Affinage

Showing NKX2-1 — TTF-1 is a alias.

NKX2-1

Homeobox protein Nkx-2.1 · UniProt P43699

Length
371 aa
Mass
38.6 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NKX2-1 (TTF-1) is a homeodomain transcription factor that serves as a master regulator of lung epithelial morphogenesis and differentiation, required for septation of the anterior foregut into trachea and esophagus, for branching morphogenesis, and for surfactant protein expression (PMID:10208743, PMID:8612983). It executes this program by directly binding cis-elements in target promoters: it activates lung-differentiation and morphogenesis genes including BMP4 (PMID:14960358), midkine (PMID:12761850), and surfactant protein C (PMID:14970209), while directly repressing Efnb2 in tracheal endoderm to enable EPH/EPHRIN-mediated cell sorting during tracheoesophageal separation (PMID:35294885). Its transcriptional output is shaped by combinatorial partners—it cooperates with TAZ to synergize on SP-C (PMID:14970209), with PAX8 on thyroid genes (PMID:16507635), and is guided to appropriate genomic loci by FOXA1/2, whose loss causes NKX2-1 mislocalization (PMID:35835117, PMID:17220277); PRDM3/16 act as co-activators that open chromatin at NKX2-1 targets to drive alveolar type 2 cell differentiation (PMID:39284798), and FOXO1 binding to the homeodomain disrupts NKX2-1 occupancy at SFTPC to toggle alveolar epithelial fate (PMID:35406686). NKX2-1 expression is itself induced via Activin/SMAD2 signaling onto its promoter (PMID:23259454) and is reinforced by a cis-acting lncRNA feedback loop (PMID:28546511). Beyond the lung, NKX2-1 specifies cortical interneuron fate by directly activating Lhx6 (PMID:18339674) and controls telencephalic astrogliogenesis via the GFAP promoter (PMID:28266561). In cancer it acts as an amplified lineage-survival oncogene in lung adenocarcinoma (PMID:18212743), inducing ROR1-dependent prosurvival PI3K-AKT signaling (PMID:22439932), while its loss unleashes ERK hyperactivation through downregulation of the phosphatase DUSP6 (PMID:34689179), promotes chemokine-driven neutrophil recruitment by derepressing CXCL1/2/5 (PMID:39113226), and drives metastasis and gastric transdifferentiation cooperatively with FOXA2/CDX2 loss (PMID:26341558, PMID:33821796). NKX2-1 also exerts a non-transcriptional function by binding DDB1 to protect CHK1 from ubiquitylation, conferring replication-stress resistance (PMID:28192407).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1995 Medium

    Established that NKX2-1 is functionally required for lung epithelial morphogenesis rather than merely a marker, answering whether the factor drives branching.

    Evidence Antisense oligonucleotide suppression in embryonic mouse lung explants

    PMID:8612983

    Open questions at the time
    • Did not identify direct transcriptional targets
    • Antisense approach lacks genetic specificity
  2. 1999 High

    Genetic knockout defined the full developmental requirement for NKX2-1 in foregut septation, branching, and epithelial differentiation, linking loss to reduced Bmp4 as a mechanistic clue.

    Evidence Homozygous targeted disruption in mice with in situ hybridization and phenotyping

    PMID:10208743

    Open questions at the time
    • Direct binding to target promoters not yet demonstrated
    • Did not resolve which targets account for each phenotype
  3. 2003 Medium

    Identified direct transcriptional targets in lung (midkine, BMP4) establishing NKX2-1 as a sequence-specific activator of differentiation/morphogenesis genes.

    Evidence Promoter-reporter assays and null mouse analysis; binding-site identification

    PMID:12761850 PMID:14960358

    Open questions at the time
    • Endogenous occupancy by ChIP not shown for all targets
    • Cofactor requirements undefined
  4. 2004 Medium

    Revealed combinatorial control by identifying physical co-regulators (TAZ activates, PAX8 synergy required for thyroid genes), explaining promoter-specific output.

    Evidence Mammalian two-hybrid, GST pull-down, reporter assays; mutant analysis in patient context

    PMID:14970209 PMID:16507635

    Open questions at the time
    • Structural basis of interactions not resolved
    • Stoichiometry and genome-wide co-binding unknown
  5. 2007 High

    Showed that partner binding can inhibit NKX2-1, as FOXA1 masks the homeodomain DNA-binding surface in a promoter-context-dependent manner.

    Evidence Co-IP, GST pull-down, EMSA, siRNA, reporter assays with deletion mapping

    PMID:17220277

    Open questions at the time
    • In vivo relevance of masking versus genomic guidance not yet distinguished
  6. 2008 High

    Extended NKX2-1 function to neural lineage specification (cortical interneurons via Lhx6) and established it as an amplified lineage-survival oncogene in lung cancer.

    Evidence ChIP and functional rescue in Nkx2.1-/- slices; genomic profiling with siRNA proliferation/cell-cycle assays

    PMID:18212743 PMID:18339674

    Open questions at the time
    • Oncogenic downstream effectors not yet identified
    • Mechanism of survival dependency undefined at the time
  7. 2012 Medium

    Placed NKX2-1 in cancer signaling and metastasis circuits—inducing ROR1-PI3K-AKT survival signaling while also activating tight-junction genes that suppress anoikis and metastasis.

    Evidence ROR1 knockdown and signaling analysis; ChIP, reporter, siRNA, anoikis/migration assays

    PMID:22439932 PMID:22761434

    Open questions at the time
    • Context dependence of pro- versus anti-tumor roles unresolved
    • Single-lab signaling placements
  8. 2013 Medium

    Identified an upstream inductive signal: Activin/GDF11 via ALK4-SMAD2 directly activates the NKX2-1 promoter in definitive endoderm.

    Evidence hESC differentiation, SMAD2 phosphorylation, ChIP at NKX2-1 promoter, pathway inhibition

    PMID:23259454

    Open questions at the time
    • Cofactors at the NKX2-1 promoter not defined
    • Specificity for endoderm versus other lineages untested
  9. 2012 High

    Genome-wide and genetic studies showed NKX2-1 haploinsufficiency cooperates with oncogenic Kras to drive mucinous adenocarcinoma and that NKX2-1 inhibits AP-1 at shared binding elements.

    Evidence Transgenic mouse model with ChIP-seq and AP-1 reporter/colony assays

    PMID:23143308

    Open questions at the time
    • Mechanism of AP-1 antagonism at the chromatin level not fully resolved
  10. 2015 Medium

    Connected NKX2-1 to p53/NF-kB and to multi-factor metastasis suppression, showing loss of NKX2-1 with FOXA2 and CDX2 jointly licenses metastatic identity.

    Evidence Reporter/ChIP for p53-IKKβ axis; triple knockdown with in vivo metastasis and expression profiling

    PMID:25881545 PMID:26341558

    Open questions at the time
    • Direct versus indirect contributions of each factor not separated
    • p53-status dependence adds context complexity
  11. 2017 Medium

    Uncovered a non-transcriptional function: NKX2-1 binds DDB1 to block CHK1 ubiquitylation and confer replication-stress resistance, broadening its mechanistic repertoire beyond transcription.

    Evidence MS interactome, co-IP, replication-stress assays (pCHK2, γH2AX)

    PMID:28192407

    Open questions at the time
    • Structural basis of DDB1 competition unresolved
    • Physiological contexts where this dominates unclear
  12. 2017 High

    Defined autoregulatory and co-activator layers controlling NKX2-1 dosage and chromatin access in lung—NANCI lncRNA feedback, PRDM3/16 co-activation, and YAP1/TAZ-MOB1 axis for AT2 differentiation.

    Evidence Mouse genetic epistasis, conditional KO, scRNA-seq, ATAC-seq, CUT&RUN

    PMID:28266561 PMID:28346423 PMID:28546511 PMID:39284798

    Open questions at the time
    • Direct biochemical interaction of PRDM3/16 with NKX2-1 versus chromatin-level cooperation needs further dissection
  13. 2021 Medium

    Cell-type-specific ChIP-seq and partner mapping revealed that NKX2-1 rewires its genomic binding and partners across tumor lineages, co-occupying enhancers with ASCL1, SOX1, and PROX1 in SCLC to enforce neuroendocrine identity.

    Evidence ChIP-seq/RNA-seq comparison, co-IP/MS, CRISPR deletion, xenografts

    PMID:31782890 PMID:34466783 PMID:35848993

    Open questions at the time
    • Determinants of lineage-specific binding redistribution incompletely defined
    • Direct versus assisted recruitment to E-box regions unclear
  14. 2021 High

    Resolved how NKX2-1 loss promotes tumor progression—derepressing CXCL chemokines to recruit neutrophils, downregulating DUSP6 to unleash ERK, conferring Wnt dependency, and enabling targeted-therapy escape via gastric identity switching.

    Evidence ATAC-seq, syngeneic models, xenografts/GEMs, organoid CRISPR engineering, inhibitor treatments

    PMID:33821796 PMID:34689179 PMID:35835117 PMID:36870059 PMID:39113226

    Open questions at the time
    • Hierarchy among these loss-driven programs not established
    • Reversibility of identity switching in patients untested
  15. 2022 Medium

    Identified a metabolic output of NKX2-1: direct activation of serine/glycine synthesis enzymes that supports proliferation under nutrient depletion.

    Evidence ChIP-qPCR, metabolomics, overexpression/knockdown, mouse tumor models

    PMID:36932191

    Open questions at the time
    • Whether this drives tumor aggressiveness in patients is untested
    • Interplay with lineage program unclear
  16. 2025 High

    Demonstrated a pioneer-factor-driven mechanism in neuroendocrine prostate cancer where FOXA2 induces NKX2-1, which then drives 3D chromatin remodeling and p300/CBP recruitment to enforce neuroendocrine transformation.

    Evidence Hi-C, ChIP-seq, ATAC-seq, bisulfite-seq, co-IP, in vivo p300/CBP inhibition

    PMID:40691407

    Open questions at the time
    • Generalizability of looping mechanism to other lineages untested
    • Direct contribution of NKX2-1 promoter-binding to looping not fully isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NKX2-1's combinatorial partner code and chromatin context determine its switch between activator and repressor, and between tumor-suppressive and oncogenic output, remains unresolved.
  • No unified model linking partner identity to activator/repressor mode
  • Structural basis of homeodomain masking versus genomic guidance unknown
  • Determinants of lineage-specific genomic redistribution undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-1643685 Disease 5 R-HSA-74160 Gene expression (Transcription) 5
Partners
ASCL1DDB1FOXA1FOXA2FOXO1PAX8SOX1TAZ

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 TTF-1/NKX2-1 is required for lung epithelial morphogenesis; antisense oligonucleotide suppression of TTF-1 translation in embryonic mouse lung explants inhibited branching morphogenesis, producing hyperplastic, unorganized epithelial cell proliferation without affecting the mesenchymal compartment. Antisense oligonucleotide inhibition in embryonic mouse lung branching morphogenesis model Developmental biology Medium 8612983
1999 NKX2-1 is required for septation of the anterior foregut into trachea and esophagus, for lung branching morphogenesis, and for pulmonary epithelial cell differentiation (including surfactant protein gene expression); Nkx2.1-/- mice form a common tracheoesophageal lumen, have hypoplastic lungs arrested at pseudoglandular stage, and lack surfactant protein expression. Reduced Bmp-4 expression in mutant lung epithelium provides a mechanistic clue for impaired branching. Homozygous targeted gene disruption in mice with in situ hybridization and phenotypic analysis Developmental biology High 10208743
2000 Two functionally distinct isoforms of NKX2.1 are expressed in pulmonary epithelium: a 371 aa major isoform and a 401 aa minor isoform with a 30 aa N-terminal extension. The longer isoform exhibits reduced transactivation activity on the SP-C promoter compared to the shorter major isoform, as demonstrated by site-directed mutagenesis suggesting the 30 aa extension causes steric interference. In vitro transcription/translation, co-transfection reporter assays, site-directed mutagenesis Biochemical and biophysical research communications Medium 10753648
2003 TTF-1/NKX2-1 directly activates transcription of the midkine (MK) gene in lung epithelium by acting on TTF-1 regulatory elements in the 5' region of the MK gene promoter; MK expression was absent in TTF-1 null mouse lungs. Promoter-reporter transfection assays, TTF-1 null mouse analysis Developmental dynamics Medium 12761850
2004 TAZ (transcriptional co-activator with PDZ-binding motif) directly interacts with the NH2-terminal domain of TTF-1/NKX2-1 and synergistically activates expression of surfactant protein C (SP-C) in the presence of TTF-1, as shown by pull-down and mammalian two-hybrid assays. Mammalian two-hybrid assay, GST pull-down, co-transfection reporter assays, deletion analysis The Journal of biological chemistry Medium 14970209
2004 NKX2-1 directly regulates transcription of the BMP4 gene in lung epithelial cells through specific cis-active NKX2.1-responsive elements on both BMP4 promoters (hBmp4.1 and hBmp4.2); DNA-binding was confirmed by co-transfection assays identifying specific binding sequences. Co-transfection reporter assays in lung epithelial cells, identification of NKX2.1 binding sites Gene Medium 14960358
2004 TTF-1/NKX2-1 binds the RET promoter at a specific site, and activates RET transcription; HSCR-associated RET promoter SNPs overlapping this TTF-1 binding site decrease TTF-1-activated RET transcription. A Gly322Ser TTF-1 mutation found in an HSCR patient compromises activation of transcription from HSCR-associated RET promoter haplotypes. Luciferase reporter assays, EMSA/binding assays, patient mutation analysis Human molecular genetics Medium 15548547
2006 A C-terminal domain deletion mutation of TTF-1/NKX2-1 (825delC) produces a protein with diminished DNA binding that fails to activate Tg, TPO, or SP-B reporter genes. This mutant has a dominant-negative effect specifically on Tg and TPO but not SP-B transcription, and impairs wild-type TTF-1's synergy with PAX8 (which is required for Tg and TPO but not SP-B transcription). The mutant protein does not compete with wild-type for coactivators. EMSA, transfection reporter assays, Gal4 reporter system, expression vector analysis The Journal of clinical endocrinology and metabolism Medium 16507635
2007 NKX2.1 physically and functionally interacts with FOXA1 through the NKX2.1 homeodomain in a DNA-independent manner. This interaction is inhibitory on the SP-C promoter (which lacks a FOXA1 binding site), where FOXA1 attenuates NKX2.1-dependent transcription by masking the homeodomain DNA-binding function. On the Ccsp promoter (which has both binding sites), FOXA1 and NKX2.1 additively activate transcription. Co-IP, GST pull-down, EMSA, siRNA knockdown, co-transfection reporter assays Molecular and cellular biology High 17220277
2007 TTF-1 directly activates transcription of growth hormone and prolactin genes in the anterior pituitary; TTF-1 inhibited growth hormone transcription but activated prolactin transcription through direct binding to TTF-1 binding motifs in their respective promoters. Deletion of these motifs abolished the regulatory effects. In situ hybridization, co-transfection reporter assays, deletion analysis in pituitary cell line Biochemical and biophysical research communications Medium 17706597
2008 NKX2.1 directly binds a highly conserved sequence in the Lhx6 promoter and activates Lhx6 expression, thereby specifying parvalbumin- and somatostatin-expressing cortical interneuron fate in the medial ganglionic eminence. Rescue of NKX2.1 expression in Nkx2.1-/- slices induced Lhx6; gain- and loss-of-function of Lhx6 were sufficient/necessary to rescue interneuron phenotypes. Electroporation of cDNA into slice cultures from Nkx2.1-/- embryos, transplantation into neonatal cortex, ChIP, promoter binding assay, gain/loss-of-function Development (Cambridge, England) High 18339674
2008 TTF-1/NKX2-1 directly binds and transcriptionally upregulates the nestin gene in vivo through the NestBS (HRE/CRE-like) site within the CNS-specific nestin enhancer; transgenic mouse analysis confirmed this regulation requires the NestBS site. Transgenic mouse reporter assay, binding site analysis The International journal of developmental biology Medium 18033672
2008 TITF1/NKX2-1 is a lineage-specific oncogene amplified at 14q13.3 in lung cancer; siRNA-mediated knockdown of TITF1 in amplified lung cancer cell lines reduced cell proliferation by decreasing cell-cycle progression and increasing apoptosis. Genomic profiling of 128 cell lines/tumors, siRNA knockdown with proliferation and cell-cycle assays Oncogene Medium 18212743
2009 Nkx2-1 acts cooperatively with Phox2b and Sox10 (but not Pax3) to mediate RET transcription in the enteric nervous system, as demonstrated by dual-luciferase reporter studies identifying the Phox2b-responsive region in the RET promoter. Dual-luciferase reporter assay, immunohistochemistry Journal of pediatric surgery Low 19853745
2009 Epigenetic silencing of TTF-1/NKX2-1 in undifferentiated thyroid carcinomas occurs through DNA hypermethylation of CpG islands in the TTF-1 promoter and reduced acetylation of histone H3-lys9; DNA demethylating agents restore TTF-1 expression in thyroid carcinoma cell lines. Methylation-specific PCR, chromatin immunoprecipitation (ChIP), 5-aza-deoxycytidine treatment Laboratory investigation Medium 19506552
2010 TTF-1/NKX2-1 directly activates transcription of the α5 nicotinic acetylcholine receptor (CHRNA5) subunit gene by binding specific TTF-1 response elements in both the 2.0-kb and 850-bp α5 promoters; site-directed mutagenesis of these elements abolished activation. Reporter assays, site-directed mutagenesis, exogenous TTF-1 expression in lung epithelial cell lines Respiratory research Medium 21143907
2012 NKX2-1/TTF-1 induces expression of the receptor tyrosine kinase-like orphan receptor ROR1, which sustains prosurvival PI3K-AKT signaling over pro-apoptotic p38 signaling in lung adenocarcinoma, via ROR1 kinase-dependent c-Src activation and kinase-independent sustainment of EGFR-ERBB3 association and ERBB3 phosphorylation. ROR1 knockdown in lung cancer cell lines, signaling pathway analysis (PI3K-AKT, p38), EGFR status evaluation Cancer cell Medium 22439932
2012 TTF-1/NKX2-1 directly transactivates the tight junction molecules occludin (OCLN) and claudin-1 (CLDN1) through direct interaction with their promoters; TTF-1 knockdown down-regulated occludin, conferred resistance to anoikis, and occludin restoration reversed this effect, establishing TTF-1-mediated occludin expression as a mechanism of metastasis suppression. ChIP, promoter reporter assays, siRNA knockdown, anoikis assay, migration assay The Journal of biological chemistry Medium 22761434
2012 NKX2-1 haploinsufficiency combined with oncogenic KrasG12D (but not EGFRL858R) causes mucinous adenocarcinoma of the lung in mice; NKX2-1 inhibits AP-1 activity and tumor colony formation in vitro. ChIP-seq identified direct association of NKX2-1 with genes induced in mucinous tumors at both AP-1 and canonical NKX2-1 binding elements. Transgenic mouse model, ChIP-seq, in vitro tumor colony formation, AP-1 reporter assay The Journal of clinical investigation High 23143308
2015 NKX2-1 directly regulates p53 transcription; NKX2-1-elevated wild-type p53 down-regulates IKKβ transcription via decreased Sp1 binding to IKKβ promoter, while NKX2-1 with mutant p53 up-regulates IKKβ via mutant p53/NF-Y complex, modulating NF-κB activation and EMT in lung adenocarcinoma in a p53-status-dependent manner. Promoter reporter assays, ChIP for Sp1 binding, xenograft tumor formation, soft-agar assay Oncotarget Medium 25881545
2015 Loss of NKX2-1, FOXA2, and CDX2 together (but not individually) synergistically promotes the metastatic potential of non-metastatic lung adenocarcinoma cells to the level of naturally arising metastatic cells in vivo, and is sufficient to account for a significant fraction of gene expression differences between metastatic and non-metastatic states, including upregulation of Tks5long, Hmga2, and Snail. Triple knockdown, in vivo transplant metastasis assay, gene expression profiling Genes & development Medium 26341558
2017 TTF-1/NKX2-1 interacts with DDB1 (damage-specific DNA binding protein 1) and blocks DDB1 binding to CHK1, thereby attenuating ubiquitylation and subsequent degradation of CHK1. TTF-1 overexpression conferred resistance to DNA replication stress and prevented DNA double-strand breaks (reduced pCHK2 and γH2AX), revealing a non-transcriptional function of TTF-1. Global proteomic interaction screen (MS), co-IP, functional replication stress assays (pCHK2, γH2AX) Oncogene Medium 28192407
2017 Nkx2.1 directly inhibits NANCI (a cis-acting lncRNA at the same locus) while NANCI in turn promotes Nkx2.1 transcription in cis, forming a feedback loop. Combined heterozygous mutations in both NANCI and Nkx2.1 produce persistent Nkx2.1 deficiency and reprogramming of lung epithelial cells to a posterior endoderm fate, impaired innate immunity, and progressive lung degeneration. Mouse genetic models, concurrent heterozygous mutations, lung epithelial fate analysis Genes & development Medium 28546511
2017 Nkx2.1 binds the GFAP promoter to regulate its expression, thereby controlling astrogliogenesis in the telencephalon; Nkx2.1-/- mice show drastic loss of astrocytes from impaired proliferation and possibly glial specification/differentiation of ventral neural stem cells. ChIP, co-transfection reporter assay, BrdU proliferation assay, neurosphere assay, knockout mouse analysis Scientific reports Medium 28266561
2017 MOB1A/B loss in bronchioalveolar epithelium causes impaired YAP1/TAZ-dependent differentiation and decreased NKX2-1-dependent surfactant protein production. YAP1/TAZ-NKX2.1 axis controls expression of collagen XVII (a hemidesmosome component required for alveolar stem cell niche maintenance); loss of MOB1 decreases collagen XVII expression through this axis. Conditional knockout mouse model, bronchioalveolar epithelium-specific deletion, cell differentiation and adhesion assays Oncogene Medium 28346423
2019 TTF-1/NKX2-1 binding profiles in SCLC vs. lung adenocarcinoma differ substantially (75% distinct binding regions); in SCLC, TTF-1 binds regions enriched for E-box motifs and co-occupies adjacent sites with ASCL1 to cooperatively regulate neuroendocrine and anti-apoptotic (Bcl-2 family) gene expression, whereas in LADC the binding profile and transcriptional targets differ. ChIP-seq, RNA-seq comparison between SCLC and LADC cell lines Molecular oncology Medium 31782890
2021 NKX2-1 induces the ERK phosphatase DUSP6, which inactivates ERK; loss of NKX2-1 in late-stage lung adenocarcinoma downregulates DUSP6 and unleashes ERK hyperactivation. Re-introduction of NKX2-1 in NKX2-1-silenced tumor cells induced DUSP6 and inhibited tumor growth and metastasis. DUSP6 is necessary for NKX2-1-mediated inhibition of tumor progression in vivo. Human tissue samples and cell lines, xenografts, genetic mouse models, in vivo rescue experiments Oncogene High 34689179
2021 NKX2-1 directly inhibits the CXCL1, CXCL2, and CXCL5 promoters, as demonstrated by ATAC-seq; NKX2-1 depletion triggers secretion of these chemokines, recruiting tumor-promoting neutrophils via CXCLs/CXCR2 signaling to promote lung adenocarcinoma progression. ATAC-seq, chemokine array, qRT-PCR, syngeneic mouse model, CXCR2 antagonist treatment Advanced science Medium 39113226
2021 In NKX2-1-positive lung adenocarcinoma, FoxA1/2 loss leads to aberrant NKX2-1 activity and genomic mislocalization, which actively inhibits tumorigenesis and drives alternative non-proliferative cellular identity programs; FoxA1/2 normally guides NKX2-1 to appropriate genomic loci to maintain a dual pulmonary-gastrointestinal identity state. FoxA1/2 knockout in KRAS-driven mouse models and human cell lines, ChIP-seq for NKX2-1 localization Developmental cell Medium 35835117
2021 PRDM3 and PRDM16 (histone methyltransferases) regulate chromatin accessibility at NKX2-1 transcriptional targets critical for alveolar type 2 (AT2) cell differentiation and surfactant homeostasis; combined deletion of Prdm3/16 in lung endoderm causes perinatal respiratory failure from loss of AT2 cells. PRDM3/16 act as NKX2-1 co-activators, and their loss leads to AT2 cells acquiring partial AT1 fate. Conditional knockout mice, single-cell RNA-seq, bulk ATAC-seq, CUT&RUN Nature communications High 39284798
2021 YAP participates with KLF5, NFIB, and NKX2-1 to regulate AGER expression in alveolar epithelial cells; YAP activation increased AT1 cell numbers and altered differentiation via this transcriptional network, while YAP deletion increased mature AT2 cell gene expression. Transgenic mice with YAP activation or deletion, motif enrichment analysis, promoter accessibility assays iScience Low 34466790
2021 In SCLC, NKX2-1 co-immunoprecipitates with SOX1 as a functional transcriptional partner to maintain neural lineage identity in the SCLC-Aα subtype; NKX2-1 CRISPR deletion inhibited SCLC-Aα cell growth and induced apoptosis; a super-enhancer at the NKX2-1 locus drives its expression in this subtype. ChIP-seq, co-immunoprecipitation followed by mass spectrometry, CRISPR-Cas9 deletion, xenograft American journal of respiratory and critical care medicine Medium 35848993
2021 In ASCL1-high SCLC, NKX2-1 complexes with ASCL1 and PROX1 to co-occupy super-enhancers and co-regulate genes in NOTCH signaling, catecholamine biosynthesis, and cell cycle; ASCL1 depletion demonstrated its role as a key dependency factor. ChIP-seq, chromatin landscape analysis, co-immunoprecipitation, ASCL1 depletion iScience Medium 34466783
2021 NKX2-1 directly represses Efnb2 (Ephrin-B2) in tracheal endoderm, as demonstrated by ChIP and reporter assays; NKX2-1 loss causes expansion of Efnb2 expression, disrupts EPH/EPHRIN-mediated cell sorting, and causes tracheoesophageal separation failure with misallocation of ventral foregut cells into the esophagus. ChIP, reporter assays, lineage tracing, genetic loss-of-function mouse model Cell reports High 35294885
2021 NKX2-1 loss of function confers Wnt dependency in lung adenocarcinoma regardless of EGFR mutation status; gene engineering of alveolar organoids demonstrated that constitutive EGFR-RAS signaling provides Wnt independence, while NKX2-1 loss overrides this to restore Wnt dependency. Patient-derived organoid biobank, CRISPR gene engineering, phenotypic screening of niche factor dependency Cell reports Medium 36870059
2022 In NKX2-1-deficient BRAFV600E-driven lung adenocarcinoma, BRAF/MEK inhibitors fail to drive tumor cells into quiescence (unlike NKX2-1-positive cells) and instead induce cell identity switching within the gastric lineage, driven partly by WNT signaling and FoxA1/2. An NKX2-1/ERK/WNT feedback loop exists where NKX2-1 modulates response to targeted therapy. NKX2-1 deletion in BRAFV600E mouse model, BRAF/MEK inhibitor treatment, cell cycle and identity analysis eLife Medium 33821796
2023 NKX2-1 directly binds and transcriptionally upregulates serine/glycine synthesis enzyme genes (PHGDH, PSAT1, PSPH, SHMT2), enabling NKX2-1-expressing cells to proliferate and invade under serine/glycine depletion. NKX2-1-driven serine/glycine synthesis generates nucleotides and redox molecules, alters cellular lipidome and methylome, and NKX2-1 tumor-bearing mice show enhanced tumor aggressiveness. ChIP-qPCR, immunoblotting, mass spectrometry metabolomics, NKX2-1 overexpression/knockdown, mouse tumor models British journal of cancer Medium 36932191
2025 In neuroendocrine prostate cancer, FOXA2 pioneer factor binding at NE enhancers initiates DNA demethylation and induces NKX2-1 expression. NKX2-1 then preferentially binds gene promoters and interacts with enhancer-bound FOXA2 through chromatin looping to drive 3D chromatin remodeling and luminal-to-neuroendocrine transformation. NKX2-1/FOXA2 recruit p300/CBP to activate NE enhancers; pharmacological p300/CBP inhibition blunts NE gene expression and abolishes NEPC tumor growth. Hi-C/3D chromatin sequencing, isogenic cell lines for NE transformation, ChIP-seq, ATAC-seq, bisulfite sequencing, co-IP, p300/CBP inhibitor treatment in vivo Nature genetics High 40691407
2013 Activin-A induces NKX2-1 expression in hESC-derived definitive endoderm through ALK4 receptor-mediated SMAD2 phosphorylation; phospho-SMAD2 directly binds to the NKX2-1 promoter and activates its transcription. GDF11 can substitute for Activin-A, but Wnt3a, SHH, FGF2, or BMP4 cannot. hESC differentiation, SMAD2 phosphorylation assay, ChIP for SMAD2 at NKX2-1 promoter, signaling pathway inhibition Stem cells and development Medium 23259454
2021 NKX2-1 functions in an epithelial cell-autonomous manner to establish the proximal-peripheral boundary in developing airways; blastocyst complementation with NKX2-1-sufficient ESCs restored peripheral lung formation and β-catenin signaling in Nkx2-1-/- basal cells, but did not complement most proximal regions, demonstrating a cell-autonomous role in boundary formation. Blastocyst complementation, chimeric mouse analysis, β-catenin signaling assessment Developmental dynamics Medium 33428297
2022 FOXO1 interacts directly with the NKX2.1 homeodomain (via its forkhead domain), disrupting NKX2.1 binding to the SFTPC promoter and causing loss of surfactant gene expression during alveolar epithelial type I differentiation. PI-3K/AKT-mediated phosphorylation of FOXO1 sequesters it from the nucleus, maintaining AT2 identity with high surfactant expression; blocking PI-3K/AKT allows nuclear FOXO1 to interact with NKX2.1 and suppress surfactant expression. Co-IP between FOXO1 and NKX2.1, ChIP for NKX2.1 at SFTPC promoter, PI-3K/AKT inhibition, KGF treatment, in vitro AEC differentiation Cells Medium 35406686

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Fate mapping Nkx2.1-lineage cells in the mouse telencephalon. The Journal of comparative neurology 457 17990269
1999 Defects in tracheoesophageal and lung morphogenesis in Nkx2.1(-/-) mouse embryos. Developmental biology 358 10208743
2002 TTF-1 expression in pulmonary adenocarcinomas. The American journal of surgical pathology 296 12023581
2002 Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. The Journal of clinical investigation 246 11854319
1994 Expression of thyroid-specific transcription factors TTF-1 and PAX-8 in human thyroid neoplasms. Cancer research 222 8062273
2012 NKX2-1/TITF1/TTF-1-Induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma. Cancer cell 216 22439932
1996 Expression of thyroid transcription factor-1(TTF-1) in fetal and neonatal human lung. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 181 8675988
2008 NKX2.1 specifies cortical interneuron fate by activating Lhx6. Development (Cambridge, England) 178 18339674
2008 Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer. Oncogene 175 18212743
2004 TAZ interacts with TTF-1 and regulates expression of surfactant protein-C. The Journal of biological chemistry 151 14970209
2009 Thyroid transcription factor-1 (TTF-1/Nkx2.1/TITF1) gene regulation in the lung. Clinical science (London, England : 1979) 145 19037882
1995 TTF-1 regulates lung epithelial morphogenesis. Developmental biology 145 8612983
2012 Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung. The Journal of clinical investigation 131 23143308
2013 NKX2-1/TTF-1: an enigmatic oncogene that functions as a double-edged sword for cancer cell survival and progression. Cancer cell 130 23763999
2008 BCH, an inhibitor of system L amino acid transporters, induces apoptosis in cancer cells. Biological & pharmaceutical bulletin 118 18520037
2005 Usefulness of CDX2 and TTF-1 in differentiating gastrointestinal from pulmonary carcinoids. American journal of clinical pathology 87 15716236
2015 Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis. Genes & development 85 26341558
2019 Npas1+-Nkx2.1+ Neurons Are an Integral Part of the Cortico-pallido-cortical Loop. The Journal of neuroscience : the official journal of the Society for Neuroscience 76 31811030
2016 KRAS and NKX2-1 Mutations in Invasive Mucinous Adenocarcinoma of the Lung. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 76 26829311
2004 TTF-1 and RET promoter SNPs: regulation of RET transcription in Hirschsprung's disease. Human molecular genetics 74 15548547
2012 PDX-1, CDX-2, TTF-1, and CK7: a reliable immunohistochemical panel for pancreatic neuroendocrine neoplasms. The American journal of surgical pathology 72 22498824
2019 Preclinical Evaluation and Pilot Clinical Study of Al18F-PSMA-BCH for Prostate Cancer PET Imaging. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 69 30796170
2006 Functional study of a novel single deletion in the TITF1/NKX2.1 homeobox gene that produces congenital hypothyroidism and benign chorea but not pulmonary distress. The Journal of clinical endocrinology and metabolism 67 16507635
2018 FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer. eLife 66 30475207
2007 Physical and functional interactions between homeodomain NKX2.1 and winged helix/forkhead FOXA1 in lung epithelial cells. Molecular and cellular biology 66 17220277
2021 Sleep down state-active ID2/Nkx2.1 interneurons in the neocortex. Nature neuroscience 62 33619404
2009 Epigenetic silencing of TTF-1/NKX2-1 through DNA hypermethylation and histone H3 modulation in thyroid carcinomas. Laboratory investigation; a journal of technical methods and pathology 62 19506552
2023 Genotype-phenotype mapping of a patient-derived lung cancer organoid biobank identifies NKX2-1-defined Wnt dependency in lung adenocarcinoma. Cell reports 60 36870059
2005 Cytology applications of p63 and TTF-1 immunostaining in differential diagnosis of lung cancers. Diagnostic cytopathology 59 16138374
1998 Structure of the human Nkx2.1 gene. Biochimica et biophysica acta 59 9545595
2013 Derivation and isolation of NKX2.1-positive basal forebrain progenitors from human embryonic stem cells. Stem cells and development 55 23351095
2008 Lethal respiratory failure and mild primary hypothyroidism in a term girl with a de novo heterozygous mutation in the TITF1/NKX2.1 gene. The Journal of clinical endocrinology and metabolism 54 18957494
2021 ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer. iScience 49 34466783
2009 Transcriptional regulation of RET by Nkx2-1, Phox2b, Sox10, and Pax3. Journal of pediatric surgery 48 19853745
2021 YAP regulates alveolar epithelial cell differentiation and AGER via NFIB/KLF5/NKX2-1. iScience 46 34466790
2014 The relationship between TTF-1 expression and EGFR mutations in lung adenocarcinomas. PloS one 45 24743427
2009 Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer. Proceedings of the National Academy of Sciences of the United States of America 45 19279207
2004 CD117, CK20, TTF-1, and DNA topoisomerase II-alpha antigen expression in small cell tumors. Journal of cutaneous pathology 45 14984578
2022 SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1-Negative Lung Adenocarcinomas. Journal of the National Cancer Institute 44 34524427
2022 FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma. Developmental cell 43 35835117
2013 Update on hypophysitis and TTF-1 expressing sellar region masses. Brain pathology (Zurich, Switzerland) 43 23701182
2012 Occludin is a direct target of thyroid transcription factor-1 (TTF-1/NKX2-1). The Journal of biological chemistry 42 22761434
2017 MOB1-YAP1/TAZ-NKX2.1 axis controls bronchioalveolar cell differentiation, adhesion and tumour formation. Oncogene 41 28346423
2012 Nkx2-1: a novel tumor biomarker of lung cancer. Journal of Zhejiang University. Science. B 40 23125078
2003 Thyroid transcription factor (TTF) -1 regulates the expression of midkine (MK) during lung morphogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 40 12761850
2002 Expression pattern of the homeobox protein NKX2-1 in the developing Xenopus forebrain. Brain research. Gene expression patterns 39 12638129
2017 Inactivating mutations and hypermethylation of the NKX2-1/TTF-1 gene in non-terminal respiratory unit-type lung adenocarcinomas. Cancer science 35 28677170
2000 Two functionally distinct forms of NKX2.1 protein are expressed in the pulmonary epithelium. Biochemical and biophysical research communications 35 10753648
2017 Nkx2.1 regulates the generation of telencephalic astrocytes during embryonic development. Scientific reports 34 28266561
2009 Small cell lung cancer: significance of RB alterations and TTF-1 expression in its carcinogenesis, phenotype, and biology. Endocrine pathology 34 19390995
2005 Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea. Neurogenetics 34 16220345
2005 Disturbed expression of type 1 and type 2 iodothyronine deiodinase as well as titf1/nkx2-1 and pax-8 transcription factor genes in papillary thyroid cancer. Thyroid : official journal of the American Thyroid Association 32 16279847
2017 The NANCI-Nkx2.1 gene duplex buffers Nkx2.1 expression to maintain lung development and homeostasis. Genes & development 30 28546511
2016 Induction of TTF-1 or PAX-8 expression on proliferation and tumorigenicity in thyroid carcinomas. International journal of oncology 30 27573549
2019 Comparative analysis of TTF-1 binding DNA regions in small-cell lung cancer and non-small-cell lung cancer. Molecular oncology 27 31782890
2015 Nkx2.1-derived astrocytes and neurons together with Slit2 are indispensable for anterior commissure formation. Nature communications 27 25904499
2014 A novel de novo mutation of the TITF1/NKX2-1 gene causing ataxia, benign hereditary chorea, hypothyroidism and a pituitary mass in a UK family and review of the literature. Cerebellum (London, England) 27 24930029
2022 Stable iPSC-derived NKX2-1+ lung bud tip progenitor organoids give rise to airway and alveolar cell types. Development (Cambridge, England) 26 36039869
2021 NKX2-1 controls lung cancer progression by inducing DUSP6 to dampen ERK activity. Oncogene 26 34689179
2011 TTF-1 positive small cell cancers: Don't think they're always primary pulmonary! World journal of gastrointestinal oncology 26 22046491
2013 TTF-1 expression in breast carcinoma: an unusual but real phenomenon. Histopathology 25 24111789
2022 Transcriptional Circuitry of NKX2-1 and SOX1 Defines an Unrecognized Lineage Subtype of Small-Cell Lung Cancer. American journal of respiratory and critical care medicine 24 35848993
2017 Pituicytoma: Review of commonalities and distinguishing features among TTF-1 positive tumors of the central nervous system. Annals of diagnostic pathology 23 28807344
2024 68Ga-NC-BCH Whole-Body PET Imaging Rapidly Targets Claudin18.2 in Lesions in Gastrointestinal Cancer Patients. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 22 38604764
2024 PRDM3/16 regulate chromatin accessibility required for NKX2-1 mediated alveolar epithelial differentiation and function. Nature communications 22 39284798
2015 The expression of TTF-1 and Napsin A in early-stage lung adenocarcinoma correlates with the results of surgical treatment. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 22 25982999
2012 Functional plasticity of the BNIP-2 and Cdc42GAP Homology (BCH) domain in cell signaling and cell dynamics. FEBS letters 22 22710163
2008 Mutation of a gene for thyroid transcription factor-1 (TITF1) in a patient with clinical features of resistance to thyrotropin. Endocrine journal 22 18506088
2021 An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma. eLife 21 33821796
2017 TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas. Oncogene 21 28192407
2016 Utility of TTF-1 and Napsin-A in the work-up of malignant effusions. Diagnostic cytopathology 20 26799356
2009 TTF-1 expression in nephroblastoma. The American journal of surgical pathology 20 19011567
2024 Neutrophils Recruited by NKX2-1 Suppression via Activation of CXCLs/CXCR2 Axis Promote Lung Adenocarcinoma Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 19 39113226
2021 CRISPRi-mediated functional analysis of NKX2-1-binding sites in the lung. Communications biology 19 33980985
2021 64Cu-PSMA-BCH: a new radiotracer for delayed PET imaging of prostate cancer. European journal of nuclear medicine and molecular imaging 19 34170361
2023 Transcription factor NKX2-1 drives serine and glycine synthesis addiction in cancer. British journal of cancer 18 36932191
2014 Expression of bkt and bch genes from Haematococcus pluvialis in transgenic Chlamydomonas. Science China. Life sciences 18 25209726
2018 Survivin knockdown induces senescence in TTF‑1-expressing, KRAS-mutant lung adenocarcinomas. International journal of oncology 17 29658609
2016 TTF-1 and PAX5 Are Frequently Expressed in Combined Merkel Cell Carcinoma. The American Journal of dermatopathology 17 27322785
2004 NKX2.1 regulates transcription of the gene for human bone morphogenetic protein-4 in lung epithelial cells. Gene 17 14960358
2018 NKX2-1 New Mutation Associated With Myoclonus, Dystonia, and Pituitary Involvement. Frontiers in genetics 16 30186310
2025 NKX2-1 drives neuroendocrine transdifferentiation of prostate cancer via epigenetic and 3D chromatin remodeling. Nature genetics 15 40691407
2019 Application of GATA 3 and TTF-1 in differentiating parathyroid and thyroid nodules on cytology specimens. Diagnostic cytopathology 15 31713988
2015 NKX2-1-mediated p53 expression modulates lung adenocarcinoma progression via modulating IKKβ/NF-κB activation. Oncotarget 15 25881545
2008 TTF-1/NKX2.1 up-regulates the in vivo transcription of nestin. The International journal of developmental biology 14 18033672
2021 SMARCA4 (BRG1) and SMARCB1 (INI1) expression in TTF-1 negative neuroendocrine carcinomas including merkel cell carcinoma. Pathology, research and practice 13 33581550
2010 TTF-1 regulates α5 nicotinic acetylcholine receptor (nAChR) subunits in proximal and distal lung epithelium. Respiratory research 13 21143907
2007 Evaluation of the thyroid transcription factor-1 gene (TITF1) as a Hirschsprung's disease locus. Annals of human genetics 13 17640327
2020 The Incidence of Labelling of Non-Lung Adenocarcinomas With Antibodies Against TTF-1 and Diagnostic Implications. Applied immunohistochemistry & molecular morphology : AIMM 12 31135446
2017 Expressions and significances of TTF-1 and PTEN in early endometrial cancer. European review for medical and pharmacological sciences 12 28745797
2022 Tracheal separation is driven by NKX2-1-mediated repression of Efnb2 and regulation of endodermal cell sorting. Cell reports 11 35294885
2022 FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells. Cells 11 35406686
2022 Detection and Characterization of a De Novo Alu Retrotransposition Event Causing NKX2-1-Related Disorder. Movement disorders : official journal of the Movement Disorder Society 11 36420574
2021 Blastocyst complementation reveals that NKX2-1 establishes the proximal-peripheral boundary of the airway epithelium. Developmental dynamics : an official publication of the American Association of Anatomists 11 33428297
2021 Structural basis for p50RhoGAP BCH domain-mediated regulation of Rho inactivation. Proceedings of the National Academy of Sciences of the United States of America 11 34006635
2021 Correlation of TTF-1 immunoexpression and EGFR mutation spectrum in non-small cell lung carcinoma. Journal of pathology and translational medicine 11 34233113
2015 NKX2.1-Related Disorders: a novel mutation with mild clinical presentation. Italian journal of pediatrics 11 26103969
2013 NKX2-1 activation by SMAD2 signaling after definitive endoderm differentiation in human embryonic stem cell. Stem cells and development 11 23259454
2007 TTF-1 regulates growth hormone and prolactin transcription in the anterior pituitary gland. Biochemical and biophysical research communications 11 17706597
2006 Mutations in TITF1 are not relevant to sporadic and familial chorea of unknown cause. Movement disorders : official journal of the Movement Disorder Society 10 16830318

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