NK2 homeobox 1

Not to be confused with transcription termination factor, RNA polymerase I or TTF1.

NKX2-1

Identifiers

NKX2-1, Nkx2-1, AV026640, Nkx2.1, T/EBP, Titf1, Ttf-1, BCH, BHC, NK-2, NKX2A, TEBP, TTF1, NMTC1, NK2 homeobox 1

External IDs

MGI: 108067 HomoloGene: 2488 GeneCards: NKX2-1

Gene ontology
Molecular function	• DNA binding • sequence-specific DNA binding • RNA polymerase II regulatory region sequence-specific DNA binding • core promoter binding • intronic transcription regulatory region DNA binding • transcription factor activity, sequence-specific DNA binding • intronic transcription regulatory region sequence-specific DNA binding • protein binding • enzyme binding • transcription regulatory region DNA binding • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding • RNA polymerase II regulatory region DNA binding
Cellular component	• transcription factor complex • nucleoplasm • nucleus
Biological process	• pattern specification process • cerebral cortex GABAergic interneuron differentiation • developmental induction • Clara cell differentiation • endoderm development • pituitary gland development • Leydig cell differentiation • forebrain neuron fate commitment • regulation of transcription, DNA-templated • locomotory behavior • lung development • rhythmic process • regulation of transcription from RNA polymerase II promoter • anatomical structure formation involved in morphogenesis • forebrain dorsal/ventral pattern formation • oligodendrocyte differentiation • neuron migration • negative regulation of transcription from RNA polymerase II promoter • negative regulation of transforming growth factor beta receptor signaling pathway • globus pallidus development • transcription, DNA-templated • axon guidance • telencephalon cell migration • positive regulation of transcription, DNA-templated • thyroid gland development • brain development • positive regulation of gene expression • negative regulation of cell migration • telencephalon development • forebrain neuron differentiation • animal organ morphogenesis • response to hormone • phospholipid metabolic process • positive regulation of circadian rhythm • forebrain development • cerebral cortex neuron differentiation • neuron fate commitment • Type II pneumocyte differentiation • lung saccule development • negative regulation of transcription, DNA-templated • cerebral cortex cell migration • hippocampus development • epithelial tube branching involved in lung morphogenesis • negative regulation of epithelial to mesenchymal transition • positive regulation of transcription from RNA polymerase II promoter
Sources:Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

Entrez


7080


21869

Ensembl


ENSG00000136352


ENSMUSG00000001496

UniProt


P43699


P50220

RefSeq (mRNA)


NM_001079668 NM_003317


NM_001146198 NM_009385

RefSeq (protein)


NP_001073136.1 NP_003308.1


NP_001139670.1 NP_033411.3

Location (UCSC)

Chr 14: 36.52 – 36.52 Mb

Chr 12: 56.53 – 56.54 Mb

PubMed search

^[1]

^[2]

Wikidata

View/Edit Human

View/Edit Mouse

NK2 homeobox 1 (NKX2-1), also known as thyroid transcription factor 1 (TTF-1), is a protein which in humans is encoded by the NKX2-1 gene.^[3]^[4]

Function

Thyroid transcription factor-1 (TTF-1) is a protein that regulates transcription of genes specific for the thyroid, lung, and diencephalon. It is also known as thyroid specific enhancer binding protein. It is used in anatomic pathology as a marker to determine if a tumor arises from the lung or thyroid. NKX2.1 can be induced by activin A via SMAD2 signaling in a human embryonic stem cell differentiation model.^[5]

Clinical significance

Micrograph of a metastatic lung adenocarcinoma (found in the brain) that exhibits nuclear staining (brown) for TTF-1.

TTF-1 positive cells are found in the lung as type II pneumocytes and club cells. In the thyroid, follicular and parafollicular cells are also positive for TTF-1.

For lung cancers, adenocarcinomas are usually positive, while squamous cell carcinomas and large cell carcinomas are rarely positive. Small cell carcinomas (of any primary site) are usually positive. TTF1 is more than merely a clinical marker of lung adenocarcinoma. It plays an active role in sustaining lung cancer cells in view of the experimental observation that it is mutated in lung cancer.^[6]^[7]^[8]^[9]

However others have found that TTF-1 staining is often positive in pulmonary adenocarcinomas, large cell carcinomas, small-cell lung carcinomas, neuroendocrine tumors other than small-cell lung carcinomas and extrapulmonary small-cell carcinomas.^[10]

It is also positive in thyroid cancers and is used for monitoring for metastasis and recurrence.^[11]

Interactions

NK2 homeobox 1 has been shown to interact with Calreticulin^[12] and PAX8.^[13]

References

↑ "Human PubMed Reference:".
↑ "Mouse PubMed Reference:".
↑ "Entrez Gene: NKX2-1".
↑ Guazzi S, Price M, De Felice M, Damante G, Mattei MG, Di Lauro R (Nov 1990). "Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity". The EMBO Journal. 9 (11): 3631–9. PMC 552115. PMID 1976511.
↑ Li Y, Eggermont K, Vanslembrouck V, Verfaillie CM (May 2013). "NKX2-1 activation by SMAD2 signaling after definitive endoderm differentiation in human embryonic stem cell". Stem Cells and Development. 22 (9): 1433–42. doi:10.1089/scd.2012.0620. PMID 23259454.
↑ Kendall J, Liu Q, Bakleh A, Krasnitz A, Nguyen KC, Lakshmi B, Gerald WL, Powers S, Mu D (Oct 2007). "Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancer". Proceedings of the National Academy of Sciences of the United States of America. 104 (42): 16663–8. doi:10.1073/pnas.0708286104. PMC 2034240. PMID 17925434.
↑ Tanaka H, Yanagisawa K, Shinjo K, Taguchi A, Maeno K, Tomida S, Shimada Y, Osada H, Kosaka T, Matsubara H, Mitsudomi T, Sekido Y, Tanimoto M, Yatabe Y, Takahashi T (Jul 2007). "Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1". Cancer Research. 67 (13): 6007–11. doi:10.1158/0008-5472.CAN-06-4774. PMID 17616654.
↑ Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R, Lin WM, Province MA, Kraja A, Johnson LA, Shah K, Sato M, Thomas RK, Barletta JA, Borecki IB, Broderick S, Chang AC, Chiang DY, Chirieac LR, Cho J, Fujii Y, Gazdar AF, Giordano T, Greulich H, Hanna M, Johnson BE, Kris MG, Lash A, Lin L, Lindeman N, Mardis ER, McPherson JD, Minna JD, Morgan MB, Nadel M, Orringer MB, Osborne JR, Ozenberger B, Ramos AH, Robinson J, Roth JA, Rusch V, Sasaki H, Shepherd F, Sougnez C, Spitz MR, Tsao MS, Twomey D, Verhaak RG, Weinstock GM, Wheeler DA, Winckler W, Yoshizawa A, Yu S, Zakowski MF, Zhang Q, Beer DG, Wistuba II, Watson MA, Garraway LA, Ladanyi M, Travis WD, Pao W, Rubin MA, Gabriel SB, Gibbs RA, Varmus HE, Wilson RK, Lander ES, Meyerson M (Dec 2007). "Characterizing the cancer genome in lung adenocarcinoma". Nature. 450 (7171): 893–8. doi:10.1038/nature06358. PMC 2538683. PMID 17982442.
↑ Kwei KA, Kim YH, Girard L, Kao J, Pacyna-Gengelbach M, Salari K, Lee J, Choi YL, Sato M, Wang P, Hernandez-Boussard T, Gazdar AF, Petersen I, Minna JD, Pollack JR (Jun 2008). "Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer". Oncogene. 27 (25): 3635–40. doi:10.1038/sj.onc.1211012. PMC 2903002. PMID 18212743.
↑ Kalhor N, Zander DS, Liu J (Aug 2006). "TTF-1 and p63 for distinguishing pulmonary small-cell carcinoma from poorly differentiated squamous cell carcinoma in previously pap-stained cytologic material". Modern Pathology. 19 (8): 1117–23. doi:10.1038/modpathol.3800629. PMID 16680154.
↑ Espinoza CR, Schmitt TL, Loos U (Aug 2001). "Thyroid transcription factor 1 and Pax8 synergistically activate the promoter of the human thyroglobulin gene". Journal of Molecular Endocrinology. 27 (1): 59–67. doi:10.1677/jme.0.0270059. PMID 11463576.
↑ Perrone L, Tell G, Di Lauro R (Feb 1999). "Calreticulin enhances the transcriptional activity of thyroid transcription factor-1 by binding to its homeodomain". The Journal of Biological Chemistry. 274 (8): 4640–5. doi:10.1074/jbc.274.8.4640. PMID 9988700.
↑ Di Palma T, Nitsch R, Mascia A, Nitsch L, Di Lauro R, Zannini M (Jan 2003). "The paired domain-containing factor Pax8 and the homeodomain-containing factor TTF-1 directly interact and synergistically activate transcription". The Journal of Biological Chemistry. 278 (5): 3395–402. doi:10.1074/jbc.M205977200. PMID 12441357.

External links

TITF1 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

PDB gallery

1ftt: THYROID TRANSCRIPTION FACTOR 1 HOMEODOMAIN (RATTUS NORVEGICUS)

Transcription factors and intracellular receptors

(1) Basic domains

(1.1) Basic leucine zipper (bZIP)	Activating transcription factor AATF 1 2 3 4 5 6 7 AP-1 c-Fos FOSB FOSL1 FOSL2 JDP2 c-Jun JUNB JunD BACH 1 2 BATF BLZF1 C/EBP α β γ δ ε ζ CREB 1 3 L1 CREM DBP DDIT3 GABPA HLF MAF B F G K NFE 2 L1 L2 L3 NFIL3 NRL NRF 1 2 3 XBP1

(1.2) Basic helix-loop-helix (bHLH)	ATOH1 AhR AHRR ARNT ASCL1 BHLH 2 3 9 ARNTL ARNTL ARNTL2 CLOCK EPAS1 FIGLA HAND 1 2 HES 5 6 HEY 1 2 L HES1 HIF 1A 3A ID 1 2 3 4 LYL1 MESP2 MXD4 MYCL1 MYCN Myogenic regulatory factors MyoD Myogenin MYF5 MYF6 Neurogenins 1 2 3 NeuroD 1 2 NPAS 1 2 3 OLIG 1 2 Pho4 Scleraxis SIM 1 2 TAL 1 2 Twist USF1

(1.3) bHLH-ZIP	AP-4 MAX MXD3 MITF MNT MLX MXI1 Myc SREBP 1 2

(1.4) NF-1	NFI A B C X SMAD R-SMAD 1 2 3 5 9 I-SMAD 6 7 4)

(1.5) RF-X	RFX 1 2 3 4 5 6 ANK

(1.6) Basic helix-span-helix (bHSH)	AP-2 α β γ δ ε

(2) Zinc finger DNA-binding domains

(2.1) Nuclear receptor (Cys₄)

subfamily 1	Thyroid hormone α β CAR FXR LXR α β PPAR α β/δ γ PXR RAR α β γ ROR α β γ Rev-ErbA α β VDR

subfamily 2	COUP-TF (I II Ear-2 HNF4 α γ PNR RXR α β γ Testicular receptor 2 4 TLX

subfamily 3	Steroid hormone Androgen Estrogen α β Glucocorticoid Mineralocorticoid Progesterone Estrogen related α β γ

subfamily 4	NUR NGFIB NOR1 NURR1

subfamily 5	LRH-1 SF1

subfamily 6	GCNF

subfamily 0	DAX1 SHP

(2.2) Other Cys₄

GATA
- 1
- 2
- 3
- 4
- 5
- 6
MTA
- 1
- 2
- 3
TRPS1

(2.3) Cys₂His₂

General transcription factors
- TFIIA
- TFIIB
- TFIID
- TFIIE
  - 1
  - 2
- TFIIF
- 1
- 2
  - TFIIH
  - 1
  - 2
  - 4
  - 2I
  - 3A
  - 3C1
  - 3C2

ATBF1
BCL
- 6
- 11A
- 11B
CTCF
E4F1
EGR
- 1
- 2
- 3
- 4
ERV3
GFI1
GLI-Krüppel family
- 1
- 2
- 3
- REST
- S1
- S2
- YY1
HIC
- 1
- 2
HIVEP
- 1
- 2
- 3
IKZF
- 1
- 2
- 3
ILF
- 2
- 3
KLF
- 1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 9
- 10
- 11
- 12
- 13
- 14
- 15
- 17
MTF1
MYT1
OSR1
PRDM9
SALL
- 1
- 2
- 3
- 4
SP
- 1
- 2
- 4
- 7
- 8
TSHZ3
WT1
Zbtb7
- 7A
- 7B
ZBTB
- 11
- 16
- 17
- 20
- 32
- 33
- 40
zinc finger
- 3
- 7
- 9
- 10
- 19
- 22
- 24
- 33B
- 34
- 35
- 41
- 43
- 44
- 51
- 74
- 143
- 146
- 148
- 165
- 202
- 217
- 219
- 238
- 239
- 259
- 267
- 268
- 281
- 295
- 300
- 318
- 330
- 346
- 350
- 365
- 366
- 384
- 423
- 451
- 452
- 471
- 593
- 638
- 644
- 649
- 655

(2.4) Cys₆

HIVEP1

(2.5) Alternating composition

AIRE
DIDO1
GRLF1
ING
- 1
- 2
- 4
JARID
- 1A
- 1B
- 1C
- 1D
- 2
JMJD1B

(2.6) WRKY

WRKY

(3) Helix-turn-helix domains

(3.1) Homeodomain	ARX CDX 1 2 CRX CUTL1 DBX 1 2 DLX 3 4 5 EMX 1 2 EN 1 2 FHL 1 2 3 HESX1 HHEX HLX Homeobox A1 A2 A3 A4 A5 A7 A9 A10 A11 A13 B1 B2 B3 B4 B5 B6 B7 B8 B9 B13 C4 C5 C6 C8 C9 C10 C11 C12 C13 D1 D3 D4 D8 D9 D10 D11 D12 D13 HOPX IRX 1 2 3 4 5 6 MKX LMX 1A 1B MEIS 1 2 MEOX2 MNX1 MSX 1 2 NANOG NKX 2-1 2-2 2-3 2-5 3-1 3-2 6-1 6-2 NOBOX PBX 1 2 3 PHF 1 3 6 8 10 16 17 20 21A PHOX 2A 2B PITX 1 2 3 POU domain PIT-1 BRN-3: A B C Octamer transcription factor: 1 2 3/4 6 7 11 OTX 1 2 PDX1 SATB2 SHOX2 SIX 1 2 3 4 5 VAX1 ZEB 1 2

(3.2) Paired box	PAX 1 2 3 4 5 6 7 8 9 PRRX 1 2 RAX

(3.3) Fork head / winged helix	E2F 1 2 3 4 5 FOX proteins A1 A2 A3 C1 C2 D3 D4 E1 E3 F1 G1 H1 I1 J1 J2 K1 K2 L2 M1 N1 N3 O1 O3 O4 P1 P2 P3 P4

(3.4) Heat shock factors	HSF 1 2 4

(3.5) Tryptophan clusters	ELF 2 4 5 EGF ELK 1 3 4 ERF ETS 1 2 ERG SPIB ETV 1 4 5 6 FLI1 Interferon regulatory factors 1 2 3 4 5 6 7 8 MYB MYBL2

(3.6) TEA domain	transcriptional enhancer factor 1 2 3 4

(4) β-Scaffold factors with minor groove contacts

(4.1) Rel homology region	NF-κB NFKB1 NFKB2 REL RELA RELB NFAT C1 C2 C3 C4 5

(4.2) STAT	STAT 1 2 3 4 5 6

(4.3) p53	p53 TBX 1 2 3 5 19 21 22 TBR1 TBR2 TFT MYRF TP63

(4.4) MADS box	Mef2 A B C D SRF

(4.6) TATA-binding proteins	TBP TBPL1

(4.7) High-mobility group	BBX HMGB 1 2 3 4 HMGN 1 2 3 4 HNF 1A 1B LEF1 SOX 1 2 3 4 5 6 8 9 10 11 12 13 14 15 18 21 SRY SSRP1 TCF 3 4 TOX 1 2 3 4

(4.9) Grainyhead	TFCP2

(4.10) Cold-shock domain	CSDA YBX1

(4.11) Runt	CBF CBFA2T2 CBFA2T3 RUNX1 RUNX2 RUNX3 RUNX1T1

(0) Other transcription factors

(0.2) HMGI(Y)	HMGA 1 2 HBP1

(0.3) Pocket domain	Rb RBL1 RBL2

(0.5) AP-2/EREBP-related factors	Apetala 2 EREBP B3

(0.6) Miscellaneous	ARID 1A 1B 2 3A 3B 4A CAP IFI 16 35 MLL 2 3 T1 MNDA NFY A B C Rho/Sigma

see also transcription factor/coregulator deficiencies

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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