CREB1_RAT
ID CREB1_RAT Reviewed; 327 AA.
AC P15337;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 07-OCT-2020, sequence version 2.
DT 03-AUG-2022, entry version 212.
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; Synonyms=Creb-1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=2521922; DOI=10.1038/337749a0;
RA Gonzalez G.A., Yamamoto K.K., Fischer W.H., Karr D., Menzel P.,
RA Biggs W. III, Vale W.W., Montminy M.R.;
RT "A cluster of phosphorylation sites on the cyclic AMP-regulated nuclear
RT factor CREB predicted by its sequence.";
RL Nature 337:749-752(1989).
RN [2]
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 [3]
RP PHOSPHORYLATION AT SER-119, AND PHOSPHORYLATION BY CAMK1 AND CAMK4.
RX PubMed=1646483; DOI=10.1126/science.1646483;
RA Sheng M., Thompson M.A., Greenberg M.E.;
RT "CREB: a Ca(2+)-regulated transcription factor phosphorylated by
RT calmodulin-dependent kinases.";
RL Science 252:1427-1430(1991).
RN [4]
RP PHOSPHORYLATION AT SER-119 AND SER-128, AND MUTAGENESIS OF SER-119 AND
RP SER-128.
RX PubMed=7958915; DOI=10.1101/gad.8.21.2527;
RA Sun P., Enslen H., Myung P.S., Maurer R.A.;
RT "Differential activation of CREB by Ca2+/calmodulin-dependent protein
RT kinases type II and type IV involves phosphorylation of a site that
RT negatively regulates activity.";
RL Genes Dev. 8:2527-2539(1994).
RN [5]
RP PHOSPHORYLATION AT SER-119, AND PHOSPHORYLATION BY CAMK1.
RX PubMed=8621702; DOI=10.1074/jbc.271.6.3066;
RA Sun P., Lou L., Maurer R.A.;
RT "Regulation of activating transcription factor-1 and the cAMP response
RT element-binding protein by Ca2+/calmodulin-dependent protein kinases type
RT I, II, and IV.";
RL J. Biol. Chem. 271:3066-3073(1996).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-128, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [7]
RP STRUCTURE BY NMR OF 105-132 IN COMPLEX WITH CREBBP.
RX PubMed=10222196; DOI=10.1006/jmbi.1999.2658;
RA Radhakrishnan I., Perez-Alvarado G.C., Parker D., Dyson H.J.,
RA Montminy M.R., Wright P.E.;
RT "Structural analyses of CREB-CBP transcriptional activator-coactivator
RT complexes by NMR spectroscopy: implications for mapping the boundaries of
RT structural domains.";
RL J. Mol. Biol. 287:859-865(1999).
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 (By similarity).
CC {ECO:0000250}.
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 Forms a complex with KMT2A and CREBBP (By similarity). Interacts with
CC TOX4; CREB1 is required for full induction of TOX4-dependent activity
CC and the interaction is increased by cAMP and inhibited by insulin (By
CC similarity). {ECO:0000250|UniProtKB:P16220,
CC ECO:0000250|UniProtKB:Q01147}.
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Delta;
CC IsoId=P15337-2; Sequence=Displayed;
CC Name=2; Synonyms=Alpha;
CC IsoId=P15337-1; Sequence=VSP_060705;
CC -!- PTM: Phosphorylation of Ser-119 allows CREBBP binding. Stimulated by
CC phosphorylation. Phosphorylation of both Ser-128 and Ser-119 in the SCN
CC regulates the activity of CREB and participate in circadian rhythm
CC generation (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. Phosphorylation of Ser-257 by
CC HIPK2 in response to genotoxic stress promotes CREB1 activity,
CC facilitating the recruitment of the coactivator CBP. Phosphorylated at
CC Ser-119 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or
CC stress stimuli (By similarity). CREBL2 positively regulates
CC phosphorylation at Ser-119 thereby stimulating CREB1 transcriptional
CC activity. In liver, phosphorylation is induced by fasting or glucagon
CC in a circadian fashion (By similarity). Phosphorylated by TSSK4 on Ser-
CC 119 (By similarity). {ECO:0000250|UniProtKB:P16220}.
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 (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the bZIP family. {ECO:0000305}.
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DR EMBL; X14788; CAA32890.1; -; mRNA.
DR EMBL; X60002; CAA42619.1; -; mRNA.
DR PIR; A35663; A35663.
DR PIR; S03343; S03343.
DR PIR; S22299; S22299.
DR RefSeq; NP_112279.1; NM_031017.1. [P15337-1]
DR RefSeq; NP_604392.1; NM_134443.1. [P15337-2]
DR RefSeq; XP_006245127.1; XM_006245065.3. [P15337-1]
DR RefSeq; XP_006245128.1; XM_006245066.3. [P15337-2]
DR PDB; 1KDX; NMR; -; B=105-132.
DR PDBsum; 1KDX; -.
DR AlphaFoldDB; P15337; -.
DR BMRB; P15337; -.
DR SMR; P15337; -.
DR BioGRID; 249546; 3.
DR DIP; DIP-36407N; -.
DR IntAct; P15337; 3.
DR MINT; P15337; -.
DR STRING; 10116.ENSRNOP00000018326; -.
DR iPTMnet; P15337; -.
DR PhosphoSitePlus; P15337; -.
DR PaxDb; P15337; -.
DR PRIDE; P15337; -.
DR ABCD; P15337; 1 sequenced antibody.
DR Ensembl; ENSRNOT00000018326; ENSRNOP00000018326; ENSRNOG00000013412. [P15337-1]
DR GeneID; 81646; -.
DR KEGG; rno:81646; -.
DR UCSC; RGD:620218; rat. [P15337-2]
DR CTD; 1385; -.
DR RGD; 620218; Creb1.
DR VEuPathDB; HostDB:ENSRNOG00000013412; -.
DR eggNOG; KOG3584; Eukaryota.
DR GeneTree; ENSGT00940000155408; -.
DR HOGENOM; CLU_042675_0_1_1; -.
DR InParanoid; P15337; -.
DR OMA; QXISTIA; -.
DR OrthoDB; 957343at2759; -.
DR PhylomeDB; P15337; -.
DR TreeFam; TF106464; -.
DR Reactome; R-RNO-198693; AKT phosphorylates targets in the nucleus.
DR Reactome; R-RNO-199920; CREB phosphorylation.
DR Reactome; R-RNO-375165; NCAM signaling for neurite out-growth.
DR Reactome; R-RNO-9031628; NGF-stimulated transcription.
DR Reactome; R-RNO-9634638; Estrogen-dependent nuclear events downstream of ESR-membrane signaling.
DR EvolutionaryTrace; P15337; -.
DR PRO; PR:P15337; -.
DR Proteomes; UP000002494; Chromosome 9.
DR Bgee; ENSRNOG00000013412; Expressed in testis and 18 other tissues.
DR Genevisible; P15337; RN.
DR GO; GO:1990589; C:ATF4-CREB1 transcription factor complex; ISO:RGD.
DR GO; GO:0030424; C:axon; IDA:RGD.
DR GO; GO:0000785; C:chromatin; IDA:BHF-UCL.
DR GO; GO:0000791; C:euchromatin; ISO:RGD.
DR GO; GO:0005759; C:mitochondrial matrix; IDA:RGD.
DR GO; GO:0005739; C:mitochondrion; IDA:RGD.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; ISO:RGD.
DR GO; GO:0005667; C:transcription regulator complex; IDA:RGD.
DR GO; GO:1990763; F:arrestin family protein binding; IPI:RGD.
DR GO; GO:0035497; F:cAMP response element binding; ISO:RGD.
DR GO; GO:0003677; F:DNA binding; ISO:RGD.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISO:RGD.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IMP:RGD.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:RGD.
DR GO; GO:0003690; F:double-stranded DNA binding; IDA:RGD.
DR GO; GO:0019899; F:enzyme binding; ISO:RGD.
DR GO; GO:0035035; F:histone acetyltransferase binding; IPI:RGD.
DR GO; GO:0030544; F:Hsp70 protein binding; IPI:RGD.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISO:RGD.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; ISO:RGD.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:RGD.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:RGD.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:RGD.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:RGD.
DR GO; GO:0001223; F:transcription coactivator binding; IPI:CAFA.
DR GO; GO:0007568; P:aging; IEP:RGD.
DR GO; GO:0007409; P:axonogenesis; ISO:RGD.
DR GO; GO:0019933; P:cAMP-mediated signaling; ISO:RGD.
DR GO; GO:0071398; P:cellular response to fatty acid; IEP:RGD.
DR GO; GO:1904322; P:cellular response to forskolin; ISO:RGD.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; ISO:RGD.
DR GO; GO:0035729; P:cellular response to hepatocyte growth factor stimulus; ISO:RGD.
DR GO; GO:1990314; P:cellular response to insulin-like growth factor stimulus; IEP:RGD.
DR GO; GO:1990830; P:cellular response to leukemia inhibitory factor; ISO:RGD.
DR GO; GO:1990090; P:cellular response to nerve growth factor stimulus; IEP:RGD.
DR GO; GO:0036120; P:cellular response to platelet-derived growth factor stimulus; IEP:RGD.
DR GO; GO:0071300; P:cellular response to retinoic acid; ISO:RGD.
DR GO; GO:0071560; P:cellular response to transforming growth factor beta stimulus; IEP:RGD.
DR GO; GO:0071294; P:cellular response to zinc ion; ISO:RGD.
DR GO; GO:0034670; P:chemotaxis to arachidonic acid; IMP:RGD.
DR GO; GO:0007623; P:circadian rhythm; IEP:RGD.
DR GO; GO:0007595; P:lactation; ISO:RGD.
DR GO; GO:0060428; P:lung epithelium development; ISO:RGD.
DR GO; GO:0060430; P:lung saccule development; ISO:RGD.
DR GO; GO:0030879; P:mammary gland development; ISO:RGD.
DR GO; GO:0007613; P:memory; IMP:RGD.
DR GO; GO:0042789; P:mRNA transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0010629; P:negative regulation of gene expression; IMP:RGD.
DR GO; GO:1901215; P:negative regulation of neuron death; IMP:RGD.
DR GO; GO:0010944; P:negative regulation of transcription by competitive promoter binding; ISO:RGD.
DR GO; GO:0021983; P:pituitary gland development; ISO:RGD.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:RGD.
DR GO; GO:0055025; P:positive regulation of cardiac muscle tissue development; ISO:RGD.
DR GO; GO:0045600; P:positive regulation of fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0046887; P:positive regulation of hormone secretion; ISO:RGD.
DR GO; GO:0046889; P:positive regulation of lipid biosynthetic process; ISS:UniProtKB.
DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; IMP:RGD.
DR GO; GO:0040018; P:positive regulation of multicellular organism growth; ISO:RGD.
DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; ISO:RGD.
DR GO; GO:0045899; P:positive regulation of RNA polymerase II transcription preinitiation complex assembly; IMP:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:RGD.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0032916; P:positive regulation of transforming growth factor beta3 production; IMP:RGD.
DR GO; GO:0006468; P:protein phosphorylation; ISO:RGD.
DR GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; IDA:RGD.
DR GO; GO:0008361; P:regulation of cell size; ISO:RGD.
DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:RGD.
DR GO; GO:0048145; P:regulation of fibroblast proliferation; IMP:RGD.
DR GO; GO:0060251; P:regulation of glial cell proliferation; IMP:RGD.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISO:RGD.
DR GO; GO:0014823; P:response to activity; IEP:RGD.
DR GO; GO:0033762; P:response to glucagon; ISS:UniProtKB.
DR GO; GO:0001666; P:response to hypoxia; IEP:RGD.
DR GO; GO:0010035; P:response to inorganic substance; ISO:RGD.
DR GO; GO:1902065; P:response to L-glutamate; IEP:RGD.
DR GO; GO:0035094; P:response to nicotine; IEP:RGD.
DR GO; GO:0010033; P:response to organic substance; ISO:RGD.
DR GO; GO:0014074; P:response to purine-containing compound; ISO:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD.
DR GO; GO:0033363; P:secretory granule organization; ISO:RGD.
DR GO; GO:0006366; P:transcription by RNA polymerase II; IMP:RGD.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IMP:RGD.
DR GO; GO:0060509; P:type I pneumocyte differentiation; ISO:RGD.
DR GO; GO:0008542; P:visual learning; IMP:RGD.
DR IDEAL; IID50004; -.
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 Differentiation; Direct protein sequencing; DNA-binding; Isopeptide bond;
KW Nucleus; Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..327
FT /note="Cyclic AMP-responsive element-binding protein 1"
FT /id="PRO_0000076599"
FT DOMAIN 8..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..29
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 126..149
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 MOD_RES 119
FT /note="Phosphoserine; by CaMK1, CaMK2, CaMK4, PKB/AKT1 or
FT PKB/AKT2, RPS6KA3, RPS6KA4, RPS6KA5 and SGK1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00312,
FT ECO:0000269|PubMed:1646483, ECO:0000269|PubMed:7958915,
FT ECO:0000269|PubMed:8621702"
FT MOD_RES 128
FT /note="Phosphoserine; by CaMK2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00312,
FT ECO:0000269|PubMed:7958915, ECO:0007744|PubMed:22673903"
FT MOD_RES 257
FT /note="Phosphoserine; by HIPK2"
FT /evidence="ECO:0000250|UniProtKB:P16220,
FT ECO:0000255|PROSITE-ProRule:PRU00312"
FT CROSSLNK 122
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:P16220"
FT CROSSLNK 271
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000250|UniProtKB:P16220"
FT CROSSLNK 290
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000250|UniProtKB:P16220"
FT VAR_SEQ 86
FT /note="V -> VQSSCKDLKRLFSGT (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_060705"
FT MUTAGEN 119
FT /note="S->A: Loss of activation by CaMK4."
FT /evidence="ECO:0000269|PubMed:7958915"
FT MUTAGEN 128
FT /note="S->A: Loss of phosphorylation by CaMK2. Activation
FT by CaMK2."
FT /evidence="ECO:0000269|PubMed:7958915"
FT CONFLICT 121
FT /note="R -> K (in Ref. 2; CAA42619)"
FT /evidence="ECO:0000305"
FT CONFLICT 305
FT /note="E -> K (in Ref. 2; CAA42619)"
FT /evidence="ECO:0000305"
FT HELIX 106..114
FT /evidence="ECO:0007829|PDB:1KDX"
FT HELIX 119..130
FT /evidence="ECO:0007829|PDB:1KDX"
SQ SEQUENCE 327 AA; 35081 MW; D6D715DEED679FF2 CRC64;
MTMDSGADNQ QSGDAAVTEA ESQQMTVQAQ 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
