION AT SER-257 BY HIPK2, MUTAGENESIS OF SER-257, AND
RP INTERACTION WITH HIPK2.
RX PubMed=20573984; DOI=10.1091/mbc.e10-01-0015;
RA Sakamoto K., Huang B.-W., Iwasaki K., Hailemariam K., Ninomiya-Tsuji J.,
RA Tsuji Y.;
RT "Regulation of genotoxic stress response by homeodomain-interacting protein
RT kinase 2 through phosphorylation of cyclic AMP response element-binding
RT protein at serine 271.";
RL Mol. Biol. Cell 21:2966-2974(2010).
RN [28]
RP INTERACTION WITH TOX3, AND MUTAGENESIS OF SER-119.
RX PubMed=21172805; DOI=10.1242/jcs.068759;
RA Dittmer S., Kovacs Z., Yuan S.H., Siszler G., Kogl M., Summer H.,
RA Geerts A., Golz S., Shioda T., Methner A.;
RT "TOX3 is a neuronal survival factor that induces transcription depending on
RT the presence of CITED1 or phosphorylated CREB in the transcriptionally
RT active complex.";
RL J. Cell Sci. 124:252-260(2011).
RN [29]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [30]
RP POSSIBLE INVOLVEMENT IN MULTIPLE CONGENITAL ANOMALIES, VARIANT GLY-102, AND
RP CHARACTERIZATION OF VARIANT GLY-102.
RX PubMed=22267179; DOI=10.1002/humu.22027;
RA Kitazawa S., Kondo T., Mori K., Yokoyama N., Matsuo M., Kitazawa R.;
RT "A p.D116G mutation in CREB1 leads to novel multiple malformation syndrome
RT resembling CrebA knockout mouse.";
RL Hum. Mutat. 33:651-654(2012).
RN [31]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-128, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [32]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [33]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-122, AND IDENTIFICATION BY MASS
RP 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 [34] {ECO:0007744|PDB:2LXT}
RP STRUCTURE BY NMR OF 102-135 IN COMPLEX WITH KMT2A AND CREBBP.
RX PubMed=23651431; DOI=10.1021/cb4002188;
RA Bruschweiler S., Konrat R., Tollinger M.;
RT "Allosteric communication in the KIX domain proceeds through dynamic
RT repacking of the hydrophobic core.";
RL ACS Chem. Biol. 8:1600-1610(2013).
CC -!- FUNCTION: Phosphorylation-dependent transcription factor that
CC stimulates transcription upon binding to the DNA cAMP response element
CC (CRE), a sequence present in many viral and cellular promoters.
CC Transcription activation is enhanced by the TORC coactivators which act
CC independently of Ser-119 phosphorylation. Involved in different
CC cellular processes including the synchronization of circadian
CC rhythmicity and the differentiation of adipose cells.
CC -!- SUBUNIT: Interacts with PPRC1. Binds DNA as a dimer. This dimer is
CC stabilized by magnesium ions. Interacts, through the bZIP domain, with
CC the coactivators TORC1/CRTC1, TORC2/CRTC2 and TORC3/CRTC3. When
CC phosphorylated on Ser-119, binds CREBBP (By similarity). Interacts with
CC CREBL2; regulates CREB1 phosphorylation, stability and transcriptional
CC activity (By similarity). Interacts (phosphorylated form) with TOX3.
CC Interacts with ARRB1. Binds to HIPK2. Interacts with SGK1. Interacts
CC with TSSK4; this interaction facilitates phosphorylation on Ser-119
CC (PubMed:15964553). Forms a complex with KMT2A and CREBBP
CC (PubMed:23651431, PubMed:14506290, PubMed:14536081, PubMed:15454081,
CC PubMed:15733869, PubMed:15964553, PubMed:16325578, PubMed:16908542,
CC PubMed:20573984, PubMed:21172805) (By similarity). Interacts with TOX4;
CC CREB1 is required for full induction of TOX4-dependent activity and the
CC interaction is increased by cAMP and inhibited by insulin (By
CC similarity). {ECO:0000250|UniProtKB:Q01147,
CC ECO:0000269|PubMed:14506290, ECO:0000269|PubMed:14536081,
CC ECO:0000269|PubMed:15454081, ECO:0000269|PubMed:15733869,
CC ECO:0000269|PubMed:15964553, ECO:0000269|PubMed:16325578,
CC ECO:0000269|PubMed:16908542, ECO:0000269|PubMed:20573984,
CC ECO:0000269|PubMed:21172805, ECO:0000269|PubMed:23651431}.
CC -!- SUBUNIT: (Microbial infection) Interacts with hepatitis B virus/HBV
CC protein X. {ECO:0000269|PubMed:1827531}.
CC -!- SUBUNIT: (Microbial infection) Interacts with HTLV-1 protein Tax.
CC {ECO:0000269|PubMed:1386673}.
CC -!- INTERACTION:
CC P16220; O95994: AGR2; NbExp=3; IntAct=EBI-711855, EBI-712648;
CC P16220; P18846: ATF1; NbExp=6; IntAct=EBI-711855, EBI-852794;
CC P16220; P16220: CREB1; NbExp=4; IntAct=EBI-711855, EBI-711855;
CC P16220; Q92793: CREBBP; NbExp=2; IntAct=EBI-711855, EBI-81215;
CC P16220; Q6UUV9: CRTC1; NbExp=6; IntAct=EBI-711855, EBI-1644259;
CC P16220; Q53ET0: CRTC2; NbExp=3; IntAct=EBI-711855, EBI-1181987;
CC P16220; P42858: HTT; NbExp=3; IntAct=EBI-711855, EBI-466029;
CC P16220; O00470: MEIS1; NbExp=9; IntAct=EBI-711855, EBI-1210694;
CC P16220; O95644: NFATC1; NbExp=3; IntAct=EBI-711855, EBI-6907210;
CC P16220; Q13469: NFATC2; NbExp=2; IntAct=EBI-711855, EBI-716258;
CC P16220; Q16649: NFIL3; NbExp=3; IntAct=EBI-711855, EBI-3951858;
CC P16220; Q96RG2: PASK; NbExp=2; IntAct=EBI-711855, EBI-1042651;
CC P16220; O75928-2: PIAS2; NbExp=3; IntAct=EBI-711855, EBI-348567;
CC P16220; P78317: RNF4; NbExp=3; IntAct=EBI-711855, EBI-2340927;
CC P16220; Q6SA08: TSSK4; NbExp=5; IntAct=EBI-711855, EBI-1202583;
CC P16220; P0C746: HBZ; Xeno; NbExp=2; IntAct=EBI-711855, EBI-10890294;
CC P16220; Q9DGW5: MDV005; Xeno; NbExp=2; IntAct=EBI-711855, EBI-10889526;
CC P16220; P03259-2; Xeno; NbExp=2; IntAct=EBI-711855, EBI-7225021;
CC P16220-1; Q09472: EP300; NbExp=2; IntAct=EBI-26386865, EBI-447295;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00312,
CC ECO:0000255|PROSITE-ProRule:PRU00978, ECO:0000269|PubMed:12552083}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=CREB-B;
CC IsoId=P16220-2; Sequence=Displayed;
CC Name=2; Synonyms=CREB-A;
CC IsoId=P16220-1; Sequence=VSP_060702;
CC Name=3; Synonyms=htCREB;
CC IsoId=P16220-3; Sequence=VSP_060702, VSP_060703;
CC -!- PTM: Stimulated by phosphorylation. Phosphorylation of both Ser-119 and
CC Ser-128 in the SCN regulates the activity of CREB and participates in
CC circadian rhythm generation. Phosphorylation of Ser-119 allows CREBBP
CC binding. In liver, phosphorylation is induced by fasting or glucagon in
CC a circadian fashion (By similarity). CREBL2 positively regulates
CC phosphorylation at Ser-119 thereby stimulating CREB1 transcriptional
CC activity (By similarity). Phosphorylated upon calcium influx by CaMK4
CC and CaMK2 on Ser-119. CaMK4 is much more potent than CaMK2 in
CC activating CREB. Phosphorylated by CaMK2 on Ser-128. Phosphorylation of
CC Ser-128 blocks CREB-mediated transcription even when Ser-119 is
CC phosphorylated. Phosphorylated by CaMK1 (By similarity).
CC Phosphorylation of Ser-257 by HIPK2 in response to genotoxic stress
CC promotes CREB1 activity, facilitating the recruitment of the
CC coactivator CBP. Phosphorylated at Ser-119 by RPS6KA3, RPS6KA4 and
CC RPS6KA5 in response to mitogenic or stress stimuli. Phosphorylated by
CC TSSK4 on Ser-119 (PubMed:15964553). {ECO:0000250,
CC ECO:0000269|PubMed:15733869, ECO:0000269|PubMed:15964553,
CC ECO:0000269|PubMed:20573984, ECO:0000269|PubMed:7608156,
CC ECO:0000269|PubMed:8065343, ECO:0000269|PubMed:9770464,
CC ECO:0000269|PubMed:9829964}.
CC -!- PTM: Sumoylated with SUMO1. Sumoylation on Lys-290, but not on Lys-271,
CC is required for nuclear localization of this protein. Sumoylation is
CC enhanced under hypoxia, promoting nuclear localization and
CC stabilization. {ECO:0000269|PubMed:12552083}.
CC -!- DISEASE: Angiomatoid fibrous histiocytoma (AFH) [MIM:612160]: A
CC distinct variant of malignant fibrous histiocytoma that typically
CC occurs in children and adolescents and is manifest by nodular
CC subcutaneous growth. Characteristic microscopic features include
CC lobulated sheets of histiocyte-like cells intimately associated with
CC areas of hemorrhage and cystic pseudovascular spaces, as well as a
CC striking cuffing of inflammatory cells, mimicking a lymph node
CC metastasis. Note=The gene represented in this entry may be involved in
CC disease pathogenesis. A chromosomal aberration involving CREB1 is found
CC in a patient with angiomatoid fibrous histiocytoma. Translocation
CC t(2;22)(q33;q12) with CREB1 generates a EWSR1/CREB1 fusion gene that is
CC most common genetic abnormality in this tumor type.
CC -!- DISEASE: Note=A CREB1 mutation has been found in a patient with
CC multiple congenital anomalies consisting of agenesis of the corpus
CC callosum, cerebellar hypoplasia, severe neonatal respiratory distress
CC refractory to surfactant, thymus hypoplasia, and thyroid follicular
CC hypoplasia. {ECO:0000269|PubMed:22267179}.
CC -!- MISCELLANEOUS: [Isoform 3]: Highly expressed in adult testis and sperm.
CC {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the bZIP family. {ECO:0000305}.
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DR EMBL; S72459; AAB20597.1; -; Genomic_DNA.
DR EMBL; X55545; CAA39151.1; -; mRNA.
DR EMBL; M34356; AAA35717.1; -; mRNA.
DR EMBL; M34356; AAA35716.1; -; mRNA.
DR EMBL; M27691; AAA35715.1; -; mRNA.
DR EMBL; X60003; CAA42620.1; -; mRNA.
DR EMBL; AY347527; AAQ24858.1; -; mRNA.
DR EMBL; BC010636; AAH10636.1; -; mRNA.
DR EMBL; S53724; AAD13869.1; -; Genomic_DNA.
DR CCDS; CCDS2374.1; -. [P16220-2]
DR CCDS; CCDS2375.1; -. [P16220-1]
DR PIR; A37340; A35769.
DR PIR; B37340; B35769.
DR PIR; S22298; S22298.
DR RefSeq; NP_004370.1; NM_004379.4. [P16220-2]
DR RefSeq; NP_604391.1; NM_134442.4. [P16220-1]
DR RefSeq; XP_011508947.1; XM_011510645.1.
DR RefSeq; XP_011508949.1; XM_011510647.2.
DR PDB; 2LXT; NMR; -; C=102-135.
DR PDB; 5ZK1; X-ray; 3.05 A; A=269-327.
DR PDB; 5ZKO; X-ray; 3.05 A; A/C=269-327.
DR PDBsum; 2LXT; -.
DR PDBsum; 5ZK1; -.
DR PDBsum; 5ZKO; -.
DR AlphaFoldDB; P16220; -.
DR BMRB; P16220; -.
DR SMR; P16220; -.
DR BioGRID; 107775; 210.
DR ComplexPortal; CPX-2494; bZIP transcription factor complex, BACH1-CREB1.
DR ComplexPortal; CPX-6405; bZIP transcription factor complex, ATF1-CREB1.
DR ComplexPortal; CPX-8; bZIP transcription factor complex, ATF4-CREB1.
DR CORUM; P16220; -.
DR DIP; DIP-765N; -.
DR IntAct; P16220; 111.
DR MINT; P16220; -.
DR STRING; 9606.ENSP00000387699; -.
DR ChEMBL; CHEMBL5587; -.
DR DrugBank; DB00131; Adenosine phosphate.
DR DrugBank; DB01183; Naloxone.
DR GlyGen; P16220; 6 sites, 2 O-linked glycans (6 sites).
DR iPTMnet; P16220; -.
DR MetOSite; P16220; -.
DR PhosphoSitePlus; P16220; -.
DR BioMuta; CREB1; -.
DR DMDM; 117434; -.
DR EPD; P16220; -.
DR jPOST; P16220; -.
DR MassIVE; P16220; -.
DR MaxQB; P16220; -.
DR PaxDb; P16220; -.
DR PeptideAtlas; P16220; -.
DR PRIDE; P16220; -.
DR ProteomicsDB; 53324; -. [P16220-1]
DR ProteomicsDB; 53325; -. [P16220-2]
DR ProteomicsDB; 53326; -. [P16220-3]
DR ABCD; P16220; 1 sequenced antibody.
DR Antibodypedia; 3536; 2247 antibodies from 54 providers.
DR DNASU; 1385; -.
DR Ensembl; ENST00000353267.8; ENSP00000236995.3; ENSG00000118260.15. [P16220-2]
DR Ensembl; ENST00000430624.5; ENSP00000405539.1; ENSG00000118260.15. [P16220-2]
DR Ensembl; ENST00000432329.6; ENSP00000387699.2; ENSG00000118260.15. [P16220-1]
DR GeneID; 1385; -.
DR KEGG; hsa:1385; -.
DR MANE-Select; ENST00000353267.8; ENSP00000236995.3; NM_004379.5; NP_004370.1.
DR CTD; 1385; -.
DR DisGeNET; 1385; -.
DR GeneCards; CREB1; -.
DR HGNC; HGNC:2345; CREB1.
DR HPA; ENSG00000118260; Low tissue specificity.
DR MalaCards; CREB1; -.
DR MIM; 123810; gene.
DR MIM; 612160; phenotype.
DR neXtProt; NX_P16220; -.
DR OpenTargets; ENSG00000118260; -.
DR Orphanet; 97338; Melanoma of soft tissue.
DR PharmGKB; PA26864; -.
DR VEuPathDB; HostDB:ENSG00000118260; -.
DR eggNOG; KOG3584; Eukaryota.
DR GeneTree; ENSGT00940000155408; -.
DR InParanoid; P16220; -.
DR OMA; QXISTIA; -.
DR PhylomeDB; P16220; -.
DR TreeFam; TF106464; -.
DR PathwayCommons; P16220; -.
DR Reactome; R-HSA-111931; PKA-mediated phosphorylation of CREB.
DR Reactome; R-HSA-111932; CaMK IV-mediated phosphorylation of CREB.
DR Reactome; R-HSA-198693; AKT phosphorylates targets in the nucleus.
DR Reactome; R-HSA-199920; CREB phosphorylation.
DR Reactome; R-HSA-2151201; Transcriptional activation of mitochondrial biogenesis.
DR Reactome; R-HSA-2197563; NOTCH2 intracellular domain regulates transcription.
DR Reactome; R-HSA-375165; NCAM signaling for neurite out-growth.
DR Reactome; R-HSA-400253; Circadian Clock.
DR Reactome; R-HSA-442720; CREB1 phosphorylation through the activation of Adenylate Cyclase.
DR Reactome; R-HSA-442729; CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde.
DR Reactome; R-HSA-442742; CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling.
DR Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer.
DR Reactome; R-HSA-881907; Gastrin-CREB signalling pathway via PKC and MAPK.
DR Reactome; R-HSA-9022692; Regulation of MECP2 expression and activity.
DR Reactome; R-HSA-9022699; MECP2 regulates neuronal receptors and channels.
DR Reactome; R-HSA-9022702; MECP2 regulates transcription of neuronal ligands.
DR Reactome; R-HSA-9022707; MECP2 regulates transcription factors.
DR Reactome; R-HSA-9031628; NGF-stimulated transcription.
DR Reactome; R-HSA-9609690; HCMV Early Events.
DR Reactome; R-HSA-9616222; Transcriptional regulation of granulopoiesis.
DR Reactome; R-HSA-9634638; Estrogen-dependent nuclear events downstream of ESR-membrane signaling.
DR Reactome; R-HSA-9660821; ADORA2B mediated anti-inflammatory cytokines production.
DR Reactome; R-HSA-9664323; FCGR3A-mediated IL10 synthesis.
DR Reactome; R-HSA-9707616; Heme signaling.
DR SignaLink; P16220; -.
DR SIGNOR; P16220; -.
DR BioGRID-ORCS; 1385; 38 hits in 1114 CRISPR screens.
DR ChiTaRS; CREB1; human.
DR GeneWiki; CREB1; -.
DR GenomeRNAi; 1385; -.
DR Pharos; P16220; Tbio.
DR PRO; PR:P16220; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; P16220; protein.
DR Bgee; ENSG00000118260; Expressed in secondary oocyte and 213 other tissues.
DR ExpressionAtlas; P16220; baseline and differential.
DR Genevisible; P16220; HS.
DR GO; GO:1990589; C:ATF4-CREB1 transcription factor complex; IDA:ParkinsonsUK-UCL.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0000791; C:euchromatin; IDA:BHF-UCL.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; IPI:ComplexPortal.
DR GO; GO:0005667; C:transcription regulator complex; IBA:GO_Central.
DR GO; GO:0035497; F:cAMP response element binding; IDA:BHF-UCL.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:BHF-UCL.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:MGI.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:BHF-UCL.
DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:BHF-UCL.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:BHF-UCL.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0007409; P:axonogenesis; IEA:Ensembl.
DR GO; GO:0019933; P:cAMP-mediated signaling; IDA:MGI.
DR GO; GO:1904322; P:cellular response to forskolin; IDA:MGI.
DR GO; GO:0035729; P:cellular response to hepatocyte growth factor stimulus; IEA:Ensembl.
DR GO; GO:1990830; P:cellular response to leukemia inhibitory factor; IEA:Ensembl.
DR GO; GO:0071300; P:cellular response to retinoic acid; ISS:ARUK-UCL.
DR GO; GO:0071294; P:cellular response to zinc ion; IEA:Ensembl.
DR GO; GO:0007623; P:circadian rhythm; ISS:UniProtKB.
DR GO; GO:0046879; P:hormone secretion; IEA:Ensembl.
DR GO; GO:0007595; P:lactation; IEA:Ensembl.
DR GO; GO:0060430; P:lung saccule development; IEA:Ensembl.
DR GO; GO:0007613; P:memory; IEA:Ensembl.
DR GO; GO:0042789; P:mRNA transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0010944; P:negative regulation of transcription by competitive promoter binding; IDA:BHF-UCL.
DR GO; GO:0030316; P:osteoclast differentiation; IEA:Ensembl.
DR GO; GO:0021983; P:pituitary gland development; IEA:Ensembl.
DR GO; GO:0055025; P:positive regulation of cardiac muscle tissue development; IEA:Ensembl.
DR GO; GO:0045600; P:positive regulation of fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0046887; P:positive regulation of hormone secretion; IEA:Ensembl.
DR GO; GO:0046889; P:positive regulation of lipid biosynthetic process; ISS:UniProtKB.
DR GO; GO:0040018; P:positive regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:NTNU_SB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:MGI.
DR GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR GO; GO:0008361; P:regulation of cell size; IEA:Ensembl.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0033762; P:response to glucagon; ISS:UniProtKB.
DR GO; GO:0010033; P:response to organic substance; IDA:MGI.
DR GO; GO:0014074; P:response to purine-containing compound; IDA:MGI.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0033363; P:secretory granule organization; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR GO; GO:0060509; P:type I pneumocyte differentiation; IEA:Ensembl.
DR DisProt; DP02003; -.
DR IDEAL; IID00442; -.
DR InterPro; IPR004827; bZIP.
DR InterPro; IPR046347; bZIP_sf.
DR InterPro; IPR003102; Coactivator_CBP_pKID.
DR InterPro; IPR029802; CREB1.
DR InterPro; IPR001630; Leuzip_CREB.
DR PANTHER; PTHR45879; PTHR45879; 1.
DR PANTHER; PTHR45879:SF1; PTHR45879:SF1; 1.
DR Pfam; PF00170; bZIP_1; 1.
DR Pfam; PF02173; pKID; 1.
DR SMART; SM00338; BRLZ; 1.
DR SUPFAM; SSF57959; SSF57959; 1.
DR PROSITE; PS50217; BZIP; 1.
DR PROSITE; PS00036; BZIP_BASIC; 1.
DR PROSITE; PS50953; KID; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; Biological rhythms;
KW Chromosomal rearrangement; Differentiation; DNA-binding;
KW Host-virus interaction; Isopeptide bond; Nucleus; Phosphoprotein;
KW Reference proteome; Transcription; Transcription regulation;
KW Ubl conjugation.
FT CHAIN 1..327
FT /note="Cyclic AMP-responsive element-binding protein 1"
FT /id="PRO_0000076597"
FT DOMAIN 87..146
FT /note="KID"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00312"
FT DOMAIN 269..327
FT /note="bZIP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 1..26
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 94..113
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 125..148
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 270..295
FT /note="Basic motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 297..318
FT /note="Leucine-zipper"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT SITE 300
FT /note="Required for binding TORCs"
FT MOD_RES 119
FT /note="Phosphoserine; by CaMK1, CaMK2, CaMK4, PKB/AKT1 or
FT PKB/AKT2, RPS6KA3, RPS6KA4, RPS6KA5, SGK1 and TSSK4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00312,
FT ECO:0000269|PubMed:15733869, ECO:0000269|PubMed:15964553,
FT ECO:0000269|PubMed:7608156, ECO:0000269|PubMed:8065343,
FT ECO:0000269|PubMed:9770464, ECO:0000269|PubMed:9829964"
FT MOD_RES 128
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 257
FT /note="Phosphoserine; by HIPK2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00312,
FT ECO:0000269|PubMed:20573984"
FT CROSSLNK 122
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT CROSSLNK 271
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000269|PubMed:12552083"
FT CROSSLNK 290
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000269|PubMed:12552083"
FT VAR_SEQ 86
FT /note="V -> VQSSCKDLKRLFSGT (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_060702"
FT VAR_SEQ 148..258
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_060703"
FT VARIANT 102
FT /note="D -> G (found in a patient with multiple congenital
FT anomalies; does not affect CREB1 phosphorylation at S-119;
FT fails to interact with CREBBP; dbSNP:rs387906617)"
FT /evidence="ECO:0000269|PubMed:22267179"
FT /id="VAR_068077"
FT MUTAGEN 119
FT /note="S->A: Does not interact with TOX3 and inhibits
FT induction of transcription by TOX3. Loss of phosphorylation
FT by CaMK4. Loss of phosphorylation by TSSK4."
FT /evidence="ECO:0000269|PubMed:15964553,
FT ECO:0000269|PubMed:21172805, ECO:0000269|PubMed:8065343"
FT MUTAGEN 141
FT /note="K->R: No effect on sumoylation."
FT /evidence="ECO:0000269|PubMed:12552083"
FT MUTAGEN 257
FT /note="S->A: Impaired phosphorylation by HIPK2 and
FT subsequent transactivation."
FT /evidence="ECO:0000269|PubMed:20573984"
FT MUTAGEN 257
FT /note="S->E: Potentiated transactivation."
FT /evidence="ECO:0000269|PubMed:20573984"
FT MUTAGEN 271
FT /note="K->R: Decreased sumoylation, in vivo and in vitro."
FT /evidence="ECO:0000269|PubMed:12552083"
FT MUTAGEN 290
FT /note="K->R: Decreased sumoylation, in vivo and in vitro.
FT Loss of nuclear localization."
FT /evidence="ECO:0000269|PubMed:12552083"
FT CONFLICT 4
FT /note="E -> D (in Ref. 5; CAA42620)"
FT /evidence="ECO:0000305"
FT CONFLICT 8
FT /note="E -> D (in Ref. 5; CAA42620)"
FT /evidence="ECO:0000305"
FT CONFLICT 146
FT /note="T -> A (in Ref. 5; CAA42620)"
FT /evidence="ECO:0000305"
FT CONFLICT 153
FT /note="T -> A (in Ref. 5; CAA42620)"
FT /evidence="ECO:0000305"
FT CONFLICT 155
FT /note="T -> A (in Ref. 5; CAA42620)"
FT /evidence="ECO:0000305"
FT CONFLICT 162
FT /note="Q -> R (in Ref. 5; CAA42620)"
FT /evidence="ECO:0000305"
FT CONFLICT 170
FT /note="A -> T (in Ref. 5; CAA42620)"
FT /evidence="ECO:0000305"
FT CONFLICT 174
FT /note="G -> R (in Ref. 5; CAA42620)"
FT /evidence="ECO:0000305"
FT CONFLICT 181
FT /note="N -> S (in Ref. 5; CAA42620)"
FT /evidence="ECO:0000305"
FT CONFLICT 196
FT /note="T -> A (in Ref. 5; CAA42620)"
FT /evidence="ECO:0000305"
FT CONFLICT 278
FT /note="K -> E (in Ref. 6; AAQ24858)"
FT /evidence="ECO:0000305"
FT HELIX 106..114
FT /evidence="ECO:0007829|PDB:2LXT"
FT HELIX 118..128
FT /evidence="ECO:0007829|PDB:2LXT"
FT HELIX 272..322
FT /evidence="ECO:0007829|PDB:5ZK1"
SQ SEQUENCE 327 AA; 35136 MW; F5BA8200EE5184B7 CRC64;
MTMESGAENQ QSGDAAVTEA ENQQMTVQAQ PQIATLAQVS MPAAHATSSA PTVTLVQLPN
GQTVQVHGVI QAAQPSVIQS PQVQTVQIST IAESEDSQES VDSVTDSQKR REILSRRPSY
RKILNDLSSD APGVPRIEEE KSEEETSAPA ITTVTVPTPI YQTSSGQYIA ITQGGAIQLA
NNGTDGVQGL QTLTMTNAAA TQPGTTILQY AQTTDGQQIL VPSNQVVVQA ASGDVQTYQI
RTAPTSTIAP GVVMASSPAL PTQPAEEAAR KREVRLMKNR EAARECRRKK KEYVKCLENR
VAVLENQNKT LIEELKALKD LYCHKSD
