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Protein

Hepatocyte nuclear factor 3-beta

Gene

Foxa2

Organism
Mus musculus (Mouse)
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. FOXA1 and FOXA2 are essential for hepatic specification. FOXA1 and FOXA2 are required for morphogenesis and cell differentiation during formation of the lung. FOXA1 and FOXA2 are involved in bile duct formation; they positively regulate the binding glucocorticoid receptor/NR3C1 to the IL6 promoter. FOXA1 and FOXA2 regulate multiple phases of midbrain dopaminergic neuron development; they regulate expression of NEUROG2 at the beginning of mDA neurogenesis and of NR4A2 and EN1 in immature mDA neurons. Modulates the transcriptional activity of nuclear hormone receptors; inhibits AR-mediated transcription from the LCN5 promoter. Binds to fibrinogen beta promoter and is involved in IL6-induced fibrinogen beta transcriptional activation. 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. In pancreatic beta cells activates transcription of potassium channel subunits KCNJ11 and ABCC8. Involved in regulation of fat metabolism; activates transcriptional programs of lipid metabolism and ketogenesis at low insulin state. Involved in transcriptional regulation of MUC2 in the intestine.By similarity11 Publications

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi159 – 252Fork-headPROSITE-ProRule annotationAdd BLAST94

GO - Molecular functioni

GO - Biological processi

  • adult locomotory behavior Source: MGI
  • anatomical structure formation involved in morphogenesis Source: MGI
  • anatomical structure morphogenesis Source: MGI
  • anterior/posterior pattern specification Source: MGI
  • cell development Source: MGI
  • cell differentiation in hindbrain Source: MGI
  • cell fate specification Source: MGI
  • chromatin modification Source: UniProtKB-KW
  • connective tissue development Source: MGI
  • dopaminergic neuron differentiation Source: MGI
  • dorsal/ventral neural tube patterning Source: MGI
  • dorsal/ventral pattern formation Source: MGI
  • ectoderm formation Source: MGI
  • endocrine pancreas development Source: MGI
  • epithelial tube branching involved in lung morphogenesis Source: MGI
  • in utero embryonic development Source: MGI
  • lung development Source: MGI
  • lung epithelial cell differentiation Source: MGI
  • negative regulation of detection of glucose Source: BHF-UCL
  • negative regulation of epithelial to mesenchymal transition Source: MGI
  • negative regulation of glucokinase activity Source: BHF-UCL
  • negative regulation of neuron differentiation Source: MGI
  • negative regulation of sequence-specific DNA binding transcription factor activity Source: MGI
  • negative regulation of transcription from RNA polymerase II promoter by glucose Source: BHF-UCL
  • neuron fate specification Source: MGI
  • Notch signaling pathway Source: MGI
  • pattern specification process Source: MGI
  • positive regulation of embryonic development Source: UniProtKB
  • positive regulation of gastrulation Source: UniProtKB
  • positive regulation of neuron differentiation Source: MGI
  • positive regulation of smoothened signaling pathway Source: MGI
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • positive regulation of transcription from RNA polymerase III promoter Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: MGI
  • positive regulation of transcription from RNA polymerase II promoter by glucose Source: BHF-UCL
  • primitive streak formation Source: UniProtKB
  • regulation of blood coagulation Source: MGI
  • regulation of gene expression Source: MGI
  • regulation of insulin secretion involved in cellular response to glucose stimulus Source: BHF-UCL
  • regulation of lipid metabolic process Source: MGI
  • regulation of steroid metabolic process Source: MGI
  • regulation of transcription, DNA-templated Source: MGI
  • regulation of transcription from RNA polymerase II promoter Source: MGI
  • response to interleukin-6 Source: UniProtKB
  • signal transduction involved in regulation of gene expression Source: MGI
  • somite rostral/caudal axis specification Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Activator, Chromatin regulator, Developmental protein

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

ReactomeiR-MMU-210745. Regulation of gene expression in beta cells.

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
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 2

Organism-specific databases

MGIiMGI:1347476. Foxa2.

Subcellular locationi

  • Nucleus PROSITE-ProRule annotation1 Publication
  • Cytoplasm 1 Publication

  • 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

  • cell junction Source: MGI
  • cytoplasm Source: UniProtKB-SubCell
  • nucleoplasm Source: MGI
  • nucleus Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

Embryonic lethal; absence of organized node and notochord formation, which leads to secondary defects in dorsal-ventral patterning of the neural tube. Mice deficient for Fox1a and deficient for Foxa2 in the endoderm from E8.5 onwards do not show hepatic bud formation. Mice deficient for Fox1a and deficient for Foxa2 in the midbrain from E10.5 onwards show almost complete loss of mDA neurons. Mice deficient for Fox1a and deficient for Foxa2 in the embryonic liver show hyperplasia of the biliary tree due to at least in part activation of IL-6 expression, a proliferative signal for cholangiocytes. Mice deficient for Fox2a in pancreatic beta cell show hypoglycemia and disorganized islets arrangements.2 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000917961 – 459Hepatocyte nuclear factor 3-betaAdd BLAST459

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei156Phosphothreonine1 Publication1
Modified residuei212PhosphoserineBy similarity1
Modified residuei284PhosphoserineBy similarity1
Modified residuei302PhosphothreonineCombined sources1
Modified residuei304PhosphoserineBy similarity1
Modified residuei307PhosphoserineBy similarity1
Modified residuei308PhosphoserineBy similarity1
Modified residuei310PhosphoserineBy similarity1
Modified residuei438PhosphoserineBy similarity1
Modified residuei459PhosphoserineBy similarity1

Post-translational modificationi

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

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiP35583.
PaxDbiP35583.
PRIDEiP35583.

PTM databases

iPTMnetiP35583.
PhosphoSitePlusiP35583.

Expressioni

Tissue specificityi

Restricted mainly to endoderm-derived tissues (lung, liver, stomach, and small intestine). Expressed in epididymis with region-specific expression pattern: no expression is observed in initial segment, low expression in proximal caput, gradiently higher levels of expression in middle and distal caput and highest level in corpus and cauda (at protein level).1 Publication

Developmental stagei

Most abundant in midgestation embryos (day 9.5).

Gene expression databases

BgeeiENSMUSG00000037025.
CleanExiMM_FOXA2.
ExpressionAtlasiP35583. baseline and differential.
GenevisibleiP35583. MM.

Interactioni

Subunit structurei

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

Binary interactionsi

WithEntry#Exp.IntActNotes
Hif1aQ612215EBI-2893341,EBI-298954

Protein-protein interaction databases

IntActiP35583. 7 interactors.
STRINGi10090.ENSMUSP00000045918.

Structurei

3D structure databases

ProteinModelPortaliP35583.
SMRiP35583.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni14 – 93Transactivation domain 1By similarityAdd BLAST80
Regioni362 – 459Transactivation domain 2By similarityAdd BLAST98

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi106 – 113Nuclear localization signalBy similarity8

Sequence similaritiesi

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

Phylogenomic databases

eggNOGiKOG3563. Eukaryota.
COG5025. LUCA.
GeneTreeiENSGT00760000118904.
HOGENOMiHOG000231817.
HOVERGENiHBG006621.
InParanoidiP35583.
KOiK08035.
TreeFamiTF316127.

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.

P35583-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MLGAVKMEGH EPSDWSSYYA EPEGYSSVSN MNAGLGMNGM NTYMSMSAAA
60 70 80 90 100
MGGGSGNMSA 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 LSFNDCFLKV PRSPDKPGKG SFWTLHPDSG NMFENGCYLR
260 270 280 290 300
RQKRFKCEKQ LALKEAAGAA SSGGKKTAPG SQASQAQLGE AAGSASETPA
310 320 330 340 350
GTESPHSSAS PCQEHKRGGL SELKGAPASA LSPPEPAPSP GQQQQAAAHL
360 370 380 390 400
LGPPHHPGLP PEAHLKPEHH YAFNHPFSIN NLMSSEQQHH HSHHHHQPHK
410 420 430 440 450
MDLKAYEQVM HYPGGYGSPM PGSLAMGPVT NKAGLDASPL AADTSYYQGV

YSRPIMNSS
Length:459
Mass (Da):48,498
Last modified:July 27, 2011 - v2
Checksum:i2F20F15AB372F557
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti10H → L in CAA52891 (PubMed:8034310).Curated1
Sequence conflicti434G → S in AAA03606 (PubMed:8306889).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X74937 mRNA. Translation: CAA52891.1.
L10409 mRNA. Translation: AAA03161.1.
AL845297 Genomic DNA. Translation: CAM17482.1.
U04197 mRNA. Translation: AAA03606.1.
CCDSiCCDS16836.1.
PIRiB54258.
RefSeqiNP_001277994.1. NM_001291065.1.
NP_034576.2. NM_010446.3.
UniGeneiMm.938.

Genome annotation databases

EnsembliENSMUST00000047315; ENSMUSP00000045918; ENSMUSG00000037025.
GeneIDi15376.
KEGGimmu:15376.
UCSCiuc008mtb.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X74937 mRNA. Translation: CAA52891.1.
L10409 mRNA. Translation: AAA03161.1.
AL845297 Genomic DNA. Translation: CAM17482.1.
U04197 mRNA. Translation: AAA03606.1.
CCDSiCCDS16836.1.
PIRiB54258.
RefSeqiNP_001277994.1. NM_001291065.1.
NP_034576.2. NM_010446.3.
UniGeneiMm.938.

3D structure databases

ProteinModelPortaliP35583.
SMRiP35583.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiP35583. 7 interactors.
STRINGi10090.ENSMUSP00000045918.

PTM databases

iPTMnetiP35583.
PhosphoSitePlusiP35583.

Proteomic databases

MaxQBiP35583.
PaxDbiP35583.
PRIDEiP35583.

Protocols and materials databases

DNASUi15376.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000047315; ENSMUSP00000045918; ENSMUSG00000037025.
GeneIDi15376.
KEGGimmu:15376.
UCSCiuc008mtb.2. mouse.

Organism-specific databases

CTDi3170.
MGIiMGI:1347476. Foxa2.

Phylogenomic databases

eggNOGiKOG3563. Eukaryota.
COG5025. LUCA.
GeneTreeiENSGT00760000118904.
HOGENOMiHOG000231817.
HOVERGENiHBG006621.
InParanoidiP35583.
KOiK08035.
TreeFamiTF316127.

Enzyme and pathway databases

ReactomeiR-MMU-210745. Regulation of gene expression in beta cells.

Miscellaneous databases

PROiP35583.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000037025.
CleanExiMM_FOXA2.
ExpressionAtlasiP35583. baseline and differential.
GenevisibleiP35583. MM.

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...

Entry informationi

Entry nameiFOXA2_MOUSE
AccessioniPrimary (citable) accession number: P35583
Secondary accession number(s): A2AR89, Q60602
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: July 27, 2011
Last modified: November 2, 2016
This is version 156 of the entry and version 2 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. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. 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.