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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)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi159 – 25294Fork-headPROSITE-ProRule annotationAdd
BLAST

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
  • 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
  • transcription from RNA polymerase II promoter Source: GOC
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

ReactomeiREACT_322034. 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
ProteomesiUP000000589 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

  • cytoplasm Source: UniProtKB-SubCell
  • 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)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 459459Hepatocyte nuclear factor 3-betaPRO_0000091796Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei156 – 1561Phosphothreonine1 Publication
Modified residuei212 – 2121PhosphoserineBy similarity
Modified residuei284 – 2841PhosphoserineBy similarity
Modified residuei304 – 3041PhosphoserineBy similarity
Modified residuei307 – 3071PhosphoserineBy similarity
Modified residuei308 – 3081PhosphoserineBy similarity
Modified residuei310 – 3101PhosphoserineBy similarity
Modified residuei438 – 4381PhosphoserineBy similarity
Modified residuei459 – 4591PhosphoserineBy similarity

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.
PRIDEiP35583.

PTM databases

PhosphoSiteiP35583.

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

BgeeiP35583.
CleanExiMM_FOXA2.
ExpressionAtlasiP35583. baseline and differential.
GenevestigatoriP35583.

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 interactions.

Structurei

3D structure databases

ProteinModelPortaliP35583.
SMRiP35583. Positions 157-256.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni14 – 9380Transactivation domain 1By similarityAdd
BLAST
Regioni362 – 45998Transactivation domain 2By similarityAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi106 – 1138Nuclear localization signalBy similarity

Sequence similaritiesi

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

Phylogenomic databases

eggNOGiCOG5025.
GeneTreeiENSGT00760000118904.
HOGENOMiHOG000231817.
HOVERGENiHBG006621.
InParanoidiP35583.
KOiK08035.
TreeFamiTF316127.

Family and domain databases

Gene3Di1.10.10.10. 1 hit.
InterProiIPR013638. Fork-head_N.
IPR018533. Forkhead_box_C.
IPR001766. TF_fork_head.
IPR018122. TF_fork_head_CS_1.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamiPF00250. Fork_head. 1 hit.
PF08430. Fork_head_N. 1 hit.
PF09354. HNF_C. 1 hit.
[Graphical view]
PRINTSiPR00053. FORKHEAD.
SMARTiSM00339. FH. 1 hit.
[Graphical view]
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)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti10 – 101H → L in CAA52891 (PubMed:8034310).Curated
Sequence conflicti434 – 4341G → S in AAA03606 (PubMed:8306889).Curated

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.
UCSCiuc008mta.1. 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. Positions 157-256.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiP35583. 7 interactions.

PTM databases

PhosphoSiteiP35583.

Proteomic databases

MaxQBiP35583.
PRIDEiP35583.

Protocols and materials databases

DNASUi15376.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000047315; ENSMUSP00000045918; ENSMUSG00000037025.
GeneIDi15376.
KEGGimmu:15376.
UCSCiuc008mta.1. mouse.

Organism-specific databases

CTDi3170.
MGIiMGI:1347476. Foxa2.

Phylogenomic databases

eggNOGiCOG5025.
GeneTreeiENSGT00760000118904.
HOGENOMiHOG000231817.
HOVERGENiHBG006621.
InParanoidiP35583.
KOiK08035.
TreeFamiTF316127.

Enzyme and pathway databases

ReactomeiREACT_322034. Regulation of gene expression in beta cells.

Miscellaneous databases

NextBioi288030.
PROiP35583.
SOURCEiSearch...

Gene expression databases

BgeeiP35583.
CleanExiMM_FOXA2.
ExpressionAtlasiP35583. baseline and differential.
GenevestigatoriP35583.

Family and domain databases

Gene3Di1.10.10.10. 1 hit.
InterProiIPR013638. Fork-head_N.
IPR018533. Forkhead_box_C.
IPR001766. TF_fork_head.
IPR018122. TF_fork_head_CS_1.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamiPF00250. Fork_head. 1 hit.
PF08430. Fork_head_N. 1 hit.
PF09354. HNF_C. 1 hit.
[Graphical view]
PRINTSiPR00053. FORKHEAD.
SMARTiSM00339. FH. 1 hit.
[Graphical view]
PROSITEiPS00657. FORK_HEAD_1. 1 hit.
PS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "The HNF-3 gene family of transcription factors in mice: gene structure, cDNA sequence, and mRNA distribution."
    Kaestner K., Hiemisch H., Luckow B., Schuetz G.
    Genomics 20:377-385(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Tissue: Liver.
  2. "Differential expression of multiple fork head related genes during gastrulation and axial pattern formation in the mouse embryo."
    Sasaki H., Hogan B.L.
    Development 118:47-59(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  3. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: C57BL/6J.
  4. "The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins."
    Ang S.-L., Wierda A., Wong D., Stevens K.A., Cascio S., Rossant J., Zaret K.S.
    Development 119:1301-1315(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 201-459.
  5. "HNF-3 beta is essential for node and notochord formation in mouse development."
    Ang S.L., Rossant J.
    Cell 78:561-574(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE, FUNCTION IN NOTOCHORD FORMATION.
  6. "Tissue-specific deletion of Foxa2 in pancreatic beta cells results in hyperinsulinemic hypoglycemia."
    Sund N.J., Vatamaniuk M.Z., Casey M., Ang S.L., Magnuson M.A., Stoffers D.A., Matschinsky F.M., Kaestner K.H.
    Genes Dev. 15:1706-1715(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE, FUNCTION.
  7. "Foxa2 (HNF3beta) controls multiple genes implicated in metabolism-secretion coupling of glucose-induced insulin release."
    Wang H., Gauthier B.R., Hagenfeldt-Johansson K.A., Iezzi M., Wollheim C.B.
    J. Biol. Chem. 277:17564-17570(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN REGULATION OF GLUCOSE HOMEOSTASIS.
  8. "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: INTERACTION WITH AKT1.
  9. "Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes."
    Wolfrum C., Asilmaz E., Luca E., Friedman J.M., Stoffel M.
    Nature 432:1027-1032(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT THR-156, SUBCELLULAR LOCATION, FUNCTION IN REGULATION OF LIPID METABOLISM AND KETOGENESIS.
  10. Cited for: FUNCTION IN LUNG DEVELOPMENT.
  11. "The initiation of liver development is dependent on Foxa transcription factors."
    Lee C.S., Friedman J.R., Fulmer J.T., Kaestner K.H.
    Nature 435:944-947(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN LIVER DEVELOPMENT.
  12. "The role of forkhead box A2 to restrict androgen-regulated gene expression of lipocalin 5 in the mouse epididymis."
    Yu X., Suzuki K., Wang Y., Gupta A., Jin R., Orgebin-Crist M.C., Matusik R.
    Mol. Endocrinol. 20:2418-2431(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, TISSUE SPECIFICITY.
  13. "Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner."
    Ferri A.L., Lin W., Mavromatakis Y.E., Wang J.C., Sasaki H., Whitsett J.A., Ang S.L.
    Development 134:2761-2769(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN NEURON DEVELOPMENT.
  14. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Liver.
  15. "Forkhead box transcription factors Foxa1 and Foxa2 are important regulators of Muc2 mucin expression in intestinal epithelial cells."
    van der Sluis M., Vincent A., Bouma J., Korteland-Van Male A., van Goudoever J.B., Renes I.B., Van Seuningen I.
    Biochem. Biophys. Res. Commun. 369:1108-1113(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  16. "Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development."
    Gao N., LeLay J., Vatamaniuk M.Z., Rieck S., Friedman J.R., Kaestner K.H.
    Genes Dev. 22:3435-3448(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PANCREAS DEVELOPMENT.
  17. "Foxa1 and Foxa2 regulate bile duct development in mice."
    Li Z., White P., Tuteja G., Rubins N., Sackett S., Kaestner K.H.
    J. Clin. Invest. 119:1537-1545(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN BILE DUCT DEVELOPMENT.

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: April 1, 2015
This is version 142 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

External Data

Dasty 3

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 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.