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Protein

Cyclic AMP-dependent transcription factor ATF-2

Gene

ATF2

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

Functioni

Transcriptional activator which regulates the transcription of various genes, including those involved in anti-apoptosis, cell growth, and DNA damage response. Dependent on its binding partner, binds to CRE (cAMP response element) consensus sequences (5'-TGACGTCA-3') or to AP-1 (activator protein 1) consensus sequences (5'-TGACTCA-3'). In the nucleus, contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. In the cytoplasm, interacts with and perturbs HK1- and VDAC1-containing complexes at the mitochondrial outer membrane, thereby impairing mitochondrial membrane potential, inducing mitochondrial leakage and promoting cell death. The phosphorylated form (mediated by ATM) plays a role in the DNA damage response and is involved in the ionizing radiation (IR)-induced S phase checkpoint control and in the recruitment of the MRN complex into the IR-induced foci (IRIF). Exhibits histone acetyltransferase (HAT) activity which specifically acetylates histones H2B and H4 in vitro. In concert with CUL3 and RBX1, promotes the degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. Can elicit oncogenic or tumor suppressor activities depending on the tissue or cell type.4 Publications

Catalytic activityi

Acetyl-CoA + [protein]-L-lysine = CoA + [protein]-N6-acetyl-L-lysine.1 Publication

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri25 – 49C2H2-typePROSITE-ProRule annotationAdd BLAST25

GO - Molecular functioni

  • cAMP response element binding Source: BHF-UCL
  • cAMP response element binding protein binding Source: BHF-UCL
  • chromatin binding Source: Ensembl
  • DNA binding transcription factor activity Source: MGI
  • enhancer sequence-specific DNA binding Source: UniProtKB
  • histone acetyltransferase activity Source: UniProtKB
  • metal ion binding Source: UniProtKB-KW
  • protein kinase binding Source: UniProtKB
  • 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 regulatory region sequence-specific DNA binding Source: NTNU_SB
  • 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: Ensembl
  • transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific DNA binding Source: NTNU_SB
  • transcription coactivator activity Source: ProtInc
  • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding Source: BHF-UCL
  • transcription factor activity, RNA polymerase II transcription factor binding Source: BHF-UCL

GO - Biological processi

  • adipose tissue development Source: Ensembl
  • amelogenesis Source: Ensembl
  • cellular response to DNA damage stimulus Source: UniProtKB
  • fat cell differentiation Source: Ensembl
  • intra-S DNA damage checkpoint Source: UniProtKB
  • negative regulation of angiogenesis Source: BHF-UCL
  • negative regulation of epithelial cell proliferation Source: Ensembl
  • negative regulation of transcription by RNA polymerase II Source: Ensembl
  • outflow tract morphogenesis Source: Ensembl
  • positive regulation of cardiac muscle myoblast proliferation Source: BHF-UCL
  • positive regulation of DNA binding transcription factor activity Source: UniProtKB
  • positive regulation of gene expression Source: BHF-UCL
  • positive regulation of mitochondrial membrane permeability involved in apoptotic process Source: UniProtKB
  • positive regulation of neuron apoptotic process Source: Ensembl
  • positive regulation of transcription by RNA polymerase II Source: NTNU_SB
  • positive regulation of transforming growth factor beta2 production Source: Ensembl
  • regulation of DNA binding transcription factor activity Source: Reactome
  • regulation of transcription, DNA-templated Source: UniProtKB
  • regulation of transcription by RNA polymerase II Source: BHF-UCL
  • response to osmotic stress Source: UniProtKB
  • response to water deprivation Source: Ensembl

Keywordsi

Molecular functionActivator, DNA-binding, Transferase
Biological processDNA damage, Transcription, Transcription regulation
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-2151201 Transcriptional activation of mitochondrial biogenesis
R-HSA-3214847 HATs acetylate histones
R-HSA-400253 Circadian Clock
R-HSA-450341 Activation of the AP-1 family of transcription factors
R-HSA-6796648 TP53 Regulates Transcription of DNA Repair Genes
R-HSA-8943724 Regulation of PTEN gene transcription
R-HSA-9018519 Estrogen-dependent gene expression
SignaLinkiP15336
SIGNORiP15336

Protein family/group databases

MoonProtiP15336

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclic AMP-dependent transcription factor ATF-2 (EC:2.3.1.481 Publication)
Short name:
cAMP-dependent transcription factor ATF-2
Alternative name(s):
Activating transcription factor 2
Cyclic AMP-responsive element-binding protein 2
Short name:
CREB-2
Short name:
cAMP-responsive element-binding protein 2
HB16
Histone acetyltransferase ATF2
cAMP response element-binding protein CRE-BP1
Gene namesi
Name:ATF2
Synonyms:CREB2, CREBP1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

EuPathDBiHostDB:ENSG00000115966.16
HGNCiHGNC:784 ATF2
MIMi123811 gene
neXtProtiNX_P15336

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

Cytoplasm, Membrane, Mitochondrion, Mitochondrion outer membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi69T → A: Weak histone acetyltransferase activity. 1 Publication1
Mutagenesisi71T → A: Impairs phosphorylation by PLK3. Weak histone acetyltransferase activity. 2 Publications1
Mutagenesisi121S → A: Reduced phosphorylation and repression of c-Jun-mediated activation of transcription. 1

Organism-specific databases

DisGeNETi1386
OpenTargetsiENSG00000115966
PharmGKBiPA25084

Chemistry databases

DrugBankiDB00852 Pseudoephedrine

Polymorphism and mutation databases

BioMutaiATF2
DMDMi215274241

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000765771 – 505Cyclic AMP-dependent transcription factor ATF-2Add BLAST505

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei52Phosphothreonine; by PKC/PRKCH1 Publication1
Modified residuei62Phosphoserine; by VRK1Combined sources1 Publication1
Modified residuei69Phosphothreonine; by MAPK11 and MAPK14Combined sources3 Publications1
Modified residuei71Phosphothreonine; by MAPK1, MAPK3, MAPK11, MAPK12, MAPK14 and PLK3Combined sources4 Publications1
Modified residuei73Phosphothreonine; by VRK11 Publication1
Modified residuei90PhosphoserineCombined sources1
Modified residuei112PhosphoserineCombined sources1
Modified residuei116PhosphothreonineCombined sources1
Modified residuei121Phosphoserine; by PKC/PRKCA and PKC/PRKCB1 Publication1
Modified residuei136PhosphoserineCombined sources1
Modified residuei328PhosphoserineCombined sources1
Modified residuei340Phosphoserine; by PKC/PRKCA and PKC/PRKCB1 Publication1
Modified residuei357N6-acetyllysine1 Publication1
Modified residuei367Phosphoserine; by PKC/PRKCA and PKC/PRKCB1 Publication1
Modified residuei374N6-acetyllysine1 Publication1
Modified residuei442PhosphoserineCombined sources1
Modified residuei446PhosphoserineCombined sources1
Modified residuei490Phosphoserine; by ATM1 Publication1
Modified residuei498Phosphoserine; by ATM1 Publication1

Post-translational modificationi

Phosphorylation of Thr-69 by MAPK14 and MAPK11, and at Thr-71 by MAPK1/ERK2, MAPK3/ERK1, MAPK11, MAPK12 and MAPK14 in response to external stimulus like insulin causes increased transcriptional activity. Phosphorylated by PLK3 following hyperosmotic stress. Also phosphorylated and activated by JNK and CaMK4. ATM-mediated phosphorylation at Ser-490 and Ser-498 stimulates its function in DNA damage response. Phosphorylation at Ser-62, Thr-73 and Ser-121 activates its transcriptional activity. Phosphorylation at Thr-69 or Thr-71 enhances its histone acetyltransferase (HAT) activity.9 Publications

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiP15336
MaxQBiP15336
PaxDbiP15336
PeptideAtlasiP15336
PRIDEiP15336

PTM databases

iPTMnetiP15336
PhosphoSitePlusiP15336

Expressioni

Tissue specificityi

Ubiquitously expressed, with more abundant expression in the brain.

Gene expression databases

BgeeiENSG00000115966
CleanExiHS_ATF2
ExpressionAtlasiP15336 baseline and differential
GenevisibleiP15336 HS

Organism-specific databases

HPAiCAB003769
HPA022134

Interactioni

Subunit structurei

Binds DNA as a dimer and can form a homodimer in the absence of DNA. Can form a heterodimer with JUN. Heterodimerization is essential for its transcriptional activity. Interacts with SMAD3 and SMAD4. Binds through its N-terminal region to UTF1 which acts as a coactivator of ATF2 transcriptional activity. Interacts with the HK1/VDAC1 complex. Interacts with NBN, MRE11, XPO1, KAT5 and CUL3.5 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • cAMP response element binding protein binding Source: BHF-UCL
  • protein kinase binding Source: UniProtKB
  • RNA polymerase II activating transcription factor binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi107776, 214 interactors
DIPiDIP-632N
ELMiP15336
IntActiP15336, 207 interactors
MINTiP15336
STRINGi9606.ENSP00000264110

Structurei

Secondary structure

1505
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Turni30 – 32Combined sources3
Beta strandi35 – 38Combined sources4
Helixi39 – 50Combined sources12
Turni51 – 55Combined sources5
Helixi355 – 412Combined sources58

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1BHINMR-A19-56[»]
1T2KX-ray3.00D354-414[»]
4H36X-ray3.00B48-55[»]
ProteinModelPortaliP15336
SMRiP15336
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP15336

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini352 – 415bZIPPROSITE-ProRule annotationAdd BLAST64

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni296 – 299Essential for its histone acetyltransferase activity4
Regioni354 – 374Basic motifPROSITE-ProRule annotationAdd BLAST21
Regioni380 – 408Leucine-zipperPROSITE-ProRule annotationAdd BLAST29

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi1 – 7Nuclear export signal 1 (N-NES)7
Motifi405 – 414Nuclear export signal 2 (C-NES)10

Domaini

The nuclear export signal 1 (N-NES) negatively regulates its nuclear localization and transcriptional activity.

Sequence similaritiesi

Belongs to the bZIP family. ATF subfamily.Curated

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri25 – 49C2H2-typePROSITE-ProRule annotationAdd BLAST25

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG1414 Eukaryota
ENOG4111CH5 LUCA
GeneTreeiENSGT00390000020106
HOGENOMiHOG000220894
HOVERGENiHBG004300
InParanoidiP15336
KOiK04450
OMAiHPESTTN
OrthoDBiEOG091G0AO8
PhylomeDBiP15336

Family and domain databases

InterProiView protein in InterPro
IPR029836 ATF2
IPR004827 bZIP
IPR016378 TF_CRE-BP1-typ
IPR036236 Znf_C2H2_sf
IPR013087 Znf_C2H2_type
PANTHERiPTHR19304:SF9 PTHR19304:SF9, 1 hit
PfamiView protein in Pfam
PF00170 bZIP_1, 1 hit
PIRSFiPIRSF003153 ATF2_CRE-BP1, 1 hit
SMARTiView protein in SMART
SM00338 BRLZ, 1 hit
SUPFAMiSSF57667 SSF57667, 1 hit
PROSITEiView protein in PROSITE
PS50217 BZIP, 1 hit
PS00036 BZIP_BASIC, 1 hit
PS00028 ZINC_FINGER_C2H2_1, 1 hit
PS50157 ZINC_FINGER_C2H2_2, 1 hit

Sequences (8)i

Sequence statusi: Complete.

This entry describes 8 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P15336-1) [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
MKFKLHVNSA RQYKDLWNMS DDKPFLCTAP GCGQRFTNED HLAVHKHKHE
60 70 80 90 100
MTLKFGPARN DSVIVADQTP TPTRFLKNCE EVGLFNELAS PFENEFKKAS
110 120 130 140 150
EDDIKKMPLD LSPLATPIIR SKIEEPSVVE TTHQDSPLPH PESTTSDEKE
160 170 180 190 200
VPLAQTAQPT SAIVRPASLQ VPNVLLTSSD SSVIIQQAVP SPTSSTVITQ
210 220 230 240 250
APSSNRPIVP VPGPFPLLLH LPNGQTMPVA IPASITSSNV HVPAAVPLVR
260 270 280 290 300
PVTMVPSVPG IPGPSSPQPV QSEAKMRLKA ALTQQHPPVT NGDTVKGHGS
310 320 330 340 350
GLVRTQSEES RPQSLQQPAT STTETPASPA HTTPQTQSTS GRRRRAANED
360 370 380 390 400
PDEKRRKFLE RNRAAASRCR QKRKVWVQSL EKKAEDLSSL NGQLQSEVTL
410 420 430 440 450
LRNEVAQLKQ LLLAHKDCPV TAMQKKSGYH TADKDDSSED ISVPSSPHTE
460 470 480 490 500
AIQHSSVSTS NGVSSTSKAE AVATSVLTQM ADQSTEPALS QIVMAPSSQS

QPSGS
Length:505
Mass (Da):54,537
Last modified:November 25, 2008 - v4
Checksum:i0190EEFAEC8891A7
GO
Isoform 2 (identifier: P15336-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-176: Missing.
     177-185: TSSDSSVII → MSTAYFQMM

Show »
Length:329
Mass (Da):35,044
Checksum:iFA37EF544698FEFA
GO
Isoform 3 (identifier: P15336-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     210-505: Missing.

Show »
Length:209
Mass (Da):23,050
Checksum:iA26AF07CA5D8D5E7
GO
Isoform 4 (identifier: P15336-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-66: MKFKLHVNSARQYKDLWNMSDDKPFLCTAPGCGQRFTNEDHLAVHKHKHEMTLKFGPARNDSVIVA → MYCAWMWP

Show »
Length:447
Mass (Da):48,013
Checksum:i344628FF8F94AAED
GO
Isoform 5 (identifier: P15336-5) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-18: Missing.

Show »
Length:487
Mass (Da):52,277
Checksum:i58ADD6240D6270E8
GO
Isoform 6 (identifier: P15336-6) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-18: Missing.
     34-394: Missing.

Show »
Length:126
Mass (Da):13,149
Checksum:iB9D2E843EB156412
GO
Isoform 7 (identifier: P15336-7) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-18: Missing.
     210-237: PVPGPFPLLLHLPNGQTMPVAIPASITS → SFDQSPWCLVFQESQVLPLPNQYSQKQK
     238-505: Missing.

Show »
Length:219
Mass (Da):24,097
Checksum:i6DA3C87FF1008F68
GO
Isoform 8 (identifier: P15336-8) [UniParc]FASTAAdd to basket
Also known as: ATF2-small

The sequence of this isoform differs from the canonical sequence as follows:
     34-394: Missing.

Show »
Length:144
Mass (Da):15,409
Checksum:i8B7F060B955355C7
GO

Sequence cautioni

The sequence AAY17203 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence AAY17207 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti209V → L in AAB64017 (PubMed:9058782).Curated1
Sequence conflicti223N → S in CAA33886 (PubMed:2529117).Curated1
Sequence conflicti223N → S in AAY17203 (Ref. 4) Curated1
Sequence conflicti223N → S in AAY17207 (Ref. 4) Curated1
Sequence conflicti223N → S in AAY17215 (Ref. 4) Curated1
Sequence conflicti311R → L in AAB64017 (PubMed:9058782).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_035999352D → H in a breast cancer sample; somatic mutation. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0005871 – 176Missing in isoform 2. 1 PublicationAdd BLAST176
Alternative sequenceiVSP_0469591 – 66MKFKL…SVIVA → MYCAWMWP in isoform 4. 1 PublicationAdd BLAST66
Alternative sequenceiVSP_0469601 – 18Missing in isoform 5, isoform 6 and isoform 7. 1 PublicationAdd BLAST18
Alternative sequenceiVSP_04759334 – 394Missing in isoform 6 and isoform 8. 2 PublicationsAdd BLAST361
Alternative sequenceiVSP_000588177 – 185TSSDSSVII → MSTAYFQMM in isoform 2. 1 Publication9
Alternative sequenceiVSP_045161210 – 505Missing in isoform 3. 1 PublicationAdd BLAST296
Alternative sequenceiVSP_047594210 – 237PVPGP…ASITS → SFDQSPWCLVFQESQVLPLP NQYSQKQK in isoform 7. 1 PublicationAdd BLAST28
Alternative sequenceiVSP_047595238 – 505Missing in isoform 7. 1 PublicationAdd BLAST268

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X15875 mRNA Translation: CAA33886.1
U16028 mRNA Translation: AAB64017.1
AY029364 mRNA Translation: AAK55760.1
DQ003037 mRNA Translation: AAY17203.1 Different initiation.
DQ003038 mRNA Translation: AAY17204.1
DQ003041 mRNA Translation: AAY17207.1 Different initiation.
DQ003044 mRNA Translation: AAY17210.1
DQ003047 mRNA Translation: AAY17213.1
DQ003049 mRNA Translation: AAY17215.1
AC131958 Genomic DNA Translation: AAX88876.1
AC074291 Genomic DNA Translation: AAY15004.1
AC007435 Genomic DNA No translation available.
AC096649 Genomic DNA No translation available.
CH471058 Genomic DNA Translation: EAX11111.1
CH471058 Genomic DNA Translation: EAX11112.1
CH471058 Genomic DNA Translation: EAX11113.1
BC026175 mRNA Translation: AAH26175.1
BC107698 mRNA Translation: AAI07699.1
BC130335 mRNA Translation: AAI30336.1
BC130337 mRNA Translation: AAI30338.1
M31630 mRNA Translation: AAA35951.1
CCDSiCCDS2262.1 [P15336-1]
CCDS58737.1 [P15336-4]
CCDS58738.1 [P15336-5]
CCDS58739.1 [P15336-3]
PIRiS05380
RefSeqiNP_001243019.1, NM_001256090.1 [P15336-1]
NP_001243020.1, NM_001256091.1 [P15336-5]
NP_001243021.1, NM_001256092.1 [P15336-4]
NP_001243022.1, NM_001256093.1
NP_001243023.1, NM_001256094.1 [P15336-3]
NP_001871.2, NM_001880.3 [P15336-1]
UniGeneiHs.592510

Genome annotation databases

EnsembliENST00000264110; ENSP00000264110; ENSG00000115966 [P15336-1]
ENST00000345739; ENSP00000340576; ENSG00000115966 [P15336-4]
ENST00000392544; ENSP00000376327; ENSG00000115966 [P15336-1]
ENST00000409499; ENSP00000386282; ENSG00000115966 [P15336-8]
ENST00000409635; ENSP00000387093; ENSG00000115966 [P15336-4]
ENST00000409833; ENSP00000386526; ENSG00000115966 [P15336-3]
ENST00000426833; ENSP00000407911; ENSG00000115966 [P15336-5]
GeneIDi1386
KEGGihsa:1386
UCSCiuc002ujk.5 human [P15336-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiATF2_HUMAN
AccessioniPrimary (citable) accession number: P15336
Secondary accession number(s): A1L3Z2
, A4D7U4, A4D7U5, A4D7V1, D3DPE9, G8JLM5, Q13000, Q3B7B7, Q4ZFU9, Q53RY2, Q8TAR1, Q96JT8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 1, 1990
Last sequence update: November 25, 2008
Last modified: May 23, 2018
This is version 201 of the entry and version 4 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
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Main funding by: National Institutes of Health