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P35583 (FOXA2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 135. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Hepatocyte nuclear factor 3-beta

Short name=HNF-3-beta
Short name=HNF-3B
Alternative name(s):
Forkhead box protein A2
Gene names
Name:Foxa2
Synonyms:Hnf3b, Tcf-3b, Tcf3b
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length459 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.5 Ref.6 Ref.7 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17

Subunit structure

Binds DNA as a monomer. Binds TLE1. Interacts with FOXA1 and FOXA3. Interacts with PRKDC By similarity. Ref.8

Subcellular location

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. Ref.9

Tissue specificity

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). Ref.12

Developmental stage

Most abundant in midgestation embryos (day 9.5).

Post-translational modification

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

Disruption phenotype

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. Ref.5 Ref.6

Sequence similarities

Contains 1 fork-head DNA-binding domain.

Ontologies

Keywords
   Biological processTranscription
Transcription regulation
   Cellular componentCytoplasm
Nucleus
   LigandDNA-binding
   Molecular functionActivator
Chromatin regulator
Developmental protein
   PTMPhosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processadult locomotory behavior

Inferred from mutant phenotype PubMed 18076286. Source: MGI

anatomical structure formation involved in morphogenesis

Inferred from genetic interaction PubMed 10498685PubMed 23383217. Source: MGI

anatomical structure morphogenesis

Inferred from genetic interaction PubMed 9226455. Source: MGI

anterior/posterior pattern specification

Inferred from genetic interaction PubMed 10498685. Source: MGI

cell development

Inferred from mutant phenotype PubMed 15680365. Source: MGI

cell differentiation in hindbrain

Inferred from mutant phenotype PubMed 17922007. Source: MGI

cell fate specification

Inferred from direct assay PubMed 18076286. Source: MGI

chromatin modification

Inferred from electronic annotation. Source: UniProtKB-KW

connective tissue development

Inferred from genetic interaction PubMed 23383217. Source: MGI

dopaminergic neuron differentiation

Inferred from mutant phenotype PubMed 18076286. Source: MGI

dorsal/ventral neural tube patterning

Inferred from direct assay PubMed 18590716. Source: MGI

dorsal/ventral pattern formation

Inferred from genetic interaction PubMed 10498685. Source: MGI

ectoderm formation

Inferred from genetic interaction PubMed 10498685. Source: MGI

endocrine pancreas development

Inferred from mutant phenotype PubMed 15680365. Source: MGI

epithelial tube branching involved in lung morphogenesis

Inferred from genetic interaction Ref.10. Source: MGI

in utero embryonic development

Inferred from mutant phenotype PubMed 9152011. Source: MGI

lung development

Inferred from genetic interaction Ref.10. Source: MGI

lung epithelial cell differentiation

Inferred from genetic interaction Ref.10. Source: MGI

negative regulation of detection of glucose

Inferred from direct assay Ref.7. Source: BHF-UCL

negative regulation of epithelial to mesenchymal transition

Inferred from electronic annotation. Source: Ensembl

negative regulation of glucokinase activity

Inferred from direct assay Ref.7. Source: BHF-UCL

negative regulation of neuron differentiation

Inferred from genetic interaction PubMed 17922007. Source: MGI

negative regulation of sequence-specific DNA binding transcription factor activity

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription from RNA polymerase II promoter by glucose

Inferred from direct assay Ref.7. Source: BHF-UCL

neuron fate specification

Inferred from mutant phenotype PubMed 17922007. Source: MGI

pattern specification process

Inferred from genetic interaction PubMed 10498685. Source: MGI

positive regulation of embryonic development

Inferred from mutant phenotype PubMed 11291865. Source: UniProtKB

positive regulation of gastrulation

Inferred from mutant phenotype PubMed 11291865. Source: UniProtKB

positive regulation of neuron differentiation

Inferred from mutant phenotype Ref.13. Source: MGI

positive regulation of smoothened signaling pathway

Inferred from genetic interaction PubMed 23383217. Source: MGI

positive regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 10859308PubMed 11914369PubMed 22696295. Source: MGI

positive regulation of transcription from RNA polymerase II promoter by glucose

Inferred from direct assay Ref.7. Source: BHF-UCL

positive regulation of transcription from RNA polymerase III promoter

Inferred from mutant phenotype PubMed 15737987. Source: UniProtKB

positive regulation of transcription, DNA-templated

Inferred from mutant phenotype PubMed 11291865. Source: UniProtKB

primitive streak formation

Inferred from mutant phenotype PubMed 11291865. Source: UniProtKB

regulation of blood coagulation

Inferred from electronic annotation. Source: Ensembl

regulation of gene expression

Inferred from genetic interaction Ref.13. Source: MGI

regulation of insulin secretion involved in cellular response to glucose stimulus

Inferred from direct assay Ref.7. Source: BHF-UCL

regulation of lipid metabolic process

Inferred from direct assay PubMed 22737085. Source: MGI

regulation of sequence-specific DNA binding transcription factor activity

Inferred from Biological aspect of Ancestor. Source: RefGenome

regulation of steroid metabolic process

Inferred from direct assay PubMed 22737085. Source: MGI

regulation of transcription from RNA polymerase II promoter involved in detection of glucose

Inferred from direct assay Ref.7. Source: BHF-UCL

regulation of transcription, DNA-templated

Inferred from direct assay PubMed 12488434. Source: MGI

response to interleukin-6

Traceable author statement PubMed 15737987. Source: UniProtKB

signal transduction involved in regulation of gene expression

Inferred from direct assay PubMed 18462699. Source: MGI

somite rostral/caudal axis specification

Inferred from mutant phenotype PubMed 11291865. Source: MGI

transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 10859308PubMed 14701942. Source: GOC

   Cellular_componentcytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from direct assay PubMed 12488434PubMed 15567715PubMed 16364283PubMed 23383217PubMed 8813084. Source: MGI

transcription factor complex

Inferred from Biological aspect of Ancestor. Source: RefGenome

   Molecular_functionDNA binding

Inferred from direct assay PubMed 12488434PubMed 15485926PubMed 15987774PubMed 16912278. Source: MGI

DNA binding, bending

Inferred from Biological aspect of Ancestor. Source: RefGenome

RNA polymerase II core promoter proximal region sequence-specific DNA binding

Inferred from electronic annotation. Source: Ensembl

RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity

Inferred from direct assay PubMed 10859308PubMed 14701942. Source: MGI

RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription

Inferred from direct assay PubMed 22696295. Source: MGI

double-stranded DNA binding

Inferred from Biological aspect of Ancestor. Source: RefGenome

protein binding

Inferred from physical interaction PubMed 20609350. Source: IntAct

sequence-specific DNA binding

Inferred from direct assay PubMed 11914369PubMed 14701942PubMed 22737085. Source: MGI

sequence-specific DNA binding transcription factor activity

Inferred from direct assay PubMed 11914369PubMed 12488434PubMed 22921202. Source: MGI

transcription factor binding

Inferred from Biological aspect of Ancestor. Source: RefGenome

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Hif1aQ612215EBI-2893341,EBI-298954

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 459459Hepatocyte nuclear factor 3-beta
PRO_0000091796

Regions

DNA binding159 – 25294Fork-head
Region14 – 9380Transactivation domain 1 By similarity
Region362 – 45998Transactivation domain 2 By similarity
Motif106 – 1138Nuclear localization signal By similarity

Amino acid modifications

Modified residue1561Phosphothreonine Ref.9
Modified residue2121Phosphoserine By similarity
Modified residue2841Phosphoserine By similarity
Modified residue3041Phosphoserine By similarity
Modified residue3071Phosphoserine By similarity
Modified residue3081Phosphoserine By similarity
Modified residue3101Phosphoserine By similarity
Modified residue4381Phosphoserine By similarity
Modified residue4591Phosphoserine By similarity

Experimental info

Sequence conflict101H → L in CAA52891. Ref.1
Sequence conflict4341G → S in AAA03606. Ref.4

Sequences

Sequence LengthMass (Da)Tools
P35583 [UniParc].

Last modified July 27, 2011. Version 2.
Checksum: 2F20F15AB372F557

FASTA45948,498
        10         20         30         40         50         60 
MLGAVKMEGH EPSDWSSYYA EPEGYSSVSN MNAGLGMNGM NTYMSMSAAA MGGGSGNMSA 

        70         80         90        100        110        120 
GSMNMSSYVG AGMSPSLAGM SPGAGAMAGM SGSAGAAGVA GMGPHLSPSL SPLGGQAAGA 

       130        140        150        160        170        180 
MGGLAPYANM NSMSPMYGQA GLSRARDPKT YRRSYTHAKP PYSYISLITM AIQQSPNKML 

       190        200        210        220        230        240 
TLSEIYQWIM DLFPFYRQNQ QRWQNSIRHS LSFNDCFLKV PRSPDKPGKG SFWTLHPDSG 

       250        260        270        280        290        300 
NMFENGCYLR RQKRFKCEKQ LALKEAAGAA SSGGKKTAPG SQASQAQLGE AAGSASETPA 

       310        320        330        340        350        360 
GTESPHSSAS PCQEHKRGGL SELKGAPASA LSPPEPAPSP GQQQQAAAHL LGPPHHPGLP 

       370        380        390        400        410        420 
PEAHLKPEHH YAFNHPFSIN NLMSSEQQHH HSHHHHQPHK MDLKAYEQVM HYPGGYGSPM 

       430        440        450 
PGSLAMGPVT NKAGLDASPL AADTSYYQGV YSRPIMNSS 

« Hide

References

« Hide 'large scale' references
[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]"Lineage-specific biology revealed by a finished genome assembly of the mouse."
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. expand/collapse author list , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
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]"Compensatory roles of Foxa1 and Foxa2 during lung morphogenesis."
Wan H., Dingle S., Xu Y., Besnard V., Kaestner K.H., Ang S.L., Wert S., Stahlman M.T., Whitsett J.A.
J. Biol. Chem. 280:13809-13816(2005) [PubMed] [Europe PMC] [Abstract]
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]"Large-scale phosphorylation analysis of mouse liver."
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X74937 mRNA. Translation: CAA52891.1.
L10409 mRNA. Translation: AAA03161.1.
AL845297 Genomic DNA. Translation: CAM17482.1.
U04197 mRNA. Translation: AAA03606.1.
CCDSCCDS16836.1.
PIRB54258.
RefSeqNP_001277994.1. NM_001291065.1.
NP_034576.2. NM_010446.3.
UniGeneMm.938.

3D structure databases

ProteinModelPortalP35583.
SMRP35583. Positions 157-256.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActP35583. 7 interactions.

PTM databases

PhosphoSiteP35583.

Proteomic databases

PRIDEP35583.

Protocols and materials databases

DNASU15376.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000047315; ENSMUSP00000045918; ENSMUSG00000037025.
GeneID15376.
KEGGmmu:15376.
UCSCuc008mta.1. mouse.

Organism-specific databases

CTD3170.
MGIMGI:1347476. Foxa2.

Phylogenomic databases

eggNOGCOG5025.
GeneTreeENSGT00740000115483.
HOGENOMHOG000231817.
HOVERGENHBG006621.
InParanoidA2AR89.
KOK08035.
TreeFamTF316127.

Gene expression databases

BgeeP35583.
CleanExMM_FOXA2.
GenevestigatorP35583.

Family and domain databases

Gene3D1.10.10.10. 1 hit.
InterProIPR013638. Fork-head_N.
IPR018533. Forkhead_box_C.
IPR001766. TF_fork_head.
IPR018122. TF_fork_head_CS.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamPF00250. Fork_head. 1 hit.
PF08430. Fork_head_N. 1 hit.
PF09354. HNF_C. 1 hit.
[Graphical view]
PRINTSPR00053. FORKHEAD.
SMARTSM00339. FH. 1 hit.
[Graphical view]
PROSITEPS00657. FORK_HEAD_1. 1 hit.
PS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio288030.
PROP35583.
SOURCESearch...

Entry information

Entry nameFOXA2_MOUSE
AccessionPrimary (citable) accession number: P35583
Secondary accession number(s): A2AR89, Q60602
Entry history
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: July 27, 2011
Last modified: July 9, 2014
This is version 135 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot