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Protein

Hepatocyte nuclear factor 3-beta

Gene

Foxa2

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Transcription factor that is involved in embryonic development, establishment of tissue-specific gene expression and regulation of gene expression in differentiated tissues. Is thought to act as a 'pioneer' factor opening the compacted chromatin for other proteins through interactions with nucleosomal core histones and thereby replacing linker histones at target enhancer and/or promoter sites. Binds DNA with the consensus sequence 5'-[AC]A[AT]T[AG]TT[GT][AG][CT]T[CT]-3' (By similarity). In embryonic development is required for notochord formation. Involved in the development of multiple endoderm-derived organ systems such as the liver, pancreas and lungs; FOXA1 and FOXA2 seem to have at least in part redundant roles. Originally described as a transcription activator for a number of liver genes such as AFP, albumin, tyrosine aminotransferase, PEPCK, etc. Interacts with the cis-acting regulatory regions of these genes. Involved in glucose homeostasis; regulates the expression of genes important for glucose sensing in pancreatic beta-cells and glucose homeostasis (By similarity). Involved in regulation of fat metabolism. Acts synergistically with ONECUT1 to activate transcription of female-specific CYP2C12; the function is inhibited by growth hormone-activated STAT5B. Acts synergistically with HNF4A to activate transcription of APOA1.By similarity2 Publications

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi159 – 25294Fork-headPROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

  • double-stranded DNA binding Source: RGD
  • kinase binding Source: RGD
  • RNA polymerase II core promoter proximal region sequence-specific DNA binding Source: BHF-UCL
  • sequence-specific DNA binding Source: RGD
  • SMAD binding Source: RGD
  • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding Source: RGD
  • transcription factor activity, sequence-specific DNA binding Source: RGD

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Activator, Chromatin regulator, Developmental protein

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Hepatocyte nuclear factor 3-beta
Short name:
HNF-3-beta
Short name:
HNF-3B
Alternative name(s):
Forkhead box protein A2
Gene namesi
Name:Foxa2
Synonyms:Hnf3b, Tcf-3b, Tcf3b
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi2808. Foxa2.

Subcellular locationi

  • Nucleus
  • Cytoplasm

  • Note: Shuttles between the nucleus and cytoplasm in a CRM1-dependent manner; in response to insulin signaling via AKT1 is exported from the nucleus.

GO - Cellular componenti

  • cytoplasm Source: UniProtKB-SubCell
  • nucleus Source: BHF-UCL
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi18 – 181Y → P: Reduces transcriptional activation. 1 Publication
Mutagenesisi110 – 1101L → A: Inhibits nuclear export; when associated with A-113. 1 Publication
Mutagenesisi113 – 1131L → A: Inhibits nuclear export; when associated with A-110. 1 Publication
Mutagenesisi153 – 1531R → K: Abolishes interaction with AKT1. 1 Publication
Mutagenesisi156 – 1561T → A: Constitutive active. Abolishes phosphorylation by PKB/AKT1; inhibits nuclear export; no effect on DNA binding. 2 Publications
Mutagenesisi280 – 2801T → A: Impairs transcriptional activation; when associated with A-283. 1 Publication
Mutagenesisi283 – 2831S → A: Abolishes in vitro phosphorylation by PRKDC. Impairs transcriptional activation; when associated with A-280. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 458458Hepatocyte nuclear factor 3-betaPRO_0000091797Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei156 – 1561Phosphothreonine; by PKB/AKT11 Publication
Modified residuei212 – 2121Phosphoserine1 Publication
Modified residuei283 – 2831Phosphoserine1 Publication
Modified residuei301 – 3011PhosphothreonineBy similarity
Modified residuei303 – 3031Phosphoserine1 Publication
Modified residuei306 – 3061Phosphoserine1 Publication
Modified residuei307 – 3071Phosphoserine1 Publication
Modified residuei309 – 3091Phosphoserine1 Publication
Modified residuei437 – 4371Phosphoserine1 Publication
Modified residuei458 – 4581Phosphoserine1 Publication

Post-translational modificationi

Phosphorylation on Thr-156 abolishes binding to target promoters and subsequent transcription activation upon insulin stimulation.3 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiP32182.

PTM databases

iPTMnetiP32182.
PhosphoSiteiP32182.

Expressioni

Tissue specificityi

Liver.

Interactioni

Subunit structurei

Binds DNA as a monomer. Binds TLE1. Interacts with FOXA1 and FOXA3 (By similarity). Interacts with PRKDC.By similarity3 Publications

GO - Molecular functioni

  • kinase binding Source: RGD
  • SMAD binding Source: RGD

Protein-protein interaction databases

IntActiP32182. 1 interaction.
STRINGi10116.ENSRNOP00000017742.

Structurei

3D structure databases

ProteinModelPortaliP32182.
SMRiP32182. Positions 159-248.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni14 – 9380Transactivation domain 1Add
BLAST
Regioni361 – 45898Transactivation domain 2Add
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi106 – 1138Nuclear localization signal1 Publication

Sequence similaritiesi

Contains 1 fork-head DNA-binding domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG3563. Eukaryota.
COG5025. LUCA.
HOGENOMiHOG000231817.
HOVERGENiHBG006621.
InParanoidiP32182.
KOiK08035.
PhylomeDBiP32182.

Family and domain databases

Gene3Di1.10.10.10. 1 hit.
InterProiIPR013638. Fork-head_N.
IPR001766. Fork_head_dom.
IPR018533. Forkhead_box_C.
IPR018122. TF_fork_head_CS_1.
IPR030456. TF_fork_head_CS_2.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamiPF00250. Forkhead. 1 hit.
PF08430. Forkhead_N. 1 hit.
PF09354. HNF_C. 1 hit.
[Graphical view]
PRINTSiPR00053. FORKHEAD.
SMARTiSM00339. FH. 1 hit.
[Graphical view]
SUPFAMiSSF46785. SSF46785. 1 hit.
PROSITEiPS00657. FORK_HEAD_1. 1 hit.
PS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P32182-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MLGAVKMEGH EPSDWSSYYA EPEGYSSVSN MNASLGMNGM NTYMSMSAAA
60 70 80 90 100
MGSGSGNMSA GSMNMSSYVG AGMSPSLAGM SPGAGAMAGM SGSAGAAGVA
110 120 130 140 150
GMGPHLSPSL SPLGGQAAGA MGGLAPYANM NSMSPMYGQA GLSRARDPKT
160 170 180 190 200
YRRSYTHAKP PYSYISLITM AIQQSPNKML TLSEIYQWIM DLFPFYRQNQ
210 220 230 240 250
QRWQNSIRHS LSFNDFLKVP RAPDKPGKGS FWTLHPDSGN MFENGCYLRR
260 270 280 290 300
QKRFKCENEL ALKEAAGAGS GGGKKTAPGT QASQVQLGEA AGSASETPAG
310 320 330 340 350
TESPHSSASP CQEHKRGGLS ELKGTPASAL SPPEPAPSPG QQQQAAAHLL
360 370 380 390 400
GPPHHPGLPP EAHLKPEHHY AFNHPFSINN LMSSEQQHHH SHHHHQPHKM
410 420 430 440 450
DLKTYEQVMH YPGGYGSPMP GSLAMGPVTN KAGLDASPLA ADTSYYQGVY

SRPIMNSS
Length:458
Mass (Da):48,484
Last modified:October 1, 1993 - v1
Checksum:i9FF754142C194055
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L09647 mRNA. Translation: AAA41338.1.
PIRiB39533.
RefSeqiNP_036875.1. NM_012743.1.
UniGeneiRn.10948.

Genome annotation databases

GeneIDi25099.
KEGGirno:25099.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L09647 mRNA. Translation: AAA41338.1.
PIRiB39533.
RefSeqiNP_036875.1. NM_012743.1.
UniGeneiRn.10948.

3D structure databases

ProteinModelPortaliP32182.
SMRiP32182. Positions 159-248.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiP32182. 1 interaction.
STRINGi10116.ENSRNOP00000017742.

PTM databases

iPTMnetiP32182.
PhosphoSiteiP32182.

Proteomic databases

PaxDbiP32182.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi25099.
KEGGirno:25099.

Organism-specific databases

CTDi3170.
RGDi2808. Foxa2.

Phylogenomic databases

eggNOGiKOG3563. Eukaryota.
COG5025. LUCA.
HOGENOMiHOG000231817.
HOVERGENiHBG006621.
InParanoidiP32182.
KOiK08035.
PhylomeDBiP32182.

Miscellaneous databases

NextBioi605409.
PROiP32182.

Family and domain databases

Gene3Di1.10.10.10. 1 hit.
InterProiIPR013638. Fork-head_N.
IPR001766. Fork_head_dom.
IPR018533. Forkhead_box_C.
IPR018122. TF_fork_head_CS_1.
IPR030456. TF_fork_head_CS_2.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamiPF00250. Forkhead. 1 hit.
PF08430. Forkhead_N. 1 hit.
PF09354. HNF_C. 1 hit.
[Graphical view]
PRINTSiPR00053. FORKHEAD.
SMARTiSM00339. FH. 1 hit.
[Graphical view]
SUPFAMiSSF46785. SSF46785. 1 hit.
PROSITEiPS00657. FORK_HEAD_1. 1 hit.
PS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "Hepatocyte nuclear factor 3 alpha belongs to a gene family in mammals that is homologous to the Drosophila homeotic gene fork head."
    Lai E., Prezioso V.R., Tao W.F., Chen W.S., Darnell J.E. Jr.
    Genes Dev. 5:416-427(1991) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  2. "Hepatocyte nuclear factor 3 beta contains two transcriptional activation domains, one of which is novel and conserved with the Drosophila fork head protein."
    Pani L., Overdier D.G., Porcella A., Qian X., Lai E., Costa R.H.
    Mol. Cell. Biol. 12:3723-3732(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: TRANSACTIVATION DOMAIN.
  3. "The DNA-binding specificity of the hepatocyte nuclear factor 3/forkhead domain is influenced by amino-acid residues adjacent to the recognition helix."
    Overdier D.G., Porcella A., Costa R.H.
    Mol. Cell. Biol. 14:2755-2766(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: DNA-BINDING CONSENSUS SEQUENCE.
  4. "Analysis of hepatocyte nuclear factor-3 beta protein domains required for transcriptional activation and nuclear targeting."
    Qian X., Costa R.H.
    Nucleic Acids Res. 23:1184-1191(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: TRANSACTIVATION DOMAIN, SUBCELLULAR LOCATION, PHOSPHORYLATION, MUTAGENESIS OF TYR-18.
  5. "Transducin-like enhancer of split proteins, the human homologs of Drosophila groucho, interact with hepatic nuclear factor 3beta."
    Wang J.-C., Waltner-Law M., Yamada K., Osawa H., Stifani S., Granner D.K.
    J. Biol. Chem. 275:18418-18423(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH TLE1.
  6. "Synergistic action of hepatocyte nuclear factors 3 and 6 on CYP2C12 gene expression and suppression by growth hormone-activated STAT5b. Proposed model for female specific expression of CYP2C12 in adult rat liver."
    Delesque-Touchard N., Park S.H., Waxman D.J.
    J. Biol. Chem. 275:34173-34182(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  7. "Insulin regulates the activity of forkhead transcription factor Hnf-3beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization."
    Wolfrum C., Besser D., Luca E., Stoffel M.
    Proc. Natl. Acad. Sci. U.S.A. 100:11624-11629(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT THR-156, SUBCELLULAR LOCATION, INTERACTION WITH AKT1, MUTAGENESIS OF ARG-153 AND THR-156.
  8. "Identification of DNA-dependent protein kinase as a cofactor for the forkhead transcription factor FoxA2."
    Nock A., Ascano J.M., Jones T., Barrero M.J., Sugiyama N., Tomita M., Ishihama Y., Malik S.
    J. Biol. Chem. 284:19915-19926(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH PRKDC, PHOSPHORYLATION AT SER-212; SER-283; SER-303; SER-306; SER-307; SER-309; SER-437 AND SER-458, MUTAGENESIS OF THR-280 AND SER-283.
  9. "Nuclear export-independent inhibition of Foxa2 by insulin."
    Howell J.J., Stoffel M.
    J. Biol. Chem. 284:24816-24824(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, MUTAGENESIS OF LEU-110; LEU-113 AND THR-156.

Entry informationi

Entry nameiFOXA2_RAT
AccessioniPrimary (citable) accession number: P32182
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1993
Last sequence update: October 1, 1993
Last modified: May 11, 2016
This is version 136 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.