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P43699 (NKX21_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 145. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Homeobox protein Nkx-2.1
Alternative name(s):
Homeobox protein NK-2 homolog A
Thyroid nuclear factor 1
Thyroid transcription factor 1
Short name=TTF-1
Thyroid-specific enhancer-binding protein
Short name=T/EBP
Gene names
Name:NKX2-1
Synonyms:NKX2A, TITF1, TTF1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length371 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Transcription factor that binds and activates the promoter of thyroid specific genes such as thyroglobulin, thyroperoxidase, and thyrotropin receptor. Crucial in the maintenance of the thyroid differentiation phenotype. May play a role in lung development and surfactant homeostasis. Activates the transcription of GNRHR and plays a role in enhancing the circadian oscillation of its gene expression. Represses the transcription of the circadian transcriptional repressor NR1D1 By similarity.

Subunit structure

Interacts with WWTR1. Ref.10

Subcellular location

Nucleus.

Tissue specificity

Thyroid and lung.

Post-translational modification

Phosphorylated on serine residues by STK3/MST2 By similarity.

Involvement in disease

Chorea, hereditary benign (BHC) [MIM:118700]: A rare autosomal dominant movement disorder, defined by early onset in childhood, a stable or non-progressive course of chorea, and no mental deterioration. Chorea is characterized by involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.11 Ref.15

Choreoathetosis, hypothyroidism, and neonatal respiratory distress (CHNRD) [MIM:610978]: This syndrome include neurological, thyroid, and respiratory problems.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.12 Ref.13 Ref.14 Ref.15

Sequence similarities

Belongs to the NK-2 homeobox family.

Contains 1 homeobox DNA-binding domain.

Sequence caution

The sequence AAH06221.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

The sequence BAA23527.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
   Biological processBiological rhythms
Transcription
Transcription regulation
   Cellular componentNucleus
   Coding sequence diversityAlternative splicing
   DiseaseDisease mutation
   DomainHomeobox
   LigandDNA-binding
   Molecular functionActivator
Repressor
   PTMPhosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processClara cell differentiation

Inferred from electronic annotation. Source: Ensembl

Leydig cell differentiation

Inferred from electronic annotation. Source: Ensembl

Type II pneumocyte differentiation

Inferred from electronic annotation. Source: Ensembl

anatomical structure formation involved in morphogenesis

Inferred from electronic annotation. Source: Ensembl

axon guidance

Inferred from electronic annotation. Source: Ensembl

brain development

Inferred from mutant phenotype Ref.11. Source: UniProtKB

cerebral cortex GABAergic interneuron differentiation

Inferred from electronic annotation. Source: Ensembl

cerebral cortex cell migration

Inferred from electronic annotation. Source: Ensembl

developmental induction

Inferred from electronic annotation. Source: Ensembl

endoderm development

Inferred from electronic annotation. Source: Ensembl

epithelial tube branching involved in lung morphogenesis

Inferred from expression pattern PubMed 8675988. Source: UniProtKB

forebrain development

Inferred from expression pattern PubMed 15494458. Source: UniProtKB

forebrain dorsal/ventral pattern formation

Inferred from electronic annotation. Source: Ensembl

forebrain neuron fate commitment

Inferred from electronic annotation. Source: Ensembl

globus pallidus development

Inferred from mutant phenotype Ref.13. Source: UniProtKB

hippocampus development

Inferred from electronic annotation. Source: Ensembl

locomotory behavior

Inferred from electronic annotation. Source: Ensembl

lung development

Inferred from expression pattern PubMed 15494458PubMed 16960125. Source: UniProtKB

lung saccule development

Inferred from electronic annotation. Source: Ensembl

menarche

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell migration

Inferred from direct assay PubMed 19293183. Source: UniProtKB

negative regulation of epithelial to mesenchymal transition

Inferred from direct assay PubMed 19293183. Source: UniProtKB

negative regulation of transcription from RNA polymerase II promoter

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription, DNA-templated

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of transforming growth factor beta receptor signaling pathway

Inferred from direct assay PubMed 19293183. Source: UniProtKB

neuron migration

Inferred from electronic annotation. Source: Ensembl

oligodendrocyte differentiation

Inferred from electronic annotation. Source: Ensembl

phospholipid metabolic process

Inferred from electronic annotation. Source: Ensembl

pituitary gland development

Inferred from electronic annotation. Source: Ensembl

positive regulation of circadian rhythm

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of gene expression

Inferred from direct assay PubMed 16960125. Source: UniProtKB

positive regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 16960125PubMed 7559607Ref.3. Source: UniProtKB

positive regulation of transcription, DNA-templated

Inferred from direct assay PubMed 14960358. Source: UniProtKB

response to hormone

Inferred from expression pattern PubMed 16960125. Source: UniProtKB

thyroid gland development

Inferred from mutant phenotype Ref.13. Source: UniProtKB

   Cellular_componentnucleoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

nucleus

Inferred from direct assay Ref.3PubMed 8675988. Source: UniProtKB

transcription factor complex

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionDNA binding

Inferred from mutant phenotype PubMed 7635972. Source: UniProtKB

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

Inferred from electronic annotation. Source: Ensembl

core promoter binding

Inferred from sequence or structural similarity. Source: UniProtKB

enzyme binding

Inferred from physical interaction PubMed 23382074. Source: UniProt

protein binding

Inferred from physical interaction Ref.10. Source: UniProtKB

sequence-specific DNA binding

Inferred from electronic annotation. Source: Ensembl

sequence-specific DNA binding transcription factor activity

Inferred from direct assay PubMed 16960125PubMed 7559607Ref.3. Source: UniProtKB

transcription regulatory region DNA binding

Inferred from direct assay PubMed 14960358PubMed 1735431PubMed 7559607. Source: UniProtKB

Complete GO annotation...

Binary interactions

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P43699-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 3 (identifier: P43699-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MWSGGSGKARGWEAAAGGRSSPGRLSRRRIM

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 371371Homeobox protein Nkx-2.1
PRO_0000049343

Regions

DNA binding161 – 22060Homeobox
Compositional bias234 – 24310Poly-Gly
Compositional bias246 – 2538Poly-Gln
Compositional bias294 – 30310Poly-Ala

Natural variations

Alternative sequence11M → MWSGGSGKARGWEAAAGGRS SPGRLSRRRIM in isoform 3.
VSP_037890
Natural variant2051V → F in CHNRD. Ref.13
VAR_034906
Natural variant2081W → L in BHC. Ref.11
Corresponds to variant rs28936672 [ dbSNP | Ensembl ].
VAR_015188
Natural variant2131R → S in BHC. Ref.11
Corresponds to variant rs28936671 [ dbSNP | Ensembl ].
VAR_015189

Experimental info

Sequence conflict491P → H in BAA23527. Ref.5
Sequence conflict491P → H in BAA23529. Ref.5
Sequence conflict611H → P in BAA23527. Ref.5
Sequence conflict611H → P in BAA23529. Ref.5
Sequence conflict1581S → T in BAA23527. Ref.5
Sequence conflict1581S → T in BAA23529. Ref.5
Sequence conflict1611R → G in BAA23527. Ref.5
Sequence conflict1611R → G in BAA23529. Ref.5

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified November 1, 1995. Version 1.
Checksum: 5F1E3B40A1BBD862

FASTA37138,596
        10         20         30         40         50         60 
MSMSPKHTTP FSVSDILSPL EESYKKVGME GGGLGAPLAA YRQGQAAPPT AAMQQHAVGH 

        70         80         90        100        110        120 
HGAVTAAYHM TAAGVPQLSH SAVGGYCNGN LGNMSELPPY QDTMRNSASG PGWYGANPDP 

       130        140        150        160        170        180 
RFPAISRFMG PASGMNMSGM GGLGSLGDVS KNMAPLPSAP RRKRRVLFSQ AQVYELERRF 

       190        200        210        220        230        240 
KQQKYLSAPE REHLASMIHL TPTQVKIWFQ NHRYKMKRQA KDKAAQQQLQ QDSGGGGGGG 

       250        260        270        280        290        300 
GTGCPQQQQA QQQSPRRVAV PVLVKDGKPC QAGAPAPGAA SLQGHAQQQA QHQAQAAQAA 

       310        320        330        340        350        360 
AAAISVGSGG AGLGAHPGHQ PGSAGQSPDL AHHAASPAAL QGQVSSLSHL NSSGSDYGTM 

       370 
SCSTLLYGRT W 

« Hide

Isoform 3 [UniParc].

Checksum: 40324D55128D4394
Show »

FASTA40141,737

References

« Hide 'large scale' references
[1]"The complete nucleotide sequence of the mouse thyroid-specific enhancer-binding protein (T/EBP) gene: extensive identity of the deduced amino acid sequence with the human protein."
Oguchi H., Pan Y.-T., Kimura S.
Biochim. Biophys. Acta 1261:304-306(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Lung.
[2]"Cloning and sequence analysis of human thyroid transcription factor 1."
Saiardi A., Tassi V., de Filippis V., Civitareale D.
Biochim. Biophys. Acta 1261:307-310(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Thyroid.
[3]"Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells."
Ikeda K., Clark J.C., Shaw-White J.R., Stahlman M.T., Boutell C.J., Whitsett J.A.
J. Biol. Chem. 270:8108-8114(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
[4]"Structure of the human Nkx2.1 gene."
Hamdan H., Liu H., Li C., Jones C., Lee M., deLemos R., Minoo P.
Biochim. Biophys. Acta 1396:336-348(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3).
Tissue: Lung.
[5]"Cloning of the human TTF-1 gene."
Endo T., Ohno M., Nakazato M.
Submitted (MAY-1995) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
Tissue: Thyroid.
[6]"Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
[7]"The DNA sequence and analysis of human chromosome 14."
Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., Du H. expand/collapse author list , Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., Waterston R., Hood L., Weissenbach J.
Nature 421:601-607(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]"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] (ISOFORM 3).
Tissue: Lung.
[10]"TAZ is a coactivator for Pax8 and TTF-1, two transcription factors involved in thyroid differentiation."
Di Palma T., D'Andrea B., Liguori G.L., Liguoro A., de Cristofaro T., Del Prete D., Pappalardo A., Mascia A., Zannini M.
Exp. Cell Res. 315:162-175(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH WWTR1.
[11]"Mutations in TITF-1 are associated with benign hereditary chorea."
Breedveld G.J., van Dongen J.W.F., Danesino C., Guala A., Percy A.K., Dure L.S., Harper P., Lazarou L.P., van der Linde H., Joosse M., Grueters A., MacDonald M.E., de Vries B.B.A., Arts W.F.M., Oostra B.A., Krude H., Heutink P.
Hum. Mol. Genet. 11:971-979(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS BHC LEU-208 AND SER-213.
[12]"Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice."
Pohlenz J., Dumitrescu A., Zundel D., Martine U., Schoenberger W., Koo E., Weiss R.E., Cohen R.N., Kimura S., Refetoff S.
J. Clin. Invest. 109:469-473(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN CHNRD.
[13]"Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency."
Krude H., Schuetz B., Biebermann H., von Moers A., Schnabel D., Neitzel H., Toennies H., Weise D., Lafferty A., Schwarz S., DeFelice M., von Deimling A., van Landeghem F., DiLauro R., Grueters A.
J. Clin. Invest. 109:475-480(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT CHNRD PHE-205.
[14]"Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2-1."
Doyle D.A., Gonzalez I., Thomas B., Scavina M.
J. Pediatr. 145:190-193(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN CHNRD.
[15]"A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa."
Asmus F., Horber V., Pohlenz J., Schwabe D., Zimprich A., Munz M., Schoening M., Gasser T.
Neurology 64:1952-1954(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN CHNRD AND IN BHC.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U19756 mRNA. Translation: AAA86099.1.
X82850 mRNA. Translation: CAA58053.1.
U19816 Genomic DNA. Translation: AAC50125.1.
U33749 mRNA. Translation: AAB52381.1.
U43203 mRNA. Translation: AAA89066.1.
D50739 Genomic DNA. Translation: BAA23527.1. Sequence problems.
D50740 mRNA. Translation: BAA23529.1.
BT009773 mRNA. Translation: AAP88775.1.
AL132857 Genomic DNA. No translation available.
CH471078 Genomic DNA. Translation: EAW65858.1.
CH471078 Genomic DNA. Translation: EAW65856.1.
CH471078 Genomic DNA. Translation: EAW65859.1.
BC006221 mRNA. Translation: AAH06221.2. Different initiation.
CCDSCCDS41945.1. [P43699-3]
CCDS9659.1. [P43699-1]
PIRG02321.
RefSeqNP_001073136.1. NM_001079668.2. [P43699-3]
NP_003308.1. NM_003317.3. [P43699-1]
UniGeneHs.94367.

3D structure databases

ProteinModelPortalP43699.
SMRP43699. Positions 161-227.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid112936. 11 interactions.
IntActP43699. 8 interactions.
MINTMINT-192847.
STRING9606.ENSP00000346879.

PTM databases

PhosphoSiteP43699.

Polymorphism databases

DMDM1174819.

Proteomic databases

MaxQBP43699.
PaxDbP43699.
PRIDEP43699.

Protocols and materials databases

DNASU7080.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000354822; ENSP00000346879; ENSG00000136352. [P43699-3]
ENST00000498187; ENSP00000429607; ENSG00000136352. [P43699-1]
ENST00000518149; ENSP00000428341; ENSG00000136352. [P43699-1]
ENST00000522719; ENSP00000429519; ENSG00000136352. [P43699-1]
GeneID7080.
KEGGhsa:7080.
UCSCuc001wtt.3. human. [P43699-1]
uc001wtu.3. human. [P43699-3]

Organism-specific databases

CTD7080.
GeneCardsGC14M036985.
HGNCHGNC:11825. NKX2-1.
HPACAB000078.
MIM118700. phenotype.
600635. gene.
610978. phenotype.
neXtProtNX_P43699.
Orphanet95713. Athyreosis.
1429. Benign familial chorea.
209905. Brain-lung-thyroid syndrome.
146. Papillary or follicular thyroid carcinoma.
95720. Thyroid hypoplasia.
PharmGKBPA36531.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG328614.
HOGENOMHOG000231923.
HOVERGENHBG006689.
InParanoidP43699.
KOK09342.
OMAKSMAPLQ.
OrthoDBEOG769ZK0.
PhylomeDBP43699.
TreeFamTF351204.

Gene expression databases

ArrayExpressP43699.
BgeeP43699.
CleanExHS_NKX2-1.
HS_TTF1.
GenevestigatorP43699.

Family and domain databases

Gene3D1.10.10.60. 1 hit.
InterProIPR017970. Homeobox_CS.
IPR001356. Homeobox_dom.
IPR020479. Homeobox_metazoa.
IPR009057. Homeodomain-like.
[Graphical view]
PfamPF00046. Homeobox. 1 hit.
[Graphical view]
PRINTSPR00024. HOMEOBOX.
SMARTSM00389. HOX. 1 hit.
[Graphical view]
SUPFAMSSF46689. SSF46689. 1 hit.
PROSITEPS00027. HOMEOBOX_1. 1 hit.
PS50071. HOMEOBOX_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiNK2_homeobox_1.
GenomeRNAi7080.
NextBio27693.
PROP43699.
SOURCESearch...

Entry information

Entry nameNKX21_HUMAN
AccessionPrimary (citable) accession number: P43699
Secondary accession number(s): D3DSA3 expand/collapse secondary AC list , O14954, O14955, Q7KZF6, Q9BRJ8
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: November 1, 1995
Last modified: July 9, 2014
This is version 145 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 14

Human chromosome 14: entries, gene names and cross-references to MIM