Affinage

NKX3-2

Homeobox protein Nkx-3.2 · UniProt P78367

Length
333 aa
Mass
34.8 kDa
Annotated
2026-06-10
60 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NKX3-2 (BAPX1) is a sequence-specific homeodomain transcriptional repressor that acts as a master regulator of somitic and skeletal chondrogenesis downstream of Shh, promoting cartilage differentiation while restraining chondrocyte maturation (PMID:11702952, PMID:16421188). It is induced by Shh and sustained by BMP signals, and its expression in the sclerotome is directly activated by Pax1/Pax9 and Meox1/Meox2 binding the Bapx1 promoter (PMID:12154128, PMID:12490554, PMID:15024065). NKX3-2 recognizes the consensus site HRAGTG, and DNA binding is required for its chondrogenic activity (PMID:12746429). It promotes chondrogenesis through a positive autoregulatory loop with Sox9 and by directly activating the Col2a1 enhancer, and it blocks alternative fates by repressing the myogenic determinant Pax3 (PMID:12154128, PMID:22511961, PMID:22768305, PMID:18796301). A central output is direct repression of the Runx2 promoter, which is required at the onset of chondrogenesis and to prevent premature hypertrophic maturation (PMID:15703179, PMID:16421188). NKX3-2's repressor function depends on BMP-dependent assembly of a complex with Smad1/Smad4 and HDAC1/Sin3A, with the homeodomain contacting HDAC1 and the NK domain contacting Smad1 (PMID:14612411). Its protein stability is tightly controlled by an acetylation/SUMO cascade in which p300 acetylation stabilizes the protein while HDAC9 deacetylation triggers PIASy-mediated sumoylation and RNF4-dependent SUMO-targeted ubiquitination, and by Ihh/Wnt5a- and PI3K/Rac1/PAK1-driven suppression that together tune cartilage hypertrophy (PMID:27312341, PMID:22507129, PMID:26363466). Beyond transcription, NKX3-2 supports chondrocyte survival by ligand-independent nuclear NF-κB activation—recruiting the RelA–IκBα complex into the nucleus and constitutively activating IKKβ through ubiquitin-dependent NEMO engagement—and it limits cartilage vascularization by driving CHIP/p62-mediated autophagic degradation of HIF-1α (PMID:17310243, PMID:21606193, PMID:28479297). Outside cartilage, NKX3-2 patterns the gut and jaw joint and modulates inflammation, autophagy, and necroptosis in non-skeletal cell types (PMID:11180960, PMID:36377467, PMID:40891783, PMID:39513923).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    Established that Nkx3.2 acts as a transcriptional repressor whose repressive activity is the functional basis for driving somitic chondrogenesis downstream of Shh, rather than acting as an activator.

    Evidence Retroviral misexpression and reverse-function (activator) mutant in chick somites in vivo, with Shh/BMP epistasis

    PMID:11702952

    Open questions at the time
    • Did not identify direct target genes repressed
    • Did not define the repressor partners recruited
  2. 2002 High

    Showed that Nkx3.2 and Sox9 form a BMP-dependent positive autoregulatory loop, explaining how a transient Shh signal is converted into a self-sustaining chondrogenic program.

    Evidence Forced expression in chick somitic explants with BMP treatment and gene expression epistasis

    PMID:12154128

    Open questions at the time
    • Whether the Sox9 induction is direct or indirect was not resolved here
    • Molecular basis of BMP dependence not defined
  3. 2003 High

    Defined the molecular machinery of repression and its DNA-binding specificity: a BMP-dependent Smad1/4–HDAC1/Sin3A co-repressor complex and the HRAGTG consensus site, with both DNA binding and complex assembly required for chondrogenic induction.

    Evidence Co-IP and domain mutagenesis in Smad4-deficient cells with rescue; site-selection/EMSA and N200Q non-binding mutant in chick mesoderm

    PMID:12746429 PMID:14612411

    Open questions at the time
    • Genome-wide direct target repertoire not mapped
    • Structural basis of the multiprotein complex not determined
  4. 2003 High

    Identified upstream activators Pax1/Pax9 (later Meox1/Meox2) that directly drive sclerotomal Bapx1 transcription, placing Nkx3.2 within the somite patterning hierarchy.

    Evidence Pax1;Pax9 and Meox1;Meox2 double-mutant mice, EMSA, ChIP, reporter assays

    PMID:12490554 PMID:15024065

    Open questions at the time
    • Combinatorial logic integrating Pax and Meox inputs not fully resolved
    • Relationship to Shh/BMP inputs on the same promoter unclear
  5. 2005 High

    Pinpointed Runx2 as a direct repression target whose silencing is required at the onset of chondrogenesis, providing a concrete anti-osteogenic mechanism.

    Evidence Promoter reporter assays mapping a -0.1 kb element and Runx2 epistasis in BMP-2-induced C3H10T1/2 chondrogenesis

    PMID:15703179

    Open questions at the time
    • Whether Smad/HDAC complex acts at this Runx2 element not directly tested
    • In vivo requirement at endogenous Runx2 locus not shown here
  6. 2006 High

    Extended Nkx3.2's role to negative regulation of chondrocyte maturation, showing PTHrP maintains its expression and that Runx2 repression underlies the maturation block.

    Evidence Forced and reverse-function expression in chick/mouse, Runx2 rescue, PTHrP-deficient mice

    PMID:16421188

    Open questions at the time
    • Direct PTHrP-to-Nkx3.2 transcriptional link not defined
    • Timing of switch from proliferation to hypertrophy mechanistically incomplete
  7. 2007 High

    Revealed a transcription-independent survival function: Nkx3.2 constitutively activates RelA/NF-κB by nuclear recruitment of the RelA–IκBα complex and proteasomal IκBα degradation.

    Evidence Co-IP, nuclear fractionation, proteasome inhibitors, gain/loss-of-function in chondrocytes

    PMID:17310243

    Open questions at the time
    • Upstream trigger for this ligand-independent activation unknown at this stage
    • NF-κB target genes mediating survival not enumerated
  8. 2011 High

    Resolved the mechanism of the survival pathway: Nkx3.2 engages NEMO via ubiquitin chains to constitutively activate nuclear IKKβ, which phosphorylates Nkx3.2 (Ser148/Ser168) to drive βTrCP-mediated IκBα degradation independent of canonical Ser32/36.

    Evidence Co-IP, ubiquitination assays, phospho-site mutagenesis, nuclear fractionation

    PMID:21606193

    Open questions at the time
    • Source of the ubiquitin chains engaging NEMO not identified
    • Physiological signal initiating the loop in vivo unknown
  9. 2012 High

    Demonstrated direct Sox9-independent activation of Col2a1 alongside the Sox9 feedback loop, and mutual repression with Pax3, clarifying how Nkx3.2 both induces cartilage genes and excludes myogenic fate.

    Evidence ChIP on the Col2a1 enhancer, reporter and RNAi assays; explant misexpression for Pax3 antagonism

    PMID:18796301 PMID:22511961 PMID:22768305

    Open questions at the time
    • Relative contribution of direct vs Sox9-mediated Col2a1 activation in vivo unclear
    • Mechanism of Pax3 promoter repression at molecular detail incomplete
  10. 2012 Medium

    Identified Ihh/Wnt5a signaling as a degradative brake on Nkx3.2 protein, linking the maturation program to controlled removal of the repressor.

    Evidence In vitro Ihh/Wnt5a treatment, proteasome inhibitors, Ihh/Smo knockout mice, Western blot

    PMID:22507129

    Open questions at the time
    • E3 ligase mediating this degradation not identified
    • Direct vs indirect role of non-canonical Wnt unresolved
  11. 2015 Medium

    Defined PI3K/p85β–Rac1–PAK1 (Akt-independent) signaling as an additional suppressor of Nkx3.2 controlling cartilage hypertrophy.

    Evidence PI3K inhibitor/activator, p85 subunit-specific constructs, Rac1/PAK1 inhibition, p85β KO mice, ex vivo bone cultures

    PMID:26363466

    Open questions at the time
    • Direct molecular target of Rac1/PAK1 on Nkx3.2 not defined
    • How transcriptional vs protein-level suppression are coordinated unclear
  12. 2016 High

    Established the post-translational stability code: p300 acetylation stabilizes Nkx3.2, while HDAC9 deacetylation initiates PIASy sumoylation and RNF4 SUMO-targeted ubiquitination for degradation, controlling survival and hypertrophy; and confirmed in vivo that Nkx3.2 gain causes endochondral dwarfism.

    Evidence Acetylation/sumoylation/ubiquitination assays, Co-IP, factor knockdown/overexpression; conditional Col2a1-Cre transgenic mice

    PMID:27253464 PMID:27312341

    Open questions at the time
    • Stoichiometry and sequence of modifications in vivo not measured
    • Crosstalk with Ihh/PI3K degradation routes not integrated
  13. 2017 Medium

    Uncovered a role in maintaining cartilage avascularity by promoting CHIP/p62-mediated autophagic (lysosomal, proteasome-independent) degradation of HIF-1α.

    Evidence Co-IP, proteasome/lysosome inhibitors, HIF reporter assays, conditional transgenic mice, IHC

    PMID:28479297

    Open questions at the time
    • Direct vs scaffolding role of Nkx3.2 in the CHIP/p62 complex unclear
    • Relationship to its NF-κB and transcriptional roles not integrated
  14. 2019 Medium

    Showed Nkx3.2 is itself epigenetically regulated and operates outside cartilage: SIRT6 deacetylates H3K9 at the NKX3-2 locus to repress it, with NKX3-2 in turn repressing GATA5 in endothelium.

    Evidence Endothelial SIRT6 KO mice, ChIP for H3K9ac, reporter assays

    PMID:30894089

    Open questions at the time
    • Whether GATA5 repression is direct not shown
    • Generalizability beyond endothelium unknown
  15. 2025 Medium

    Broadened the functional repertoire to non-skeletal contexts—gut/jaw patterning and modulation of inflammation, necroptosis, and autophagy—indicating Nkx3.2 couples transcriptional control to protein-turnover pathways across tissues.

    Evidence Chick gut misexpression and Bapx1 KO mice; zebrafish JRS1 enhancer deletion; RPE necroptosis (RIP3 degradation) and ovarian cancer autophagy/migration knockdown studies

    PMID:11180960 PMID:36377467 PMID:39513923 PMID:40891783

    Open questions at the time
    • Shared molecular logic linking these diverse roles not established
    • Direct transcriptional targets in non-cartilage tissues largely undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple protein-stability inputs (acetylation/SUMO cascade, Ihh/Wnt5a, PI3K/Rac1/PAK1) and the transcription-independent NF-κB and HIF-1α functions are integrated to time the proliferation-to-hypertrophy transition in vivo remains unresolved.
  • No unified in vivo model coordinating transcriptional and post-translational regulation
  • Genome-wide direct target map lacking
  • No structural model of the repressor or degradation complexes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0140110 transcription regulator activity 3 GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-9612973 Autophagy 2
Partners
EP300HDAC1IKBKGNFKBIARELARNF4SMAD1SMAD4
Complex memberships
Nkx3.2–Smad1/Smad4–HDAC1/Sin3A co-repressor complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Nkx3.2 functions as a transcriptional repressor to promote somitic chondrogenesis downstream of Shh; its transcriptional repressor activity is essential for this function, as a 'reverse function' mutant converted into a transcriptional activator inhibits axial chondrogenesis in vivo. Somitic expression of Nkx3.2 is initiated by Shh and sustained by BMP signals. Retroviral misexpression in chick somitic tissue, reverse-function mutagenesis, in vivo chick embryo assays Developmental cell High 11702952
2002 Shh induces Nkx3.2 expression in somitic tissue; forced Nkx3.2 expression induces Sox9 expression; in the presence of BMP signals, Sox9 and Nkx3.2 induce each other's expression, establishing a positive autoregulatory loop that promotes axial chondrogenesis. Retroviral forced expression in chick somitic explants, in vitro BMP treatment, gene expression analysis Genes & development High 12154128
2003 Nkx3.2 forms a complex in vivo with HDAC1 and Smad1/Smad4 in a BMP-dependent manner. The homeodomain of Nkx3.2 supports interaction with HDAC1, while the NK domain supports interaction with Smad1. Both domains are required for transcriptional repressor activity. Recruitment of the HDAC/Sin3A complex to Nkx3.2 requires Nkx3.2–Smad1/4 interaction; in Smad4-deficient cells, Nkx3.2 fails to associate with HDAC/Sin3A and fails to repress target gene transcription. Co-immunoprecipitation in vivo, domain deletion/mutagenesis, reporter gene assays in Smad4-deficient cell lines with rescue by exogenous Smad4 Molecular and cellular biology High 14612411
2003 Nkx3.2 binds DNA in a sequence-specific manner; the consensus binding site is HRAGTG (identified by site-selection assay and confirmed by EMSA). A DNA non-binding point mutant (N200Q) retains intrinsic transcriptional repressor activity but is unable to activate the chondrocyte differentiation program in somitic mesoderm, demonstrating that DNA binding is required for chondrogenic induction. DNA binding site selection assay, EMSA, point mutagenesis, retroviral misexpression in chick somitic mesoderm The Journal of biological chemistry High 12746429
2005 Nkx3.2 directly represses the Runx2 promoter through a regulatory element ~0.1 kb upstream of the transcriptional start site, acting as a sequence-specific repressor. This repression of Runx2 is required at the onset of chondrogenesis; adenoviral introduction of Runx2 prevents BMP-2-induced chondrogenesis in C3H10T1/2 cells. Reporter gene (luciferase) assays, adenoviral overexpression, BMP-2-induced chondrogenesis model in C3H10T1/2 cells The Journal of biological chemistry High 15703179
2006 Nkx3.2/Bapx1 acts as a negative regulator of chondrocyte maturation by repressing Runx2 expression. PTHrP signaling maintains Nkx3.2 expression in proliferating chondrocytes; loss of PTHrP signaling reduces Nkx3.2 expression. Forced Nkx3.2 expression blocks chondrocyte maturation, while a reverse-function activator mutant accelerates maturation. Runx2 misexpression rescues the Nkx3.2-induced block of chondrocyte maturation. Retroviral forced expression in chick and mouse, reverse-function Nkx3.2 mutant, genetic rescue with Runx2 misexpression, PTHrP-deficient mouse analysis Development (Cambridge, England) High 16421188
2007 Nkx3.2 supports chondrocyte survival by constitutively activating RelA/NF-κB through a ligand-independent mechanism: Nkx3.2 recruits the RelA–IκBα heteromeric complex into the nucleus via direct protein–protein interactions and activates RelA through proteasome-dependent IκBα degradation in the nucleus. Co-immunoprecipitation, nuclear fractionation, proteasome inhibitor assays, loss-of-function and gain-of-function in chondrocytes Nature cell biology High 17310243
2011 Nkx3.2 constitutively activates IKKβ in the nucleus in the absence of exogenous signals. Nkx3.2 forms ubiquitin chain-dependent interactions with NEMO (IKKγ), leading to constitutive IKKβ activation. IKKβ then phosphorylates Nkx3.2 at Ser148 and Ser168, enabling βTrCP engagement and IκBα ubiquitination independent of IκBα phosphorylation at Ser32/Ser36. Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis of phosphorylation sites, nuclear fractionation Molecular and cellular biology High 21606193
2012 Nkx3.2 promotes primary chondrogenesis by two mechanisms: (1) direct, Sox9-independent upregulation of Col2a1 transcription by binding the Col2a1 enhancer element (confirmed by ChIP); (2) upregulation of Sox9 mRNA under a positive feedback system. Partial restoration of Col2a1 expression by Nkx3.2 was observed even after Sox9 knockdown. Dual luciferase reporter assays, RNAi knockdown, ChIP assay demonstrating Nkx3.2 binding to Col2a1 enhancer, overexpression in C3H10T1/2 and N1511 cells PloS one High 22511961
2012 Indian Hedgehog (Ihh) signaling induces proteasomal degradation of Nkx3.2 protein. This pathway requires Wnt5a downstream of Ihh; Ihh suppresses Lrp (Wnt co-receptor) and Sfrp expression, selectively enhancing non-canonical Wnt signaling. Nkx3.2 protein levels are elevated in mice deficient for Ihh or smoothened. In vitro Ihh and Wnt5a treatment of chondrocytes, proteasome inhibitor assays, Ihh/smoothened knockout mouse analysis, Western blotting The Biochemical journal Medium 22507129
2012 Nkx3.2 acts as a transcriptional repressor to repress the Pax3 promoter and block myogenic differentiation, and is required for Sox9 to promote chondrogenic differentiation of muscle satellite cells. A reverse-function activator mutant of Nkx3.2 blocks Sox9's ability to inhibit myogenesis and induce chondrogenesis. Ectopic expression in chick muscle satellite cells, reverse-function Nkx3.2 mutant, Pax3 promoter reporter assays, TGFβ3/BMP2-induced chondrogenesis model, in vivo mouse fracture healing lineage tracing PloS one Medium 22768305
2016 Nkx3.2 protein stability is controlled by a post-translational modification cascade: p300-mediated acetylation stabilizes Nkx3.2, while HDAC9-mediated deacetylation triggers PIASy-mediated sumoylation, which in turn enables RNF4-mediated SUMO-targeted ubiquitination and degradation. This cascade regulates chondrocyte survival and hypertrophic maturation. Co-immunoprecipitation, ubiquitination and sumoylation assays, acetylation assays, overexpression/knockdown of HDAC9, PIASy, RNF4, p300 in chondrocyte cultures Cellular signalling High 27312341
2015 PI3K signaling suppresses Nkx3.2 at both mRNA and protein levels in chondrocytes. Specifically, p85β (not p85α) is the regulatory PI3K subunit employed for Nkx3.2 suppression. This suppression requires Rac1–PAK1 but not Akt signaling downstream of PI3K, and controls cartilage hypertrophy during skeletal development. PI3K inhibitor/activator treatment, p85α/p85β-specific constructs, Rac1/PAK1 inhibition, embryonic limb bud cultures, ex vivo long bone cultures, p85β knockout mice Cellular signalling Medium 26363466
2017 Nkx3.2, in conjunction with CHIP E3 ligase and p62/SQSTM1 adaptor, induces oxygen concentration-independent, proteasome-independent, lysosomal (macroautophagy) degradation of HIF-1α. Nkx3.2 suppresses HIF-dependent reporter activity and endogenous HIF target genes. Cartilage-specific Nkx3.2 overexpression in mice attenuates HIF-1α protein levels and vascularization in growth plates. Co-immunoprecipitation, proteasome and lysosome inhibitor assays, reporter gene assays, conditional transgenic mouse overexpression, immunohistochemistry Cellular signalling Medium 28479297
2019 SIRT6 inhibits NKX3.2 transcription by deacetylating histone H3K9 at the NKX3.2 locus in endothelial cells. NKX3.2 represses GATA5 expression; SIRT6-mediated deacetylation of H3K9 reduces NKX3.2 expression, thereby de-repressing GATA5 and maintaining endothelial function. Endothelial-specific SIRT6 knockout mice, ChIP for H3K9 acetylation at NKX3.2 locus, reporter assays, SIRT6 overexpression in vivo Circulation research Medium 30894089
2003 Pax1 and Pax9 directly activate Bapx1 transcription by physically interacting with and transactivating regulatory sequences in the Bapx1 promoter, as shown by EMSA and ChIP. In Pax1;Pax9 double mutant mice, Bapx1 expression in the sclerotome is lost in a gene-dose-dependent manner. Pax1;Pax9 double mutant mouse analysis, retroviral Pax1 overexpression in chick explants, transient transfection reporter assays, EMSA, ChIP Development (Cambridge, England) High 12490554
2004 Meox1 and Meox2 are required for Bapx1 expression in the sclerotome; Meox1 directly binds a palindromic TAATTA sequence in the Bapx1 promoter (confirmed by EMSA and ChIP) and activates Bapx1 transcription. This activity is enhanced by Pax1 and/or Pax9. Meox1;Meox2 double mutant mouse analysis, transient transfection reporter assays, EMSA, ChIP Molecular and cellular biology High 15024065
2008 Nkx3.2 and Pax3 establish mutually repressing cell fates in somites: forced Nkx3.2 expression blocks somitic expression of the dermomyotomal marker Pax3 both in vitro and in vivo, while forced Pax3 expression blocks Shh-mediated induction of sclerotomal gene expression and chondrocyte differentiation in vitro. Forced expression in presomitic mesoderm explants cultured with Wnt3a and Shh gradients, retroviral misexpression in chick somites in vivo Developmental biology Medium 18796301
2004 Fgf signals from oral epithelium restrict Bapx1 expression to the caudal half of the mandibular arch, while Bmp4 signals in the distal arch restrict Bapx1 to the proximal mandible. Application of Fgf8 or Bmp4 beads to proximal mesenchyme leads to loss of Bapx1 expression and subsequent jaw joint fusion. Bead implantation of Fgf8/Bmp4 in chick mandibular arch, in situ hybridization for Bapx1 expression, phenotypic analysis of jaw joint fusion Developmental biology Medium 14729484
2009 Recombinant Nkx3.2 binds strongly to and preferentially represses transcription from a mutant neu1 promoter carrying an ectopically generated Nkx3 consensus binding site (created by a -519G→A mutation), demonstrating sequence-specific transcriptional repressor activity of Nkx3.2 on a non-developmental target gene. EMSA with recombinant Nkx3.2, reporter assays in cell lines, promoter mutagenesis Molecular genetics and metabolism Medium 19217813
2016 Cartilage-specific, Cre-dependent Nkx3.2 overexpression in mice causes postnatal dwarfism in endochondral but not intramembranous bones, with significant delays in cartilage hypertrophy, confirming that Nkx3.2 controls hypertrophic maturation in vivo. Conditional transgenic mouse (ciTg-Nkx3.2) with Col2a1-Cre, histological and molecular analysis of growth plates Journal of cellular physiology Medium 27253464
2001 Bapx1 regulates Bmp4 and Wnt5a expression to pattern the avian stomach: ectopic Bapx1 expression in the proventriculus induces a gizzard-like morphology and inhibits proventricular Bmp4 and Wnt5a expression. Overexpression of a reverse-function Bapx1 construct results in a small stomach and ectopic extension of Bmp4/Wnt5a into the gizzard. Retroviral overexpression of wild-type and reverse-function Bapx1 in chick proventriculus, morphological and gene expression analysis Developmental biology Medium 11180960
2004 In Bapx1 null mice, the splanchnic mesodermal plate (SMP) is defective and Fgf10 expression (but not Fgf9) is downregulated, with the dorsal pancreas remaining at the midline. This places Bapx1 upstream of Fgf10 in regulating SMP function required for pancreatic laterality. Bapx1 knockout mouse analysis, in situ hybridization for Fgf9/Fgf10, morphological analysis of SMP and pancreas Development (Cambridge, England) Medium 15329346
2009 Bapx1 expression is placed downstream of Barx1 in gut mesenchyme: Bapx1 expression is lost in the absence of Barx1, establishing a Barx1→Bapx1 hierarchy in distal stomach development. Bapx1 is non-redundantly required for antral segment development and pyloric constriction. Bapx1(Cre) knock-in allele for lineage tracing; single and compound Barx1;Bapx1 mutant mouse analysis; histological phenotyping Gastroenterology Medium 19208343
2025 Nkx3.2 suppresses inflammatory responses (downregulates pro-inflammatory cytokines/chemokines, upregulates anti-inflammatory factors) and inhibits necroptosis in retinal pigment epithelium (RPE) by inducing proteasomal degradation of RIP3 (receptor-interacting protein kinase 3). In vitro RPE cell assays, in vivo mouse retinal degeneration models (aging, oxidative stress, VEGF, laser-induced), Western blotting, transcriptome analysis, proteasomal degradation assays Investigative ophthalmology & visual science Medium 40891783
2024 NKX3-2 silencing in ovarian cancer cells abrogates LPA-induced cell migration. Mechanistically, NKX3-2 silencing restores HDAC6-mediated relocation of lysosomes to the para-Golgi area, increases autolysosome formation and upregulates autophagy. Silencing ATG7 or BECN1 rescues the migratory phenotype of NKX3-2-silenced cells, placing autophagy suppression downstream of NKX3-2 in LPA-driven migration. siRNA knockdown of NKX3-2 in ovarian cancer cell lines, cell migration assays, lysosome localization imaging, autophagy flux assays, epistasis with ATG7/BECN1 knockdown Cells Medium 39513923
2022 NKX3-2 knockdown in SW1353 chondrocytes increases RUNX2 expression, decreases 47S pre-rRNA transcriptional activity and rRNA expression, reducing protein translational capacity. BMP7 increases NKX3-2 expression and 47S promoter activity in a NKX3-2-dependent manner, connecting BMP7 signaling to ribosome biogenesis via the NKX3-2–RUNX2 axis. siRNA knockdown of NKX3-2, 47S promoter-reporter assay, RT-qPCR, SUnSET protein synthesis assay, BMP7 treatment PloS one Medium 35139106
2022 A proximal cis-regulatory enhancer element (JRS1) of Nkx3.2 is deeply conserved in gnathostomes, active in the developing jaw joint region of zebrafish, and required for early nkx3.2 expression; CRISPR/Cas9 deletion of JRS1 causes reduced nkx3.2 expression and transient jaw joint deformation/partial fusion. CRISPR/Cas9 enhancer deletion in zebrafish, transgenic reporter assay across gnathostome species, in situ hybridization eLife Medium 36377467

Source papers

Stage 0 corpus · 60 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The murine Bapx1 homeobox gene plays a critical role in embryonic development of the axial skeleton and spleen. Development (Cambridge, England) 201 10572046
2003 Two endothelin 1 effectors, hand2 and bapx1, pattern ventral pharyngeal cartilage and the jaw joint. Development (Cambridge, England) 187 12588851
2002 Shh establishes an Nkx3.2/Sox9 autoregulatory loop that is maintained by BMP signals to induce somitic chondrogenesis. Genes & development 171 12154128
2019 Endothelial SIRT6 Is Vital to Prevent Hypertension and Associated Cardiorenal Injury Through Targeting Nkx3.2-GATA5 Signaling. Circulation research 133 30894089
2001 The chick transcriptional repressor Nkx3.2 acts downstream of Shh to promote BMP-dependent axial chondrogenesis. Developmental cell 113 11702952
2003 Pax1 and Pax9 activate Bapx1 to induce chondrogenic differentiation in the sclerotome. Development (Cambridge, England) 110 12490554
2006 Nkx3.2/Bapx1 acts as a negative regulator of chondrocyte maturation. Development (Cambridge, England) 95 16421188
1997 Bapx1: an evolutionary conserved homologue of the Drosophila bagpipe homeobox gene is expressed in splanchnic mesoderm and the embryonic skeleton. Mechanisms of development 95 9256352
2004 Bapx1 regulates patterning in the middle ear: altered regulatory role in the transition from the proximal jaw during vertebrate evolution. Development (Cambridge, England) 90 14973294
2004 Fgf and Bmp signals repress the expression of Bapx1 in the mandibular mesenchyme and control the position of the developing jaw joint. Developmental biology 88 14729484
2004 The splanchnic mesodermal plate directs spleen and pancreatic laterality, and is regulated by Bapx1/Nkx3.2. Development (Cambridge, England) 88 15329346
2003 Smad-dependent recruitment of a histone deacetylase/Sin3A complex modulates the bone morphogenetic protein-dependent transcriptional repressor activity of Nkx3.2. Molecular and cellular biology 88 14612411
2000 Targeted disruption of the homeobox transcription factor Bapx1 results in lethal skeletal dysplasia with asplenia and gastroduodenal malformation. Genes to cells : devoted to molecular & cellular mechanisms 88 10886375
1999 The homeobox gene NKX3.2 is a target of left-right signalling and is expressed on opposite sides in chick and mouse embryos. Current biology : CB 78 10469600
2005 Nkx3.2-mediated repression of Runx2 promotes chondrogenic differentiation. The Journal of biological chemistry 70 15703179
2009 Role of the homeodomain transcription factor Bapx1 in mouse distal stomach development. Gastroenterology 66 19208343
2006 Histone acetylation dependent allelic expression imbalance of BAPX1 in patients with the oculo-auriculo-vertebral spectrum. Human molecular genetics 58 16407370
2008 A gradient of Shh establishes mutually repressing somitic cell fates induced by Nkx3.2 and Pax3. Developmental biology 45 18796301
2007 Constitutive RelA activation mediated by Nkx3.2 controls chondrocyte viability. Nature cell biology 42 17310243
2002 Transcription factors Nkx3.1 and Nkx3.2 (Bapx1) play an overlapping role in sclerotomal development of the mouse. Mechanisms of development 42 12204261
2012 Interplay of Nkx3.2, Sox9 and Pax3 regulates chondrogenic differentiation of muscle progenitor cells. PloS one 39 22768305
2001 Gizzard formation and the role of Bapx1. Developmental biology 39 11180960
2001 The role of Bapx1 (Nkx3.2) in the development and evolution of the axial skeleton. Journal of anatomy 39 11523821
1997 Molecular cloning, chromosomal mapping and developmental expression of BAPX1, a novel human homeobox-containing gene homologous to Drosophila bagpipe. Gene 36 9426254
2004 Meox homeodomain proteins are required for Bapx1 expression in the sclerotome and activate its transcription by direct binding to its promoter. Molecular and cellular biology 35 15024065
2003 Characterization of Nkx3.2 DNA binding specificity and its requirement for somitic chondrogenesis. The Journal of biological chemistry 33 12746429
2009 Homozygous inactivating mutations in the NKX3-2 gene result in spondylo-megaepiphyseal-metaphyseal dysplasia. American journal of human genetics 29 20004766
2012 Nkx3.2 promotes primary chondrogenic differentiation by upregulating Col2a1 transcription. PloS one 24 22511961
2012 Indian Hedgehog signalling triggers Nkx3.2 protein degradation during chondrocyte maturation. The Biochemical journal 21 22507129
2005 Expression and function of Bapx1 during chick limb development. Anatomy and embryology 21 15887045
2011 Nkx3.2-induced suppression of Runx2 is a crucial mediator of hypoxia-dependent maintenance of chondrocyte phenotypes. Biochemical and biophysical research communications 20 22093831
2016 Cordycepin inhibits chondrocyte hypertrophy of mesenchymal stem cells through PI3K/Bapx1 and Notch signaling pathway. BMB reports 19 27439604
2014 The role of Nkx3.2 in chondrogenesis. Frontiers in biology 17 27158253
2016 A post-translational modification cascade employing HDAC9-PIASy-RNF4 axis regulates chondrocyte hypertrophy by modulating Nkx3.2 protein stability. Cellular signalling 16 27312341
2014 In vivo genome-wide analysis of multiple tissues identifies gene regulatory networks, novel functions and downstream regulatory genes for Bapx1 and its co-regulation with Sox9 in the mammalian vertebral column. BMC genomics 16 25480362
2017 Bapx1 mediates transforming growth factor-β- induced epithelial-mesenchymal transition and promotes a malignancy phenotype of gastric cancer cells. Biochemical and biophysical research communications 15 28315334
2013 Expression pattern of the homeotic gene Bapx1 during early chick gastrointestinal tract development. Gene expression patterns : GEP 14 23727297
1997 Sequence and chromosomal assignment of human BAPX1, a bagpipe-related gene, to 4p16.1: a candidate gene for skeletal dysplasia. Genomics 14 9344671
2020 nkx3.2 mutant zebrafish accommodate jaw joint loss through a phenocopy of the head shapes of Paleozoic jawless fish. The Journal of experimental biology 13 32527964
2021 The broad role of Nkx3.2 in the development of the zebrafish axial skeleton. PloS one 12 34411150
2017 Nkx3.2 induces oxygen concentration-independent and lysosome-dependent degradation of HIF-1α to modulate hypoxic responses in chondrocytes. Cellular signalling 11 28479297
2015 Suppression of Nkx3.2 by phosphatidylinositol-3-kinase signaling regulates cartilage development by modulating chondrocyte hypertrophy. Cellular signalling 11 26363466
2011 Exogenous signal-independent nuclear IkappaB kinase activation triggered by Nkx3.2 enables constitutive nuclear degradation of IkappaB-alpha in chondrocytes. Molecular and cellular biology 11 21606193
2009 A point mutation in the neu1 promoter recruits an ectopic repressor, Nkx3.2 and results in a mouse model of sialidase deficiency. Molecular genetics and metabolism 11 19217813
2021 Zebrafish model for spondylo-megaepiphyseal-metaphyseal dysplasia reveals post-embryonic roles of Nkx3.2 in the skeleton. Development (Cambridge, England) 9 33462117
2018 Aberrant activity of NKL homeobox gene NKX3-2 in a T-ALL subset. PloS one 9 29746601
2018 Bapx1 is required for jaw joint development in amphibians. Evolution & development 9 30168254
2016 Cartilage-Specific and Cre-Dependent Nkx3.2 Overexpression In Vivo Causes Skeletal Dwarfism by Delaying Cartilage Hypertrophy. Journal of cellular physiology 9 27253464
2012 New Bapx1(Cre-EGFP) mouse lines for lineage tracing and conditional knockout studies. Genesis (New York, N.Y. : 2000) 9 21913311
2006 Bapx1 homeobox gene gain-of-function mice show preaxial polydactyly and activated Shh signaling in the developing limb. Developmental dynamics : an official publication of the American Association of Anatomists 8 16791844
2022 A novel cis-regulatory element drives early expression of Nkx3.2 in the gnathostome primary jaw joint. eLife 5 36377467
2018 Bapx1 upregulation is associated with ectopic mandibular cartilage development in amphibians. Zoological letters 5 29942645
2024 Pseudogenization of NK3 homeobox 2 (Nkx3.2) in monotremes provides insight into unique gastric anatomy and physiology. Open biology 4 38955222
2023 Comprehensive Analysis of NKX3.2 in Liver Hepatocellular Carcinoma by Bigdata. Medicina (Kaunas, Lithuania) 4 37893500
2021 Suppression of Osteoarthritis progression by post-natal Induction of Nkx3.2. Biochemical and biophysical research communications 4 34330063
2024 NKX3-2 Induces Ovarian Cancer Cell Migration by HDAC6-Mediated Repositioning of Lysosomes and Inhibition of Autophagy. Cells 3 39513923
2018 A novel NKX3-2 mutation associated with perinatal lethal phenotype of spondylo-megaepiphyseal-metaphyseal dysplasia in a neonate. European journal of medical genetics 3 29704686
2022 BMP7 increases protein synthesis in SW1353 cells and determines rRNA levels in a NKX3-2-dependent manner. PloS one 2 35139106
2016 Genome wide binding (ChIP-Seq) of murine Bapx1 and Sox9 proteins in vivo and in vitro. Genomics data 2 27672560
2025 Nkx3.2 Inhibits Retinal Degeneration by Modulating Inflammation and Cell Death in RPE. Investigative ophthalmology & visual science 0 40891783

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