P43699 (NKX21_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Gene names

Name:	NKX2-1
Synonyms:	NKX2A, TITF1, TTF1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	371 AA.
Sequence status	Complete.
Protein existence	Evidence 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.
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. The sequence BAA23527.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing
Disease	Disease mutation
Domain	Homeobox
Ligand	DNA-binding
Molecular function	Activator
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Clara cell differentiation Inferred from electronic annotation. Source: Compara Leydig cell differentiation Inferred from electronic annotation. Source: Compara Type II pneumocyte differentiation Inferred from electronic annotation. Source: Compara anatomical structure formation involved in morphogenesis Inferred from electronic annotation. Source: Compara axon guidance Inferred from electronic annotation. Source: Compara cerebral cortex GABAergic interneuron differentiation Inferred from electronic annotation. Source: Compara cerebral cortex cell migration Inferred from electronic annotation. Source: Compara developmental induction Inferred from electronic annotation. Source: Compara endoderm development Inferred from electronic annotation. Source: Compara epithelial tube branching involved in lung morphogenesis Inferred from expression pattern PubMed 8675988. Source: UniProtKB forebrain dorsal/ventral pattern formation Inferred from electronic annotation. Source: Compara forebrain neuron fate commitment Inferred from electronic annotation. Source: Compara globus pallidus development Inferred from mutant phenotype Ref.13. Source: UniProtKB hippocampus development Inferred from electronic annotation. Source: Compara locomotory behavior Inferred from electronic annotation. Source: Compara lung saccule development Inferred from electronic annotation. Source: Compara menarche Inferred from electronic annotation. Source: Compara 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: Compara 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: Compara oligodendrocyte differentiation Inferred from electronic annotation. Source: Compara phospholipid metabolic process Inferred from electronic annotation. Source: Compara pituitary gland development Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 16960125PubMed 7559607Ref.3. Source: UniProtKB response to hormone stimulus Inferred from expression pattern PubMed 16960125. Source: UniProtKB thyroid gland development Inferred from mutant phenotype Ref.13. Source: UniProtKB
Cellular_component	nucleoplasm Inferred from sequence or structural similarity. Source: UniProtKB transcription factor complex Inferred from electronic annotation. Source: Compara
Molecular_function	RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity Inferred from electronic annotation. Source: Compara sequence-specific DNA binding Inferred from electronic annotation. Source: Compara 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

With	Entry	#Exp.	IntAct	Notes
CCDC59	Q9P031	4	EBI-1391923,EBI-1047110
NCK1	P16333	2	EBI-1391923,EBI-389883

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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 371	371	Homeobox protein Nkx-2.1		PRO_0000049343
Regions
	DNA binding	161 – 220	60	Homeobox
	Compositional bias	234 – 243	10	Poly-Gly
	Compositional bias	246 – 253	8	Poly-Gln
	Compositional bias	294 – 303	10	Poly-Ala
Natural variations
	Alternative sequence	1	1	M → MWSGGSGKARGWEAAAGGRS SPGRLSRRRIM in isoform 3.		VSP_037890
	Natural variant	205	1	V → F in CHNRD. Ref.13		VAR_034906
	Natural variant	208	1	W → L in BHC. Ref.11 Corresponds to variant rs28936672 [ dbSNP | Ensembl ].		VAR_015188
	Natural variant	213	1	R → S in BHC. Ref.11 Corresponds to variant rs28936671 [ dbSNP | Ensembl ].		VAR_015189
Experimental info
	Sequence conflict	49	1	P → H in BAA23527. Ref.5
	Sequence conflict	49	1	P → H in BAA23529. Ref.5
	Sequence conflict	61	1	H → P in BAA23527. Ref.5
	Sequence conflict	61	1	H → P in BAA23529. Ref.5
	Sequence conflict	158	1	S → T in BAA23527. Ref.5
	Sequence conflict	158	1	S → T in BAA23529. Ref.5
	Sequence conflict	161	1	R → G in BAA23527. Ref.5
	Sequence conflict	161	1	R → G in BAA23529. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 1, 1995. Version 1. Checksum: 5F1E3B40A1BBD862	FASTA	371	38,596
	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
	Isoform 3 [UniParc]. Checksum: 40324D55128D4394	FASTA	401	41,737
	10 20 30 40 50 60 MWSGGSGKAR GWEAAAGGRS SPGRLSRRRI MSMSPKHTTP FSVSDILSPL EESYKKVGME 70 80 90 100 110 120 GGGLGAPLAA YRQGQAAPPT AAMQQHAVGH HGAVTAAYHM TAAGVPQLSH SAVGGYCNGN 130 140 150 160 170 180 LGNMSELPPY QDTMRNSASG PGWYGANPDP RFPAISRFMG PASGMNMSGM GGLGSLGDVS 190 200 210 220 230 240 KNMAPLPSAP RRKRRVLFSQ AQVYELERRF KQQKYLSAPE REHLASMIHL TPTQVKIWFQ 250 260 270 280 290 300 NHRYKMKRQA KDKAAQQQLQ QDSGGGGGGG GTGCPQQQQA QQQSPRRVAV PVLVKDGKPC 310 320 330 340 350 360 QAGAPAPGAA SLQGHAQQQA QHQAQAAQAA AAAISVGSGG AGLGAHPGHQ PGSAGQSPDL 370 380 390 400 AHHAASPAAL QGQVSSLSHL NSSGSDYGTM SCSTLLYGRT W

References

	« Hide 'large scale' referencesShow '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. , 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. , 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.

Web resources

GeneReviews

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.
IPI	IPI00472988. IPI00816620.
PIR	G02321.
RefSeq	NP_001073136.1. NM_001079668.2. NP_003308.1. NM_003317.3.
UniGene	Hs.94367.
3D structure databases
ProteinModelPortal	P43699.
ModBase	Search...
Protein-protein interaction databases
IntAct	P43699. 7 interactions.
MINT	MINT-192847.
STRING	9606.ENSP00000346879.
PTM databases
PhosphoSite	P43699.
Polymorphism databases
DMDM	1174819.
Proteomic databases
PaxDb	P43699.
PRIDE	P43699.
Protocols and materials databases
DNASU	7080.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000354822; ENSP00000346879; ENSG00000136352. ENST00000498187; ENSP00000429607; ENSG00000136352. ENST00000518149; ENSP00000428341; ENSG00000136352. ENST00000522719; ENSP00000429519; ENSG00000136352.
GeneID	7080.
KEGG	hsa:7080.
UCSC	uc001wtt.3. human. uc001wtu.3. human.
Organism-specific databases
CTD	7080.
GeneCards	GC14M036985.
HGNC	HGNC:11825. NKX2-1.
HPA	CAB000078.
MIM	118700. phenotype. 600635. gene. 610978. phenotype.
neXtProt	NX_P43699.
Orphanet	95713. Athyreosis. 1429. Benign familial chorea. 209905. Brain-lung-thyroid syndrome. 146. Papillary or follicular thyroid carcinoma. 95720. Thyroid hypoplasia.
PharmGKB	PA36531.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG328614.
HOGENOM	HOG000231923.
HOVERGEN	HBG006689.
InParanoid	P43699.
KO	K09342.
OMA	MRNSASA.
OrthoDB	EOG4V9TSG.
Enzyme and pathway databases
Pathway_Interaction_DB	hnf3bpathway. FOXA2 and FOXA3 transcription factor networks.
Gene expression databases
ArrayExpress	P43699.
Bgee	P43699.
CleanEx	HS_NKX2-1. HS_TTF1.
Genevestigator	P43699.
GermOnline	ENSG00000136352. Homo sapiens.
Family and domain databases
Gene3D	1.10.10.60. 1 hit.
InterPro	IPR017970. Homeobox_CS. IPR020479. Homeobox_metazoa. IPR001356. Homeodomain. IPR009057. Homeodomain-like. [Graphical view]
Pfam	PF00046. Homeobox. 1 hit. [Graphical view]
PRINTS	PR00024. HOMEOBOX.
SMART	SM00389. HOX. 1 hit. [Graphical view]
SUPFAM	SSF46689. Homeodomain_like. 1 hit.
PROSITE	PS00027. HOMEOBOX_1. 1 hit. PS50071. HOMEOBOX_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	7080.
NextBio	27693.
SOURCE	Search...

Entry information

Entry name

NKX21_HUMAN

Accession

Primary (citable) accession number: P43699
Secondary accession number(s): D3DSA3 , O14954, O14955, Q7KZF6, Q9BRJ8

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	November 1, 1995
Last modified:	May 1, 2013
This is version 133 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.