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Protein

Hepatocyte nuclear factor 3-alpha

Gene

Foxa1

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). Proposed to play a role in translating the epigenetic signatures into cell type-specific enhancer-driven transcriptional programs. Involved in the development of multiple endoderm-derived organ systems such as the liver, pancreas, lungs and prostate; FOXA1 and FOXA2 seem to have at least in part redundant roles. Plays a role in prostate morphogenesis and epithelial cell differentiation. 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 of 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. Is involved in ESR1-mediated transcription. Inhibits NKX2-1-mediated transcription from the SFTPC promoter in lung epithel independently from DNA-binding. Involved in regulation of apoptosis. Involved in cell cycle regulation. 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; activates the GCG promoter.By similarity9 Publications

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi169 – 26092Fork-headPROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

GO - Biological processi

  • anatomical structure formation involved in morphogenesis Source: MGI
  • chromatin remodeling Source: UniProtKB
  • connective tissue development Source: MGI
  • dorsal/ventral neural tube patterning Source: MGI
  • epithelial cell maturation involved in prostate gland development Source: MGI
  • epithelial-mesenchymal signaling involved in prostate gland development Source: MGI
  • epithelial tube branching involved in lung morphogenesis Source: MGI
  • glucose homeostasis Source: MGI
  • hormone metabolic process Source: MGI
  • lung development Source: MGI
  • lung epithelial cell differentiation Source: MGI
  • negative regulation of epithelial to mesenchymal transition Source: MGI
  • negative regulation of transcription from RNA polymerase II promoter Source: MGI
  • neuron fate specification Source: MGI
  • positive regulation of intracellular estrogen receptor signaling pathway Source: MGI
  • positive regulation of mitotic cell cycle Source: MGI
  • positive regulation of neuron differentiation Source: MGI
  • positive regulation of sequence-specific DNA binding transcription factor activity Source: MGI
  • positive regulation of smoothened signaling pathway Source: MGI
  • positive regulation of transcription from RNA polymerase II promoter Source: MGI
  • prostate gland epithelium morphogenesis Source: MGI
  • prostate gland stromal morphogenesis Source: MGI
  • regulation of cell cycle Source: MGI
  • regulation of gene expression Source: MGI
  • response to estradiol Source: MGI
  • secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development Source: MGI
  • tube morphogenesis Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Activator, Chromatin regulator, Developmental protein, Repressor

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Hepatocyte nuclear factor 3-alpha
Short name:
HNF-3-alpha
Short name:
HNF-3A
Alternative name(s):
Forkhead box protein A1
Gene namesi
Name:Foxa1
Synonyms:Hnf3a, Tcf-3a, Tcf3a
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 12

Organism-specific databases

MGIiMGI:1347472. Foxa1.

Subcellular locationi

GO - Cellular componenti

  • microvillus Source: MGI
  • nucleolus Source: MGI
  • nucleus Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Disruption phenotypei

The prostate shows a severely altered ductal pattern that resembles primitive epithelial cords surrounded by thick stromal layers; no differentiated or mature luminal epithelial cells are found. Dehydration and electrolyte imbalance, development of mild nephrogenic diabetes insipidus. Severe hypoglycemia due to at least in part diminished expression of GCG. 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.3 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 468468Hepatocyte nuclear factor 3-alphaPRO_0000091793Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei223 – 2231PhosphoserineBy similarity
Modified residuei289 – 2891PhosphoserineBy similarity
Modified residuei303 – 3031PhosphoserineBy similarity
Modified residuei327 – 3271PhosphoserineBy similarity
Modified residuei468 – 4681PhosphoserineBy similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

PRIDEiP35582.

PTM databases

PhosphoSiteiP35582.

Expressioni

Tissue specificityi

Restricted mainly to endoderm-derived tissues (lung, liver, stomach, and small intestine). Expressed in the prostate.1 Publication

Developmental stagei

Most abundant in midgestation embryos (day 9.5). In embryonic lung expressed at E12 and E18 with highest levels in proximal airways and lowest levels in the distal lung.1 Publication

Gene expression databases

BgeeiP35582.
CleanExiMM_FOXA1.
GenevestigatoriP35582.

Interactioni

Subunit structurei

Binds DNA as a monomer. Interacts with FOXA2. Interacts with NKX2-1. Interacts with HDAC7. Interacts with the histone H3-H4 heterodimer. Associates with nucleosomes containing histone H2A. Interacts with AR. Interacts with NR0B2 (By similarity).By similarity

Protein-protein interaction databases

BioGridi200351. 2 interactions.

Structurei

3D structure databases

ProteinModelPortaliP35582.
SMRiP35582. Positions 168-267.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni251 – 28838Essential for DNA bindingAdd
BLAST

Sequence similaritiesi

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

Phylogenomic databases

eggNOGiCOG5025.
GeneTreeiENSGT00760000118904.
HOGENOMiHOG000231817.
HOVERGENiHBG006621.
InParanoidiP35582.
KOiK09387.
OMAiTMNTYMT.
OrthoDBiEOG7C8GHD.
PhylomeDBiP35582.
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.

P35582-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MLGTVKMEGH ESNDWNSYYA DTQEAYSSVP VSNMNSGLGS MNSMNTYMTM
60 70 80 90 100
NTMTTSGNMT PASFNMSYAN TGLGAGLSPG AVAGMPGASA GAMNSMTAAG
110 120 130 140 150
VTAMGTALSP GGMGSMGAQP ATSMNGLGPY AAAMNPCMSP MAYAPSNLGR
160 170 180 190 200
SRAGGGGDAK TFKRSYPHAK PPYSYISLIT MAIQQAPSKM LTLSEIYQWI
210 220 230 240 250
MDLFPYYRQN QQRWQNSIRH SLSFNDCFVK VARSPDKPGK GSYWTLHPDS
260 270 280 290 300
GNMFENGCYL RRQKRFKCEK QPGAGGGSGG GGSKGGPESR KDPSGPGNPS
310 320 330 340 350
AESPLHRGVH GKASQLEGAP APGPAASPQT LDHSGATATG GASELKSPAS
360 370 380 390 400
SSAPPISSGP GALASVPPSH PAHGLAPHES QLHLKGDPHY SFNHPFSINN
410 420 430 440 450
LMSSSEQQHK LDFKAYEQAL QYSPYGATLP ASLPLGSASV ATRSPIEPSA
460
LEPAYYQGVY SRPVLNTS
Length:468
Mass (Da):48,854
Last modified:November 1, 1997 - v2
Checksum:i8513D17623D434FD
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti121 – 1211A → V in CAA52890 (PubMed:8034310).Curated
Sequence conflicti307 – 3071R → W in CAA52890 (PubMed:8034310).Curated
Sequence conflicti389 – 3891H → R in AAA86760 (Ref. 2) Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X74936 mRNA. Translation: CAA52890.1.
U44752 mRNA. Translation: AAA86760.1.
BC096524 mRNA. Translation: AAH96524.1.
CCDSiCCDS25926.1.
PIRiA54258.
RefSeqiNP_032285.2. NM_008259.3.
XP_006515542.1. XM_006515479.2.
XP_006515543.1. XM_006515480.1.
XP_006515544.1. XM_006515481.2.
XP_006515546.1. XM_006515483.1.
UniGeneiMm.4578.

Genome annotation databases

EnsembliENSMUST00000044380; ENSMUSP00000041118; ENSMUSG00000035451.
GeneIDi15375.
KEGGimmu:15375.
UCSCiuc007nps.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X74936 mRNA. Translation: CAA52890.1.
U44752 mRNA. Translation: AAA86760.1.
BC096524 mRNA. Translation: AAH96524.1.
CCDSiCCDS25926.1.
PIRiA54258.
RefSeqiNP_032285.2. NM_008259.3.
XP_006515542.1. XM_006515479.2.
XP_006515543.1. XM_006515480.1.
XP_006515544.1. XM_006515481.2.
XP_006515546.1. XM_006515483.1.
UniGeneiMm.4578.

3D structure databases

ProteinModelPortaliP35582.
SMRiP35582. Positions 168-267.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi200351. 2 interactions.

PTM databases

PhosphoSiteiP35582.

Proteomic databases

PRIDEiP35582.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000044380; ENSMUSP00000041118; ENSMUSG00000035451.
GeneIDi15375.
KEGGimmu:15375.
UCSCiuc007nps.1. mouse.

Organism-specific databases

CTDi3169.
MGIiMGI:1347472. Foxa1.

Phylogenomic databases

eggNOGiCOG5025.
GeneTreeiENSGT00760000118904.
HOGENOMiHOG000231817.
HOVERGENiHBG006621.
InParanoidiP35582.
KOiK09387.
OMAiTMNTYMT.
OrthoDBiEOG7C8GHD.
PhylomeDBiP35582.
TreeFamiTF316127.

Miscellaneous databases

NextBioi288026.
PROiP35582.
SOURCEiSearch...

Gene expression databases

BgeeiP35582.
CleanExiMM_FOXA1.
GenevestigatoriP35582.

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. Farrington S.M., Baron M.H.
    Submitted (JAN-1996) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  3. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: C57BL/6.
  4. "Inactivation of the winged helix transcription factor HNF3alpha affects glucose homeostasis and islet glucagon gene expression in vivo."
    Kaestner K.H., Katz J., Liu Y., Drucker D.J., Schutz G.
    Genes Dev. 13:495-504(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE, FUNCTION IN GLUCOSE HOMEOSTASIS.
  5. "Transcription factor FoxA (HNF3) on a nucleosome at an enhancer complex in liver chromatin."
    Chaya D., Hayamizu T., Bustin M., Zaret K.S.
    J. Biol. Chem. 276:44385-44389(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: ASSOCIATION WITH NUCLEOSOMES.
  6. "Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4."
    Cirillo L.A., Lin F.R., Cuesta I., Friedman D., Jarnik M., Zaret K.S.
    Mol. Cell 9:279-289(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN CHROMATIN OPENING, INTERACTION WITH HISTONES H3 AND H4.
  7. "Mild nephrogenic diabetes insipidus caused by Foxa1 deficiency."
    Behr R., Brestelli J., Fulmer J.T., Miyawaki N., Kleyman T.R., Kaestner K.H.
    J. Biol. Chem. 279:41936-41941(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE.
  8. "Forkhead box A1 regulates prostate ductal morphogenesis and promotes epithelial cell maturation."
    Gao N., Ishii K., Mirosevich J., Kuwajima S., Oppenheimer S.R., Roberts R.L., Jiang M., Yu X., Shappell S.B., Caprioli R.M., Stoffel M., Hayward S.W., Matusik R.J.
    Development 132:3431-3443(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PROSTATE DEVELOPMENT, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DISRUPTION PHENOTYPE.
  9. "FoxA1 binding to the MMTV LTR modulates chromatin structure and transcription."
    Holmqvist P.H., Belikov S., Zaret K.S., Wrange O.
    Exp. Cell Res. 304:593-603(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN CHROMATIN OPENING.
  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. "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.
  13. "Physical and functional interactions between homeodomain NKX2.1 and winged helix/forkhead FOXA1 in lung epithelial cells."
    Minoo P., Hu L., Xing Y., Zhu N.L., Chen H., Li M., Borok Z., Li C.
    Mol. Cell. Biol. 27:2155-2165(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: DEVELOPMENTAL STAGE.
  14. "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.
  15. "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 nameiFOXA1_MOUSE
AccessioniPrimary (citable) accession number: P35582
Secondary accession number(s): Q4VA63, Q61108
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: November 1, 1997
Last modified: April 29, 2015
This is version 139 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.