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Protein

Cyclic AMP-responsive element-binding protein 1

Gene

CREB1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-133 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei314Required for binding TORCs1

GO - Molecular functioni

  • cAMP response element binding Source: BHF-UCL
  • DNA binding transcription factor activity Source: MGI
  • enzyme binding Source: UniProtKB
  • identical protein binding Source: IntAct
  • RNA polymerase II activating transcription factor binding Source: BHF-UCL
  • RNA polymerase II distal enhancer sequence-specific DNA binding Source: BHF-UCL
  • RNA polymerase II proximal promoter sequence-specific DNA binding Source: NTNU_SB
  • RNA polymerase II transcription coactivator binding Source: Ensembl
  • RNA polymerase II transcription factor activity, sequence-specific DNA binding Source: NTNU_SB
  • transcriptional activator activity, RNA polymerase II proximal promoter sequence-specific DNA binding Source: NTNU_SB
  • transcriptional activator activity, RNA polymerase II transcription factor binding Source: BHF-UCL
  • transcription cofactor activity Source: ProtInc
  • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding Source: BHF-UCL

GO - Biological processi

Keywordsi

Molecular functionActivator, DNA-binding
Biological processBiological rhythms, Differentiation, Host-virus interaction, Transcription, Transcription regulation

Enzyme and pathway databases

ReactomeiR-HSA-111931 PKA-mediated phosphorylation of CREB
R-HSA-111932 CaMK IV-mediated phosphorylation of CREB
R-HSA-198693 AKT phosphorylates targets in the nucleus
R-HSA-199920 CREB phosphorylation
R-HSA-2151201 Transcriptional activation of mitochondrial biogenesis
R-HSA-2197563 NOTCH2 intracellular domain regulates transcription
R-HSA-375165 NCAM signaling for neurite out-growth
R-HSA-400253 Circadian Clock
R-HSA-442717 CREB phosphorylation through the activation of CaMKK
R-HSA-442720 CREB phosphorylation through the activation of Adenylate Cyclase
R-HSA-442729 CREB phosphorylation through the activation of CaMKII
R-HSA-442742 CREB phosphorylation through the activation of Ras
R-HSA-5674400 Constitutive Signaling by AKT1 E17K in Cancer
R-HSA-881907 Gastrin-CREB signalling pathway via PKC and MAPK
SignaLinkiP16220
SIGNORiP16220

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclic AMP-responsive element-binding protein 1
Short name:
CREB-1
Short name:
cAMP-responsive element-binding protein 1
Gene namesi
Name:CREB1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi

Organism-specific databases

EuPathDBiHostDB:ENSG00000118260.14
HGNCiHGNC:2345 CREB1
MIMi123810 gene
neXtProtiNX_P16220

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Involvement in diseasei

Angiomatoid fibrous histiocytoma (AFH)
The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving CREB1 is found in a patient with angiomatoid fibrous histiocytoma. Translocation t(2;22)(q33;q12) with CREB1 generates a EWSR1/CREB1 fusion gene that is most common genetic abnormality in this tumor type.
Disease descriptionA distinct variant of malignant fibrous histiocytoma that typically occurs in children and adolescents and is manifest by nodular subcutaneous growth. Characteristic microscopic features include lobulated sheets of histiocyte-like cells intimately associated with areas of hemorrhage and cystic pseudovascular spaces, as well as a striking cuffing of inflammatory cells, mimicking a lymph node metastasis.
See also OMIM:612160
A CREB1 mutation has been found in a patient with multiple congenital anomalies consisting of agenesis of the corpus callosum, cerebellar hypoplasia, severe neonatal respiratory distress refractory to surfactant, thymus hypoplasia, and thyroid follicular hypoplasia.1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi133S → A: Does not interact with TOX3 and inhibits induction of transcription by TOX3. Loss of phosphorylation by CaMK4. 2 Publications1
Mutagenesisi155K → R: No effect on sumoylation. 1 Publication1
Mutagenesisi271S → A: Impaired phosphorylation by HIPK2 and subsequent transactivation. 1 Publication1
Mutagenesisi271S → E: Potentiated transactivation. 1 Publication1
Mutagenesisi285K → R: Decreased sumoylation, in vivo and in vitro. 1 Publication1
Mutagenesisi304K → R: Decreased sumoylation, in vivo and in vitro. Loss of nuclear localization. 1 Publication1

Organism-specific databases

DisGeNETi1385
MalaCardsiCREB1
MIMi612160 phenotype
OpenTargetsiENSG00000118260
Orphaneti97338 Melanoma of soft parts
PharmGKBiPA26864

Chemistry databases

ChEMBLiCHEMBL5587
DrugBankiDB00131 Adenosine monophosphate
DB01183 Naloxone

Polymorphism and mutation databases

BioMutaiCREB1
DMDMi117434

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000765971 – 341Cyclic AMP-responsive element-binding protein 1Add BLAST341

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei133Phosphoserine; by CaMK1, CaMK2, CaMK4, PKB/AKT1 or PKB/AKT2, RPS6KA3, RPS6KA4, RPS6KA5 and SGK1PROSITE-ProRule annotation5 Publications1
Cross-linki136Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Modified residuei142PhosphoserineCombined sources1
Modified residuei271Phosphoserine; by HIPK2PROSITE-ProRule annotation1 Publication1
Cross-linki285Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)1 Publication
Cross-linki304Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)1 Publication

Post-translational modificationi

Stimulated by phosphorylation. Phosphorylation of both Ser-133 and Ser-142 in the SCN regulates the activity of CREB and participates in circadian rhythm generation. Phosphorylation of Ser-133 allows CREBBP binding. In liver, phosphorylation is induced by fasting or glucagon in a circadian fashion (By similarity). CREBL2 positively regulates phosphorylation at Ser-133 thereby stimulating CREB1 transcriptional activity (By similarity). Phosphorylated upon calcium influx by CaMK4 and CaMK2 on Ser-133. CaMK4 is much more potent than CaMK2 in activating CREB. Phosphorylated by CaMK2 on Ser-142. Phosphorylation of Ser-142 blocks CREB-mediated transcription even when Ser-133 is phosphorylated. Phosphorylated by CaMK1 (By similarity). Phosphorylation of Ser-271 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP. Phosphorylated at Ser-133 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli.By similarity6 Publications
Sumoylated with SUMO1. Sumoylation on Lys-304, but not on Lys-285, is required for nuclear localization of this protein. Sumoylation is enhanced under hypoxia, promoting nuclear localization and stabilization.1 Publication

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP16220
PaxDbiP16220
PeptideAtlasiP16220
PRIDEiP16220

PTM databases

iPTMnetiP16220
PhosphoSitePlusiP16220

Miscellaneous databases

PMAP-CutDBiP16220

Expressioni

Gene expression databases

BgeeiENSG00000118260
CleanExiHS_CREB1
ExpressionAtlasiP16220 baseline and differential
GenevisibleiP16220 HS

Organism-specific databases

HPAiCAB003803
HPA019150

Interactioni

Subunit structurei

Interacts with PPRC1. Binds DNA as a dimer. This dimer is stabilized by magnesium ions. Interacts, through the bZIP domain, with the coactivators TORC1/CRTC1, TORC2/CRTC2 and TORC3/CRTC3. When phosphorylated on Ser-133, binds CREBBP (By similarity). Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity (By similarity). Interacts (phosphorylated form) with TOX3. Interacts with ARRB1. Binds to HIPK2. Interacts with SGK1.By similarity10 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • enzyme binding Source: UniProtKB
  • identical protein binding Source: IntAct
  • RNA polymerase II activating transcription factor binding Source: BHF-UCL
  • RNA polymerase II transcription coactivator binding Source: Ensembl

Protein-protein interaction databases

BioGridi107775, 145 interactors
CORUMiP16220
DIPiDIP-765N
IntActiP16220, 78 interactors
MINTiP16220
STRINGi9606.ENSP00000387699

Structurei

Secondary structure

1341
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi120 – 128Combined sources9
Helixi132 – 142Combined sources11

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2LXTNMR-C116-149[»]
ProteinModelPortaliP16220
SMRiP16220
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini101 – 160KIDPROSITE-ProRule annotationAdd BLAST60
Domaini283 – 341bZIPPROSITE-ProRule annotationAdd BLAST59

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni284 – 309Basic motifPROSITE-ProRule annotationAdd BLAST26
Regioni311 – 332Leucine-zipperPROSITE-ProRule annotationAdd BLAST22

Sequence similaritiesi

Belongs to the bZIP family.Curated

Phylogenomic databases

eggNOGiKOG3584 Eukaryota
ENOG410ZZJZ LUCA
GeneTreeiENSGT00390000008655
HOGENOMiHOG000007365
HOVERGENiHBG011077
InParanoidiP16220
KOiK05870
OMAiQXISTIA
OrthoDBiEOG091G0FTJ
PhylomeDBiP16220
TreeFamiTF106464

Family and domain databases

InterProiView protein in InterPro
IPR004827 bZIP
IPR003102 Coactivator_CBP_pKID
IPR029802 CREB1
IPR001630 Leuzip_CREB
PANTHERiPTHR22952:SF200 PTHR22952:SF200, 1 hit
PfamiView protein in Pfam
PF00170 bZIP_1, 1 hit
PF02173 pKID, 1 hit
PRINTSiPR00041 LEUZIPPRCREB
SMARTiView protein in SMART
SM00338 BRLZ, 1 hit
PROSITEiView protein in PROSITE
PS50217 BZIP, 1 hit
PS00036 BZIP_BASIC, 1 hit
PS50953 KID, 1 hit

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform CREB-A (identifier: P16220-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MTMESGAENQ QSGDAAVTEA ENQQMTVQAQ PQIATLAQVS MPAAHATSSA
60 70 80 90 100
PTVTLVQLPN GQTVQVHGVI QAAQPSVIQS PQVQTVQSSC KDLKRLFSGT
110 120 130 140 150
QISTIAESED SQESVDSVTD SQKRREILSR RPSYRKILND LSSDAPGVPR
160 170 180 190 200
IEEEKSEEET SAPAITTVTV PTPIYQTSSG QYIAITQGGA IQLANNGTDG
210 220 230 240 250
VQGLQTLTMT NAAATQPGTT ILQYAQTTDG QQILVPSNQV VVQAASGDVQ
260 270 280 290 300
TYQIRTAPTS TIAPGVVMAS SPALPTQPAE EAARKREVRL MKNREAAREC
310 320 330 340
RRKKKEYVKC LENRVAVLEN QNKTLIEELK ALKDLYCHKS D
Length:341
Mass (Da):36,688
Last modified:May 1, 1992 - v2
Checksum:iD5E989AE40BF69AF
GO
Isoform CREB-B (identifier: P16220-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     88-101: Missing.

Show »
Length:327
Mass (Da):35,136
Checksum:iF5BA8200EE5184B7
GO
Isoform 3 (identifier: P16220-3) [UniParc]FASTAAdd to basket
Also known as: htCREB

The sequence of this isoform differs from the canonical sequence as follows:
     162-272: Missing.

Note: Highly expressed in adult testis and sperm.
Show »
Length:230
Mass (Da):25,445
Checksum:i9FD8CA28F7632FBD
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti4E → D in CAA42620 (PubMed:1831258).Curated1
Sequence conflicti8E → D in CAA42620 (PubMed:1831258).Curated1
Sequence conflicti160T → A in CAA42620 (PubMed:1831258).Curated1
Sequence conflicti167T → A in CAA42620 (PubMed:1831258).Curated1
Sequence conflicti169T → A in CAA42620 (PubMed:1831258).Curated1
Sequence conflicti176Q → R in CAA42620 (PubMed:1831258).Curated1
Sequence conflicti184A → T in CAA42620 (PubMed:1831258).Curated1
Sequence conflicti188G → R in CAA42620 (PubMed:1831258).Curated1
Sequence conflicti195N → S in CAA42620 (PubMed:1831258).Curated1
Sequence conflicti210T → A in CAA42620 (PubMed:1831258).Curated1
Sequence conflicti292K → E in AAQ24858 (PubMed:15579595).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_068077116D → G Found in a patient with multiple congenital anomalies; does not affect CREB1 phosphorylation at S-133; fails to interact with CREBBP. 1 PublicationCorresponds to variant dbSNP:rs387906617EnsemblClinVar.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_00059688 – 101Missing in isoform CREB-B. 2 PublicationsAdd BLAST14
Alternative sequenceiVSP_043914162 – 272Missing in isoform 3. 1 PublicationAdd BLAST111

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
S72459 Genomic DNA Translation: AAB20597.1
X55545 mRNA Translation: CAA39151.1
M34356 mRNA Translation: AAA35717.1
M34356 mRNA Translation: AAA35716.1
M27691 mRNA Translation: AAA35715.1
X60003 mRNA Translation: CAA42620.1
AY347527 mRNA Translation: AAQ24858.1
BC010636 mRNA Translation: AAH10636.1
S53724 Genomic DNA Translation: AAD13869.1
CCDSiCCDS2374.1 [P16220-2]
CCDS2375.1 [P16220-1]
PIRiA37340 A35769
B37340 B35769
S22298
RefSeqiNP_004370.1, NM_004379.4 [P16220-2]
NP_604391.1, NM_134442.4 [P16220-1]
XP_011508947.1, XM_011510645.1 [P16220-1]
XP_011508949.1, XM_011510647.2 [P16220-2]
UniGeneiHs.516646
Hs.717136

Genome annotation databases

EnsembliENST00000353267; ENSP00000236995; ENSG00000118260 [P16220-2]
ENST00000430624; ENSP00000405539; ENSG00000118260 [P16220-2]
ENST00000432329; ENSP00000387699; ENSG00000118260 [P16220-1]
GeneIDi1385
KEGGihsa:1385

Keywords - Coding sequence diversityi

Alternative splicing, Chromosomal rearrangement, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiCREB1_HUMAN
AccessioniPrimary (citable) accession number: P16220
Secondary accession number(s): P21934, Q6V963, Q9UMA7
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 1, 1990
Last sequence update: May 1, 1992
Last modified: May 23, 2018
This is version 219 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

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