NKX21_RAT
ID NKX21_RAT Reviewed; 372 AA.
AC P23441; O08630; O70121;
DT 01-NOV-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1991, sequence version 1.
DT 03-AUG-2022, entry version 170.
DE RecName: Full=Homeobox protein Nkx-2.1;
DE AltName: Full=Thyroid nuclear factor 1;
DE AltName: Full=Thyroid transcription factor 1;
DE Short=TTF-1;
GN Name=Nkx2-1 {ECO:0000312|RGD:3866}; Synonyms=Nkx-2.1, Titf1, Ttf-1, Ttf1;
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=1976511; DOI=10.1002/j.1460-2075.1990.tb07574.x;
RA Guazzi S., Price M., de Felice M., Damante G., Mattei M.-G., di Lauro R.;
RT "Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a
RT novel DNA binding specificity.";
RL EMBO J. 9:3631-3639(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Liver;
RX PubMed=7980615; DOI=10.1006/bbrc.1994.2613;
RA Endo T., Ohta K., Saito T., Haraguchi K., Nakazato M., Kogai T., Onaya T.;
RT "Structure of the rat thyroid transcription factor-1 (TTF-1) gene.";
RL Biochem. Biophys. Res. Commun. 204:1358-1363(1994).
RN [3]
RP PHOSPHORYLATION.
RX PubMed=9430685; DOI=10.1074/jbc.273.3.1477;
RA Aurisicchio L., Dilauro R., Zannini M.;
RT "Identification of the thyroid transcription factor 1 as a target for rat
RT MST2 kinase.";
RL J. Biol. Chem. 273:1477-1482(1998).
RN [4]
RP FUNCTION, AND INDUCTION.
RX PubMed=22356123; DOI=10.1111/j.1365-2826.2012.02302.x;
RA Matagne V., Kim J.G., Ryu B.J., Hur M.K., Kim M.S., Kim K., Park B.S.,
RA Damante G., Smiley G., Lee B.J., Ojeda S.R.;
RT "Thyroid transcription factor 1, a homeodomain containing transcription
RT factor, contributes to regulating periodic oscillations in GnRH gene
RT expression.";
RL J. Neuroendocrinol. 24:916-929(2012).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-255, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [6]
RP STRUCTURE BY NMR OF 161-227.
RX PubMed=8282100; DOI=10.1016/0014-5793(93)80845-l;
RA Viglino P., Fogolari F., Formisiano S., Bortolotti N., Damante G.,
RA di Lauro R., Esposito G.;
RT "Structural study of rat thyroid transcription factor 1 homeodomain (TTF-1
RT HD) by nuclear magnetic resonance.";
RL FEBS Lett. 336:397-402(1993).
RN [7]
RP STRUCTURE BY NMR OF 161-227.
RX PubMed=8898894; DOI=10.1111/j.1432-1033.1996.0101t.x;
RA Esposito G., Fogolari F., Damante G., Formisano S., Tell G., Leonardi A.,
RA di Lauro R., Viglino P.;
RT "Analysis of the solution structure of the homeodomain of rat thyroid
RT transcription factor 1 by 1H-NMR spectroscopy and restrained molecular
RT mechanics.";
RL Eur. J. Biochem. 241:101-113(1996).
CC -!- FUNCTION: Transcription factor that binds and activates the promoter of
CC thyroid specific genes such as thyroglobulin, thyroperoxidase, and
CC thyrotropin receptor. Crucial in the maintenance of the thyroid
CC differentiation phenotype. May play a role in lung development and
CC surfactant homeostasis. Forms a regulatory loop with GRHL2 that
CC coordinates lung epithelial cell morphogenesis and differentiation (By
CC similarity). Activates the transcription of GNRHR and plays a role in
CC enhancing the circadian oscillation of its gene expression. Represses
CC the transcription of the circadian transcriptional repressor NR1D1
CC (PubMed:22356123). {ECO:0000250|UniProtKB:P50220,
CC ECO:0000269|PubMed:22356123}.
CC -!- SUBUNIT: Interacts with WWTR1. {ECO:0000250|UniProtKB:P43699}.
CC -!- INTERACTION:
CC P23441; P51974: Pax8; NbExp=5; IntAct=EBI-1223127, EBI-1223113;
CC P23441; Q9EPK5: Wwtr1; Xeno; NbExp=3; IntAct=EBI-1223127, EBI-1211920;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:P50220}.
CC -!- TISSUE SPECIFICITY: Thyroid, lung and CNS. Expressed in restricted
CC regions of the developing brain within the diencephalon, in parts of
CC the hypothalamus and neurohypophysis, and in the telencephalon.
CC -!- INDUCTION: Expression oscillates in a diurnal and melatonin-dependent
CC fashion in the preoptic area (POA) region in the hypothalamus, with
CC maximal expression attained during the dark phase of the light/dark
CC cycle. {ECO:0000269|PubMed:22356123}.
CC -!- PTM: Phosphorylated on serine residues by STK3/MST2.
CC {ECO:0000269|PubMed:9430685}.
CC -!- SIMILARITY: Belongs to the NK-2 homeobox family. {ECO:0000305}.
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DR EMBL; X53858; CAA37851.1; -; mRNA.
DR EMBL; D38035; BAA07231.1; ALT_SEQ; Genomic_DNA.
DR PIR; S12002; S12002.
DR PDB; 1FTT; NMR; -; A=161-227.
DR PDBsum; 1FTT; -.
DR AlphaFoldDB; P23441; -.
DR BMRB; P23441; -.
DR SMR; P23441; -.
DR IntAct; P23441; 2.
DR MINT; P23441; -.
DR STRING; 10116.ENSRNOP00000011453; -.
DR iPTMnet; P23441; -.
DR PhosphoSitePlus; P23441; -.
DR PaxDb; P23441; -.
DR UCSC; RGD:3866; rat.
DR RGD; 3866; Nkx2-1.
DR eggNOG; KOG0842; Eukaryota.
DR InParanoid; P23441; -.
DR PhylomeDB; P23441; -.
DR EvolutionaryTrace; P23441; -.
DR PRO; PR:P23441; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005654; C:nucleoplasm; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IMP:CAFA.
DR GO; GO:0005667; C:transcription regulator complex; ISO:RGD.
DR GO; GO:0001046; F:core promoter sequence-specific DNA binding; IMP:CAFA.
DR GO; GO:0003677; F:DNA binding; IDA:RGD.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IMP:NTNU_SB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:MGI.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISO:RGD.
DR GO; GO:0019899; F:enzyme binding; ISO:RGD.
DR GO; GO:0042802; F:identical protein binding; IMP:CAFA.
DR GO; GO:0001161; F:intronic transcription regulatory region sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:RGD.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:RGD.
DR GO; GO:0017025; F:TBP-class protein binding; IPI:CAFA.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISO:RGD.
DR GO; GO:0001221; F:transcription coregulator binding; IPI:RGD.
DR GO; GO:0048646; P:anatomical structure formation involved in morphogenesis; ISO:RGD.
DR GO; GO:0009887; P:animal organ morphogenesis; ISO:RGD.
DR GO; GO:0007411; P:axon guidance; ISO:RGD.
DR GO; GO:0007420; P:brain development; ISO:RGD.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0044320; P:cellular response to leptin stimulus; IEP:RGD.
DR GO; GO:0021795; P:cerebral cortex cell migration; ISO:RGD.
DR GO; GO:0021892; P:cerebral cortex GABAergic interneuron differentiation; ISO:RGD.
DR GO; GO:0021895; P:cerebral cortex neuron differentiation; ISO:RGD.
DR GO; GO:0007623; P:circadian rhythm; IEP:UniProtKB.
DR GO; GO:0060486; P:club cell differentiation; ISO:RGD.
DR GO; GO:0046545; P:development of primary female sexual characteristics; IEP:RGD.
DR GO; GO:0031128; P:developmental induction; ISO:RGD.
DR GO; GO:1990401; P:embryonic lung development; IEP:RGD.
DR GO; GO:0007492; P:endoderm development; ISO:RGD.
DR GO; GO:0060441; P:epithelial tube branching involved in lung morphogenesis; ISO:RGD.
DR GO; GO:0007631; P:feeding behavior; IMP:RGD.
DR GO; GO:0030900; P:forebrain development; ISO:RGD.
DR GO; GO:0021798; P:forebrain dorsal/ventral pattern formation; ISO:RGD.
DR GO; GO:0021879; P:forebrain neuron differentiation; ISO:RGD.
DR GO; GO:0021877; P:forebrain neuron fate commitment; ISO:RGD.
DR GO; GO:0010467; P:gene expression; ISO:RGD.
DR GO; GO:0021759; P:globus pallidus development; ISO:RGD.
DR GO; GO:0021766; P:hippocampus development; ISO:RGD.
DR GO; GO:0042538; P:hyperosmotic salinity response; IDA:RGD.
DR GO; GO:0021854; P:hypothalamus development; ISO:RGD.
DR GO; GO:0033327; P:Leydig cell differentiation; ISO:RGD.
DR GO; GO:0007626; P:locomotory behavior; ISO:RGD.
DR GO; GO:0030324; P:lung development; ISO:RGD.
DR GO; GO:0060430; P:lung saccule development; ISO:RGD.
DR GO; GO:0030336; P:negative regulation of cell migration; ISO:RGD.
DR GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; ISO:RGD.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; ISO:RGD.
DR GO; GO:0048663; P:neuron fate commitment; ISO:RGD.
DR GO; GO:0001764; P:neuron migration; ISO:RGD.
DR GO; GO:0048709; P:oligodendrocyte differentiation; ISO:RGD.
DR GO; GO:0007389; P:pattern specification process; ISO:RGD.
DR GO; GO:0006644; P:phospholipid metabolic process; ISO:RGD.
DR GO; GO:0021983; P:pituitary gland development; ISO:RGD.
DR GO; GO:0042753; P:positive regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:0010628; P:positive regulation of gene expression; ISO:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0002016; P:regulation of blood volume by renin-angiotensin; IDA: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:0045471; P:response to ethanol; IEP:RGD.
DR GO; GO:0009725; P:response to hormone; ISO:RGD.
DR GO; GO:0032496; P:response to lipopolysaccharide; IDA:RGD.
DR GO; GO:0022029; P:telencephalon cell migration; ISO:RGD.
DR GO; GO:0021537; P:telencephalon development; ISO:RGD.
DR GO; GO:0030878; P:thyroid gland development; ISO:RGD.
DR GO; GO:0060510; P:type II pneumocyte differentiation; ISO:RGD.
DR CDD; cd00086; homeodomain; 1.
DR DisProt; DP00071; -.
DR InterPro; IPR009057; Homeobox-like_sf.
DR InterPro; IPR017970; Homeobox_CS.
DR InterPro; IPR001356; Homeobox_dom.
DR InterPro; IPR020479; Homeobox_metazoa.
DR Pfam; PF00046; Homeodomain; 1.
DR PRINTS; PR00024; HOMEOBOX.
DR SMART; SM00389; HOX; 1.
DR SUPFAM; SSF46689; SSF46689; 1.
DR PROSITE; PS00027; HOMEOBOX_1; 1.
DR PROSITE; PS50071; HOMEOBOX_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Biological rhythms; DNA-binding; Homeobox;
KW Nucleus; Phosphoprotein; Reference proteome; Repressor; Transcription;
KW Transcription regulation.
FT CHAIN 1..372
FT /note="Homeobox protein Nkx-2.1"
FT /id="PRO_0000049345"
FT DNA_BIND 161..220
FT /note="Homeobox"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108"
FT REGION 219..258
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 269..288
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 312..340
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 255
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT STRAND 162..164
FT /evidence="ECO:0007829|PDB:1FTT"
FT HELIX 170..182
FT /evidence="ECO:0007829|PDB:1FTT"
FT STRAND 183..185
FT /evidence="ECO:0007829|PDB:1FTT"
FT HELIX 188..198
FT /evidence="ECO:0007829|PDB:1FTT"
FT HELIX 202..218
FT /evidence="ECO:0007829|PDB:1FTT"
SQ SEQUENCE 372 AA; 38554 MW; 8694421DA25D4135 CRC64;
MSMSPKHTTP FSVSDILSPL EESYKKVGME GGGLGAPLAA YRQGQAAPPA AAMQQHAVGH
HGAVTAAYHM TAAGVPQLSH SAVGGYCNGN LGNMSELPPY QDTMRNSASG PGWYGANPDP
RFPAISRFMG PASGMNMSGM GGLGSLGDVS KNMAPLPSAP RRKRRVLFSQ AQVYELERRF
KQQKYLSAPE REHLASMIHL TPTQVKIWFQ NHRYKMKRQA KDKAAQQQLQ QDSGGGGGGG
GGAGCPQQQQ AQQQSPRRVA VPVLVKDGKP CQAGAPAPGA ASLQGHAQQQ AQQQAQAAQA
AAAAISVGSG GAGLGAHPGH QPGSAGQSPD LAHHAASPAA LQGQVSSLSH LNSSGSDYGA
MSCSTLLYGR TW
