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P35583

- FOXA2_MOUSE

UniProt

P35583 - FOXA2_MOUSE

Protein

Hepatocyte nuclear factor 3-beta

Gene

Foxa2

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 137 (01 Oct 2014)
      Sequence version 2 (27 Jul 2011)
      Previous versions | rss
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    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

    1. DNA binding Source: MGI
    2. protein binding Source: IntAct
    3. RNA polymerase II core promoter proximal region sequence-specific DNA binding Source: Ensembl
    4. RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity Source: MGI
    5. RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription Source: MGI
    6. sequence-specific DNA binding Source: MGI
    7. sequence-specific DNA binding transcription factor activity Source: MGI

    GO - Biological processi

    1. adult locomotory behavior Source: MGI
    2. anatomical structure formation involved in morphogenesis Source: MGI
    3. anatomical structure morphogenesis Source: MGI
    4. anterior/posterior pattern specification Source: MGI
    5. cell development Source: MGI
    6. cell differentiation in hindbrain Source: MGI
    7. cell fate specification Source: MGI
    8. chromatin modification Source: UniProtKB-KW
    9. connective tissue development Source: MGI
    10. dopaminergic neuron differentiation Source: MGI
    11. dorsal/ventral neural tube patterning Source: MGI
    12. dorsal/ventral pattern formation Source: MGI
    13. ectoderm formation Source: MGI
    14. endocrine pancreas development Source: MGI
    15. epithelial tube branching involved in lung morphogenesis Source: MGI
    16. in utero embryonic development Source: MGI
    17. lung development Source: MGI
    18. lung epithelial cell differentiation Source: MGI
    19. negative regulation of detection of glucose Source: BHF-UCL
    20. negative regulation of epithelial to mesenchymal transition Source: Ensembl
    21. negative regulation of glucokinase activity Source: BHF-UCL
    22. negative regulation of neuron differentiation Source: MGI
    23. negative regulation of sequence-specific DNA binding transcription factor activity Source: Ensembl
    24. negative regulation of transcription from RNA polymerase II promoter by glucose Source: BHF-UCL
    25. neuron fate specification Source: MGI
    26. pattern specification process Source: MGI
    27. positive regulation of embryonic development Source: UniProtKB
    28. positive regulation of gastrulation Source: UniProtKB
    29. positive regulation of neuron differentiation Source: MGI
    30. positive regulation of smoothened signaling pathway Source: MGI
    31. positive regulation of transcription, DNA-templated Source: UniProtKB
    32. positive regulation of transcription from RNA polymerase III promoter Source: UniProtKB
    33. positive regulation of transcription from RNA polymerase II promoter Source: MGI
    34. positive regulation of transcription from RNA polymerase II promoter by glucose Source: BHF-UCL
    35. primitive streak formation Source: UniProtKB
    36. regulation of blood coagulation Source: Ensembl
    37. regulation of gene expression Source: MGI
    38. regulation of insulin secretion involved in cellular response to glucose stimulus Source: BHF-UCL
    39. regulation of lipid metabolic process Source: MGI
    40. regulation of steroid metabolic process Source: MGI
    41. regulation of transcription, DNA-templated Source: MGI
    42. regulation of transcription from RNA polymerase II promoter involved in detection of glucose Source: BHF-UCL
    43. response to interleukin-6 Source: UniProtKB
    44. signal transduction involved in regulation of gene expression Source: MGI
    45. somite rostral/caudal axis specification Source: MGI
    46. transcription from RNA polymerase II promoter Source: GOC

    Keywords - Molecular functioni

    Activator, Chromatin regulator, Developmental protein

    Keywords - Biological processi

    Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding

    Enzyme and pathway databases

    ReactomeiREACT_214529. 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: Chromosome 2

    Organism-specific databases

    MGIiMGI:1347476. Foxa2.

    Subcellular locationi

    Nucleus 1 PublicationPROSITE-ProRule annotation. 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

    1. cytoplasm Source: UniProtKB-SubCell
    2. nucleus Source: MGI

    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

    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.
    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.
    GeneTreeiENSGT00740000115483.
    HOGENOMiHOG000231817.
    HOVERGENiHBG006621.
    InParanoidiA2AR89.
    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.
    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

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    MLGAVKMEGH EPSDWSSYYA EPEGYSSVSN MNAGLGMNGM NTYMSMSAAA    50
    MGGGSGNMSA GSMNMSSYVG AGMSPSLAGM SPGAGAMAGM SGSAGAAGVA 100
    GMGPHLSPSL SPLGGQAAGA MGGLAPYANM NSMSPMYGQA GLSRARDPKT 150
    YRRSYTHAKP PYSYISLITM AIQQSPNKML TLSEIYQWIM DLFPFYRQNQ 200
    QRWQNSIRHS LSFNDCFLKV PRSPDKPGKG SFWTLHPDSG NMFENGCYLR 250
    RQKRFKCEKQ LALKEAAGAA SSGGKKTAPG SQASQAQLGE AAGSASETPA 300
    GTESPHSSAS PCQEHKRGGL SELKGAPASA LSPPEPAPSP GQQQQAAAHL 350
    LGPPHHPGLP PEAHLKPEHH YAFNHPFSIN NLMSSEQQHH HSHHHHQPHK 400
    MDLKAYEQVM HYPGGYGSPM PGSLAMGPVT NKAGLDASPL AADTSYYQGV 450
    YSRPIMNSS 459
    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:
    EMBL
    GenBank
    DDBJ
    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:
    EMBL
    GenBank
    DDBJ
    Links Updated
    X74937 mRNA. Translation: CAA52891.1 .
    L10409 mRNA. Translation: AAA03161.1 .
    AL845297 Genomic DNA. Translation: CAM17482.1 .
    U04197 mRNA. Translation: AAA03606.1 .
    CCDSi CCDS16836.1.
    PIRi B54258.
    RefSeqi NP_001277994.1. NM_001291065.1.
    NP_034576.2. NM_010446.3.
    UniGenei Mm.938.

    3D structure databases

    ProteinModelPortali P35583.
    SMRi P35583. Positions 157-256.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    IntActi P35583. 7 interactions.

    PTM databases

    PhosphoSitei P35583.

    Proteomic databases

    PRIDEi P35583.

    Protocols and materials databases

    DNASUi 15376.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000047315 ; ENSMUSP00000045918 ; ENSMUSG00000037025 .
    GeneIDi 15376.
    KEGGi mmu:15376.
    UCSCi uc008mta.1. mouse.

    Organism-specific databases

    CTDi 3170.
    MGIi MGI:1347476. Foxa2.

    Phylogenomic databases

    eggNOGi COG5025.
    GeneTreei ENSGT00740000115483.
    HOGENOMi HOG000231817.
    HOVERGENi HBG006621.
    InParanoidi A2AR89.
    KOi K08035.
    TreeFami TF316127.

    Enzyme and pathway databases

    Reactomei REACT_214529. Regulation of gene expression in beta cells.

    Miscellaneous databases

    NextBioi 288030.
    PROi P35583.
    SOURCEi Search...

    Gene expression databases

    Bgeei P35583.
    CleanExi MM_FOXA2.
    Genevestigatori P35583.

    Family and domain databases

    Gene3Di 1.10.10.10. 1 hit.
    InterProi IPR013638. Fork-head_N.
    IPR018533. Forkhead_box_C.
    IPR001766. TF_fork_head.
    IPR018122. TF_fork_head_CS.
    IPR011991. WHTH_DNA-bd_dom.
    [Graphical view ]
    Pfami PF00250. Fork_head. 1 hit.
    PF08430. Fork_head_N. 1 hit.
    PF09354. HNF_C. 1 hit.
    [Graphical view ]
    PRINTSi PR00053. FORKHEAD.
    SMARTi SM00339. FH. 1 hit.
    [Graphical view ]
    PROSITEi PS00657. FORK_HEAD_1. 1 hit.
    PS00658. FORK_HEAD_2. 1 hit.
    PS50039. FORK_HEAD_3. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    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: October 1, 2014
    This is version 137 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