NK2 homeobox 1

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RefSeq (mRNA)



RefSeq (protein)



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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.[1][2]


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.[3]

Clinical significance

File:Lung adenocarcinoma - TTF-1 - high mag.jpg
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.[4][5][6][7]

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.[8]

It is also positive in thyroid cancers and is used for monitoring for metastasis and recurrence.[9]


NK2 homeobox 1 has been shown to interact with Calreticulin[10] and PAX8.[11]


  1. "Entrez Gene: NKX2-1".
  2. 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.
  3. 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. PMC 3629846. PMID 23259454.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.

Further reading

External links

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