FOXA2_RAT
ID FOXA2_RAT Reviewed; 458 AA.
AC P32182;
DT 01-OCT-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1993, sequence version 1.
DT 25-MAY-2022, entry version 168.
DE RecName: Full=Hepatocyte nuclear factor 3-beta;
DE Short=HNF-3-beta;
DE Short=HNF-3B;
DE AltName: Full=Forkhead box protein A2;
GN Name=Foxa2; Synonyms=Hnf3b, Tcf-3b, Tcf3b;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1672118; DOI=10.1101/gad.5.3.416;
RA Lai E., Prezioso V.R., Tao W.F., Chen W.S., Darnell J.E. Jr.;
RT "Hepatocyte nuclear factor 3 alpha belongs to a gene family in mammals that
RT is homologous to the Drosophila homeotic gene fork head.";
RL Genes Dev. 5:416-427(1991).
RN [2]
RP TRANSACTIVATION DOMAIN.
RX PubMed=1324404; DOI=10.1128/mcb.12.9.3723-3732.1992;
RA Pani L., Overdier D.G., Porcella A., Qian X., Lai E., Costa R.H.;
RT "Hepatocyte nuclear factor 3 beta contains two transcriptional activation
RT domains, one of which is novel and conserved with the Drosophila fork head
RT protein.";
RL Mol. Cell. Biol. 12:3723-3732(1992).
RN [3]
RP DNA-BINDING CONSENSUS SEQUENCE.
RX PubMed=8139574; DOI=10.1128/mcb.14.4.2755-2766.1994;
RA Overdier D.G., Porcella A., Costa R.H.;
RT "The DNA-binding specificity of the hepatocyte nuclear factor 3/forkhead
RT domain is influenced by amino-acid residues adjacent to the recognition
RT helix.";
RL Mol. Cell. Biol. 14:2755-2766(1994).
RN [4]
RP TRANSACTIVATION DOMAIN, SUBCELLULAR LOCATION, PHOSPHORYLATION, AND
RP MUTAGENESIS OF TYR-18.
RX PubMed=7739897; DOI=10.1093/nar/23.7.1184;
RA Qian X., Costa R.H.;
RT "Analysis of hepatocyte nuclear factor-3 beta protein domains required for
RT transcriptional activation and nuclear targeting.";
RL Nucleic Acids Res. 23:1184-1191(1995).
RN [5]
RP INTERACTION WITH TLE1.
RX PubMed=10748198; DOI=10.1074/jbc.m910211199;
RA Wang J.-C., Waltner-Law M., Yamada K., Osawa H., Stifani S., Granner D.K.;
RT "Transducin-like enhancer of split proteins, the human homologs of
RT Drosophila groucho, interact with hepatic nuclear factor 3beta.";
RL J. Biol. Chem. 275:18418-18423(2000).
RN [6]
RP FUNCTION.
RX PubMed=10931833; DOI=10.1074/jbc.m004027200;
RA Delesque-Touchard N., Park S.H., Waxman D.J.;
RT "Synergistic action of hepatocyte nuclear factors 3 and 6 on CYP2C12 gene
RT expression and suppression by growth hormone-activated STAT5b. Proposed
RT model for female specific expression of CYP2C12 in adult rat liver.";
RL J. Biol. Chem. 275:34173-34182(2000).
RN [7]
RP PHOSPHORYLATION AT THR-156, SUBCELLULAR LOCATION, INTERACTION WITH AKT1,
RP AND MUTAGENESIS OF ARG-153 AND THR-156.
RX PubMed=14500912; DOI=10.1073/pnas.1931483100;
RA Wolfrum C., Besser D., Luca E., Stoffel M.;
RT "Insulin regulates the activity of forkhead transcription factor Hnf-
RT 3beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic
RT localization.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:11624-11629(2003).
RN [8]
RP FUNCTION, INTERACTION WITH PRKDC, PHOSPHORYLATION AT SER-212; SER-283;
RP SER-303; SER-306; SER-307; SER-309; SER-437 AND SER-458, AND MUTAGENESIS OF
RP THR-280 AND SER-283.
RX PubMed=19478084; DOI=10.1074/jbc.m109.016295;
RA Nock A., Ascano J.M., Jones T., Barrero M.J., Sugiyama N., Tomita M.,
RA Ishihama Y., Malik S.;
RT "Identification of DNA-dependent protein kinase as a cofactor for the
RT forkhead transcription factor FoxA2.";
RL J. Biol. Chem. 284:19915-19926(2009).
RN [9]
RP SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, AND MUTAGENESIS OF
RP LEU-110; LEU-113 AND THR-156.
RX PubMed=19589781; DOI=10.1074/jbc.m109.042135;
RA Howell J.J., Stoffel M.;
RT "Nuclear export-independent inhibition of Foxa2 by insulin.";
RL J. Biol. Chem. 284:24816-24824(2009).
CC -!- FUNCTION: Transcription factor that is involved in embryonic
CC development, establishment of tissue-specific gene expression and
CC regulation of gene expression in differentiated tissues. Is thought to
CC act as a 'pioneer' factor opening the compacted chromatin for other
CC proteins through interactions with nucleosomal core histones and
CC thereby replacing linker histones at target enhancer and/or promoter
CC sites. Binds DNA with the consensus sequence 5'-
CC [AC]A[AT]T[AG]TT[GT][AG][CT]T[CT]-3' (By similarity). In embryonic
CC development is required for notochord formation. Involved in the
CC development of multiple endoderm-derived organ systems such as the
CC liver, pancreas and lungs; FOXA1 and FOXA2 seem to have at least in
CC part redundant roles. Originally described as a transcription activator
CC for a number of liver genes such as AFP, albumin, tyrosine
CC aminotransferase, PEPCK, etc. Interacts with the cis-acting regulatory
CC regions of these genes. Involved in glucose homeostasis; regulates the
CC expression of genes important for glucose sensing in pancreatic beta-
CC cells and glucose homeostasis (By similarity). Involved in regulation
CC of fat metabolism. Acts synergistically with ONECUT1 to activate
CC transcription of female-specific CYP2C12; the function is inhibited by
CC growth hormone-activated STAT5B. Acts synergistically with HNF4A to
CC activate transcription of APOA1. {ECO:0000250,
CC ECO:0000269|PubMed:10931833, ECO:0000269|PubMed:19478084}.
CC -!- SUBUNIT: Binds DNA as a monomer. Binds TLE1. Interacts with FOXA1 and
CC FOXA3 (By similarity). Interacts with PRKDC. {ECO:0000250,
CC ECO:0000269|PubMed:10748198, ECO:0000269|PubMed:14500912,
CC ECO:0000269|PubMed:19478084}.
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Note=Shuttles between the
CC nucleus and cytoplasm in a CRM1-dependent manner; in response to
CC insulin signaling via AKT1 is exported from the nucleus.
CC -!- TISSUE SPECIFICITY: Liver.
CC -!- PTM: Phosphorylation on Thr-156 abolishes binding to target promoters
CC and subsequent transcription activation upon insulin stimulation.
CC {ECO:0000269|PubMed:14500912, ECO:0000269|PubMed:19478084,
CC ECO:0000269|PubMed:7739897}.
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DR EMBL; L09647; AAA41338.1; -; mRNA.
DR PIR; B39533; B39533.
DR RefSeq; NP_036875.1; NM_012743.1.
DR AlphaFoldDB; P32182; -.
DR SMR; P32182; -.
DR IntAct; P32182; 1.
DR STRING; 10116.ENSRNOP00000017742; -.
DR iPTMnet; P32182; -.
DR PhosphoSitePlus; P32182; -.
DR PaxDb; P32182; -.
DR GeneID; 25099; -.
DR KEGG; rno:25099; -.
DR CTD; 3170; -.
DR RGD; 2808; Foxa2.
DR eggNOG; KOG3563; Eukaryota.
DR InParanoid; P32182; -.
DR OrthoDB; 1181467at2759; -.
DR PhylomeDB; P32182; -.
DR PRO; PR:P32182; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0005667; C:transcription regulator complex; ISO:RGD.
DR GO; GO:0003682; F:chromatin binding; ISO:RGD.
DR GO; GO:0003677; F:DNA binding; ISO:RGD.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:RGD.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:RGD.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISO:RGD.
DR GO; GO:0003690; F:double-stranded DNA binding; IDA:RGD.
DR GO; GO:0019900; F:kinase binding; IPI:RGD.
DR GO; GO:0019904; F:protein domain specific binding; IEA:InterPro.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:BHF-UCL.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:RGD.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:RGD.
DR GO; GO:0046332; F:SMAD binding; IDA:RGD.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISO:RGD.
DR GO; GO:0008344; P:adult locomotory behavior; ISS:ParkinsonsUK-UCL.
DR GO; GO:0048646; P:anatomical structure formation involved in morphogenesis; ISO:RGD.
DR GO; GO:0009653; P:anatomical structure morphogenesis; ISO:RGD.
DR GO; GO:0009952; P:anterior/posterior pattern specification; ISO:RGD.
DR GO; GO:0048468; P:cell development; ISO:RGD.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0021533; P:cell differentiation in hindbrain; ISO:RGD.
DR GO; GO:0001708; P:cell fate specification; ISS:ParkinsonsUK-UCL.
DR GO; GO:0071276; P:cellular response to cadmium ion; ISO:RGD.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0061448; P:connective tissue development; ISO:RGD.
DR GO; GO:0071542; P:dopaminergic neuron differentiation; ISS:ParkinsonsUK-UCL.
DR GO; GO:0021904; P:dorsal/ventral neural tube patterning; ISO:RGD.
DR GO; GO:0009953; P:dorsal/ventral pattern formation; ISO:RGD.
DR GO; GO:0001705; P:ectoderm formation; ISO:RGD.
DR GO; GO:0031018; P:endocrine pancreas development; ISO:RGD.
DR GO; GO:0060441; P:epithelial tube branching involved in lung morphogenesis; ISO:RGD.
DR GO; GO:0001701; P:in utero embryonic development; ISO:RGD.
DR GO; GO:0030324; P:lung development; ISO:RGD.
DR GO; GO:0060487; P:lung epithelial cell differentiation; ISO:RGD.
DR GO; GO:0048382; P:mesendoderm development; ISO:RGD.
DR GO; GO:2000971; P:negative regulation of detection of glucose; ISO:RGD.
DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; ISO:RGD.
DR GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; ISO:RGD.
DR GO; GO:0033132; P:negative regulation of glucokinase activity; ISO:RGD.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; ISO:RGD.
DR GO; GO:0061987; P:negative regulation of transcription from RNA polymerase II promoter by glucose; ISO:RGD.
DR GO; GO:0048665; P:neuron fate specification; ISO:RGD.
DR GO; GO:0007219; P:Notch signaling pathway; ISO:RGD.
DR GO; GO:0007389; P:pattern specification process; ISO:RGD.
DR GO; GO:0040019; P:positive regulation of embryonic development; ISS:UniProtKB.
DR GO; GO:2000543; P:positive regulation of gastrulation; ISS:UniProtKB.
DR GO; GO:0045666; P:positive regulation of neuron differentiation; ISO:RGD.
DR GO; GO:0045880; P:positive regulation of smoothened signaling pathway; ISO:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:RGD.
DR GO; GO:0045945; P:positive regulation of transcription by RNA polymerase III; ISO:RGD.
DR GO; GO:0000432; P:positive regulation of transcription from RNA polymerase II promoter by glucose; ISO:RGD.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0090009; P:primitive streak formation; ISS:UniProtKB.
DR GO; GO:0030193; P:regulation of blood coagulation; ISO:RGD.
DR GO; GO:0010468; P:regulation of gene expression; ISO:RGD.
DR GO; GO:0061178; P:regulation of insulin secretion involved in cellular response to glucose stimulus; ISO:RGD.
DR GO; GO:0019216; P:regulation of lipid metabolic process; ISO:RGD.
DR GO; GO:0019218; P:regulation of steroid metabolic process; ISO:RGD.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IDA:RGD.
DR GO; GO:0032868; P:response to insulin; IEP:RGD.
DR GO; GO:0023019; P:signal transduction involved in regulation of gene expression; ISO:RGD.
DR GO; GO:0032525; P:somite rostral/caudal axis specification; ISO:RGD.
DR CDD; cd00059; FH; 1.
DR Gene3D; 1.10.10.10; -; 1.
DR InterPro; IPR013638; Fork-head_N.
DR InterPro; IPR001766; Fork_head_dom.
DR InterPro; IPR018533; Forkhead_box_C.
DR InterPro; IPR018122; TF_fork_head_CS_1.
DR InterPro; IPR030456; TF_fork_head_CS_2.
DR InterPro; IPR036388; WH-like_DNA-bd_sf.
DR InterPro; IPR036390; WH_DNA-bd_sf.
DR Pfam; PF00250; Forkhead; 1.
DR Pfam; PF08430; Forkhead_N; 1.
DR Pfam; PF09354; HNF_C; 1.
DR PRINTS; PR00053; FORKHEAD.
DR SMART; SM00339; FH; 1.
DR SUPFAM; SSF46785; SSF46785; 1.
DR PROSITE; PS00657; FORK_HEAD_1; 1.
DR PROSITE; PS00658; FORK_HEAD_2; 1.
DR PROSITE; PS50039; FORK_HEAD_3; 1.
PE 1: Evidence at protein level;
KW Activator; Chromatin regulator; Cytoplasm; Developmental protein;
KW DNA-binding; Nucleus; Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation.
FT CHAIN 1..458
FT /note="Hepatocyte nuclear factor 3-beta"
FT /id="PRO_0000091797"
FT DNA_BIND 159..252
FT /note="Fork-head"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT REGION 14..93
FT /note="Transactivation domain 1"
FT REGION 286..365
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 361..458
FT /note="Transactivation domain 2"
FT MOTIF 106..113
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000269|PubMed:19589781"
FT COMPBIAS 286..310
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 156
FT /note="Phosphothreonine; by PKB/AKT1"
FT /evidence="ECO:0000269|PubMed:14500912"
FT MOD_RES 212
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:19478084"
FT MOD_RES 283
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:19478084"
FT MOD_RES 301
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P35583"
FT MOD_RES 303
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:19478084"
FT MOD_RES 306
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:19478084"
FT MOD_RES 307
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:19478084"
FT MOD_RES 309
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:19478084"
FT MOD_RES 437
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:19478084"
FT MOD_RES 458
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:19478084"
FT MUTAGEN 18
FT /note="Y->P: Reduces transcriptional activation."
FT /evidence="ECO:0000269|PubMed:7739897"
FT MUTAGEN 110
FT /note="L->A: Inhibits nuclear export; when associated with
FT A-113."
FT /evidence="ECO:0000269|PubMed:19589781"
FT MUTAGEN 113
FT /note="L->A: Inhibits nuclear export; when associated with
FT A-110."
FT /evidence="ECO:0000269|PubMed:19589781"
FT MUTAGEN 153
FT /note="R->K: Abolishes interaction with AKT1."
FT /evidence="ECO:0000269|PubMed:14500912"
FT MUTAGEN 156
FT /note="T->A: Constitutive active. Abolishes phosphorylation
FT by PKB/AKT1; inhibits nuclear export; no effect on DNA
FT binding."
FT /evidence="ECO:0000269|PubMed:14500912,
FT ECO:0000269|PubMed:19589781"
FT MUTAGEN 280
FT /note="T->A: Impairs transcriptional activation; when
FT associated with A-283."
FT /evidence="ECO:0000269|PubMed:19478084"
FT MUTAGEN 283
FT /note="S->A: Abolishes in vitro phosphorylation by PRKDC.
FT Impairs transcriptional activation; when associated with A-
FT 280."
FT /evidence="ECO:0000269|PubMed:19478084"
SQ SEQUENCE 458 AA; 48484 MW; 9FF754142C194055 CRC64;
MLGAVKMEGH EPSDWSSYYA EPEGYSSVSN MNASLGMNGM NTYMSMSAAA MGSGSGNMSA
GSMNMSSYVG AGMSPSLAGM SPGAGAMAGM SGSAGAAGVA GMGPHLSPSL SPLGGQAAGA
MGGLAPYANM NSMSPMYGQA GLSRARDPKT YRRSYTHAKP PYSYISLITM AIQQSPNKML
TLSEIYQWIM DLFPFYRQNQ QRWQNSIRHS LSFNDFLKVP RAPDKPGKGS FWTLHPDSGN
MFENGCYLRR QKRFKCENEL ALKEAAGAGS GGGKKTAPGT QASQVQLGEA AGSASETPAG
TESPHSSASP CQEHKRGGLS ELKGTPASAL SPPEPAPSPG QQQQAAAHLL GPPHHPGLPP
EAHLKPEHHY AFNHPFSINN LMSSEQQHHH SHHHHQPHKM DLKTYEQVMH YPGGYGSPMP
GSLAMGPVTN KAGLDASPLA ADTSYYQGVY SRPIMNSS
