Affinage

NKD1

Protein naked cuticle homolog 1 · UniProt Q969G9

Length
470 aa
Mass
52.3 kDa
Annotated
2026-06-10
27 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NKD1 is a Wnt-inducible negative feedback regulator of the canonical Wnt/beta-catenin pathway, encoding an EF-hand-containing protein that antagonizes signaling by binding Dishevelled (Dvl) and limiting beta-catenin nuclear accumulation (PMID:15546883, PMID:19956716). Upon Wnt ligand stimulation NKD1 is recruited with Dvl2 to the Wnt signalosome and subsequently relocates to the cytoplasm to engage beta-catenin and block its nuclear entry, with activity that is strictly dependent on receptor-level ligand activation (PMID:25904337); it binds and destabilizes Dvl proteins, and cancer-derived mutations that weaken Dvl binding stabilize beta-catenin and drive proliferation (PMID:19956716, PMID:20858476). The EF-hand motif is required for this inhibitory function in vivo, as its deletion in mice elevates nuclear beta-catenin and disrupts spermatogenesis (PMID:15546883). NKD1 operates within a layered feedback hierarchy, acting downstream of Axin2 (PMID:38656801), and its abundance is set by FGFR signaling, which induces NKD1 as an immediate-early gene to restrain Wnt during hepatic progenitor specification (PMID:26637527), and by YTHDF3-mediated m6A modification that suppresses its expression (PMID:39127439). Beyond Wnt antagonism, NKD1 has context-dependent pro-tumorigenic activities in colorectal and hepatocellular cancer: it interacts with and promotes ubiquitin-proteasomal degradation of Rac1 and PCM1 (PMID:27231134, PMID:37338734), binds APC to enhance its ubiquitination by restraining USP15 (PMID:36445120), stabilizes MYC through its EF-hand by blocking LC3B-mediated autophagic degradation (PMID:40675969), and can act as a nuclear transcriptional activator of YWHAE to promote glucose uptake (PMID:37202194). NKD1 also partners with the transcription factors MSX1 and PPARdelta in differentiation and proliferation programs (PMID:40675969, PMID:41526338).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2001 Low

    Established human NKD1 as a Dishevelled-binding, EF-hand-containing candidate negative regulator of Wnt/beta-catenin/TCF signaling by homology to mouse Nkd.

    Evidence Molecular cloning, sequence and domain analysis

    PMID:11604995

    Open questions at the time
    • Computational/sequence inference only, no direct functional assay on human NKD1
    • Dvl binding not biochemically demonstrated for the human protein here
  2. 2004 High

    Defined the EF-hand motif as functionally necessary for Wnt antagonism in vivo, showing domain-specific loss elevates nuclear beta-catenin and impairs spermatogenesis.

    Evidence Targeted EF-hand deletion knock-in mouse, nuclear beta-catenin immunostaining, sperm count

    PMID:15546883

    Open questions at the time
    • Does not resolve the molecular ligand or partner engaged by the EF-hand
    • Mechanism linking EF-hand to Dvl destabilization not addressed
  3. 2007 High

    Genetic loss-of-function showed Nkd1/Nkd2 bind Dvl and antagonize Wnt but are individually dispensable for murine development, defining them as modulatory rather than essential.

    Evidence Dvl-binding-domain replacement, double-knockout mouse, morphological analysis

    PMID:17438140

    Open questions at the time
    • Subtle phenotype leaves the in vivo physiological context underdefined
    • Paralog redundancy not fully dissected
  4. 2009 High

    Connected NKD1 dysfunction to colorectal cancer by demonstrating tumor-derived mutations reduce Dvl binding/destabilization, stabilize beta-catenin and drive proliferation.

    Evidence Tumor mutation analysis, Wnt reporter, beta-catenin stability, proliferation, Co-IP

    PMID:19956716

    Open questions at the time
    • Does not establish whether mutations act dominantly or recessively in tumors
    • Mechanism of Dvl destabilization not resolved
  5. 2010 High

    Showed Nkd1 promotes Dvl degradation and is required in dorsal forerunner cells for ciliogenesis and left-right axis establishment, extending its antagonism to developmental patterning.

    Evidence Zebrafish overexpression Dvl-degradation assay, DFC-targeted morpholino knockdown, patterning analysis

    PMID:20858476

    Open questions at the time
    • Biochemical mechanism of Dvl degradation unresolved
    • Link between ciliogenesis defect and beta-catenin not fully separated
  6. 2013 Medium

    Refined NKD1 as a passive antagonist whose activity manifests only when Wnt signaling is destabilized, clarifying it is a buffering rather than constitutive suppressor.

    Evidence Genetic epistasis in zebrafish Wnt/PCP mutants, Wnt8a overexpression, Nkd1 rescue

    PMID:24009776

    Open questions at the time
    • Molecular basis of conditional/passive behavior not defined
    • Single-lab epistasis
  7. 2015 Medium

    Placed NKD1 dynamically in the pathway: ligand-triggered recruitment to the signalosome with Dvl2 followed by cytoplasmic relocation to block beta-catenin nuclear accumulation.

    Evidence Wnt-responsive zebrafish blastula cell assays, signalosome recruitment and beta-catenin localization assays

    PMID:25904337

    Open questions at the time
    • Recruitment mechanism to signalosome not defined
    • Direct beta-catenin binding not biochemically isolated
  8. 2015 High

    Identified NKD1 as an FGFR-induced immediate-early gene that restrains Wnt during endoderm-to-hepatic-progenitor transition, linking it to lineage specification.

    Evidence FGFR inhibition, NKD1 knockdown in human iPSC differentiation, pharmacological Wnt-antagonist rescue

    PMID:26637527

    Open questions at the time
    • Direct FGFR-to-NKD1 transcriptional mechanism not mapped
    • Whether Dvl binding mediates this hepatic role untested
  9. 2016 Medium

    Revealed a non-Wnt activity: NKD1 binds Rac1 and drives its proteasomal degradation affecting cytoskeleton and E-cadherin, within a Rac1-EZH2-NKD1 feedback loop.

    Evidence Co-IP, overexpression/knockdown, proteasome inhibitor assay, invasion and E-cadherin assays in HCC

    PMID:27231134

    Open questions at the time
    • No identified E3 ligase mediating Rac1 degradation
    • Single-lab; reciprocal loop mechanism incomplete
  10. 2016 Medium

    Distinguished Nkd1 from Nkd2 mechanistically by showing Rnf25/AO7 disrupts the Nkd1-Axin inhibitory complex to positively regulate Wnt.

    Evidence Co-IP, Wnt target gene expression, zebrafish morpholino knockdown

    PMID:27007149

    Open questions at the time
    • E3-ligase-independent disruption mechanism unclear
    • Stoichiometry of Nkd1-Axin complex undefined
  11. 2022 Medium

    Showed a pro-oncogenic Wnt-activating role in colon cancer: NKD1 promotes APC ubiquitination by restraining USP15, enhancing beta-catenin nuclear accumulation.

    Evidence Co-IP, ubiquitination assay, USP15 interaction, luciferase reporter, loss/gain-of-function

    PMID:36445120

    Open questions at the time
    • Reconciliation with NKD1's Wnt-antagonist role not addressed
    • Direct E3 ligase for APC not identified
  12. 2023 Medium

    Demonstrated a nuclear transcriptional function: NKD1 binds the YWHAE promoter to activate transcription and promote glucose uptake in colon cancer.

    Evidence ChIP, dual-luciferase reporter, overexpression/knockout, immunofluorescence, glucose uptake assay

    PMID:37202194

    Open questions at the time
    • No DNA-binding domain defined for NKD1
    • Mechanism of nuclear translocation unresolved
  13. 2023 Medium

    Identified PCM1 as an NKD1 interactor degraded via the ubiquitin-proteasome pathway, linking NKD1 to cell-cycle progression in colorectal cancer.

    Evidence Quantitative proteomics, Co-IP, immunofluorescence, siRNA, cell cycle analysis

    PMID:37338734

    Open questions at the time
    • E3 ligase mediating PCM1 degradation not identified
    • Single-lab; reciprocal validation limited
  14. 2024 High

    Placed Nkd1 downstream of Axin2 in the Wnt feedback hierarchy via rigorous double-mutant epistasis.

    Evidence CRISPR axin2/nkd1 double-mutant zebrafish, qRT-PCR, RNA-seq, mass spectrometry, Wnt sensitivity assays

    PMID:38656801

    Open questions at the time
    • Direct molecular link between Axin2 and Nkd1 not defined
    • Does not address non-Wnt NKD1 functions
  15. 2024 Medium

    Established m6A control of NKD1: YTHDF3 suppresses NKD1 transcription and translation, derepressing Wnt/beta-catenin to promote HCC migration and invasion.

    Evidence RNA-seq, meRIP-seq, Lace-seq, Western blot, in vitro/in vivo functional assays

    PMID:39127439

    Open questions at the time
    • Specific m6A sites on NKD1 transcript not finely mapped
    • Single-lab
  16. 2025 Medium

    Defined an EF-hand-dependent MYC-stabilizing axis: NKD1 binds MYC, blocks LC3B-mediated autophagic degradation, and promotes its nuclear entry, downstream of PPARdelta.

    Evidence Differential proteomics (SW620 vs nkd1-/-), Co-IP, autophagy analysis, EF-hand mutant, PPARdelta ChIP on NKD1 promoter

    PMID:40675969

    Open questions at the time
    • How EF-hand binding blocks LC3B-MYC interaction structurally unresolved
    • Reconciliation with NKD1 tumor-suppressive activity not addressed
  17. 2026 Medium

    Showed Wnt3a induces NKD1 and triggers its membrane detachment, enabling direct MSX1 interaction and nuclear translocation to drive odontogenic gene activation and reparative dentin formation.

    Evidence scRNA-seq, SCENIC, CUT&Tag, co-localization, in vivo murine pulp exposure model, overexpression

    PMID:41526338

    Open questions at the time
    • Mechanism of NKD1 membrane detachment undefined
    • Direct vs indirect NKD1-MSX1 binding not biochemically isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NKD1 switches between Wnt-antagonist and Wnt/proliferation-promoting roles, and how its cytoplasmic-degradation and nuclear-transcriptional activities are coordinated, remains unresolved.
  • No structural model of EF-hand engagement with distinct partners (MYC, beta-catenin, Dvl)
  • No defined E3 ligase for NKD1-promoted degradation of Rac1/PCM1/APC
  • Context determinants of antagonist vs oncogenic behavior undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060089 molecular transducer activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
APCAXINDVL2MSX1MYCPCM1RAC1YWHAE
Complex memberships
Wnt signalosome

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Human NKD1 protein contains an EF-hand motif in its NH2 domain and shows 43.8% amino acid identity with NKD2; it was cloned and characterized as a Dishevelled-binding protein functioning as a negative regulator of the WNT-beta-catenin-TCF signaling pathway, based on homology to mouse Nkd. Molecular cloning, sequence analysis, domain prediction International journal of oncology Low 11604995
2004 The EF-hand motif of Nkd1 is required for its inhibitory function in the Wnt/beta-catenin signaling pathway; targeted deletion of the EF-hand in mice resulted in increased nuclear beta-catenin in elongating spermatids and reduced sperm count, demonstrating that the EF-hand is necessary for Nkd1-mediated inhibition of Wnt/beta-catenin signaling in spermatogenesis. Targeted knock-in mutagenesis (EF-hand deletion), mouse genetic model, nuclear beta-catenin immunostaining, sperm count analysis The Journal of biological chemistry High 15546883
2007 Mouse Nkd1 and Nkd2 proteins bind Dvl (Dishevelled) proteins and inhibit Wnt signaling; targeted replacement of nkd exons encoding Dvl-binding sequences with IRES-lacZ/neomycin cassettes generated viable double-knockout mice with subtle cranial bone morphology alterations, showing that nkd1 and nkd2 are dispensable for murine embryonic development but play a role in Wnt/beta-catenin antagonism via Dvl binding. Gene targeting (Dvl-binding domain replacement), double-knockout mouse generation, morphological analysis Molecular and cellular biology High 17438140
2009 Mutations in human NKD1 found in colorectal cancer reduce its ability to inhibit Wnt signaling, stabilize beta-catenin, promote cell proliferation, and reduce NKD1's ability to bind and destabilize Dvl proteins, establishing NKD1 as a functional Wnt pathway antagonist acting through Dvl binding and destabilization. Mutation identification in colorectal tumors, functional assays (Wnt signaling reporter, beta-catenin stabilization, cell proliferation), co-immunoprecipitation for Dvl binding PloS one High 19956716
2010 Zebrafish Nkd1 promotes Dvl protein degradation upon overexpression; knockdown of Nkd1 specifically in dorsal forerunner cells leads to beta-catenin nuclear localization, transcriptional activation, defects in DFC migration, Kupffer's vesicle formation, ciliogenesis, and left-right patterning, establishing Nkd1 as a beta-catenin antagonist required for left-right axis establishment. Nkd1 overexpression (Dvl degradation assay), morpholino knockdown targeted to DFCs, beta-catenin nuclear localization assay, left-right patterning analysis, ciliogenesis analysis Developmental biology High 20858476
2013 Nkd1 functions as a passive antagonist of Wnt/beta-catenin signaling in zebrafish, meaning its antagonistic activity is enhanced only when canonical Wnt signaling levels have been destabilized (e.g., in Wnt/PCP mutants silberblick/wnt11 and trilobite/vangl2), rather than actively suppressing normal Wnt levels. Genetic epistasis using zebrafish Wnt/PCP mutant lines (slb/wnt11, tri/vangl2), Wnt8a overexpression, phenotypic rescue by Nkd1 PloS one Medium 24009776
2015 Nkd1 activity is specifically dependent on Wnt ligand activation of the receptor; Nkd1 is recruited to the Wnt signalosome with Dvl2 upon Wnt ligand stimulation, then moves into the cytoplasm to interact with beta-catenin and inhibit its nuclear accumulation. Wnt-responsive zebrafish blastula cell assays, signalosome recruitment assay, beta-catenin nuclear localization assay Molecular biology of the cell Medium 25904337
2015 NKD1 is an immediate early target gene induced by FGF receptor signaling; NKD1 suppresses canonical WNT signaling during the transition from endoderm to hepatic progenitor cells, and loss of NKD1 impairs hepatic progenitor cell formation from human iPSCs in a manner rescued by pharmacological WNT antagonism. FGFR inhibitor treatment, NKD1 knockdown in human iPSC differentiation, pharmacological WNT antagonist rescue Genes & development High 26637527
2016 NKD1 interacts with Rac1 in the cytoplasm and promotes its degradation via the ubiquitin-proteasome pathway; NKD1 overexpression in HCC cells reduces Rac1 expression and activity, affecting cytoskeletal organization and E-cadherin expression; conversely, Rac1 overexpression enhances NKD1 transcription by negatively regulating EZH2, forming a feedback loop. Co-immunoprecipitation, overexpression/knockdown, ubiquitin-proteasome inhibitor assay, in vitro and in vivo invasion assays, E-cadherin expression analysis Scientific reports Medium 27231134
2016 Rnf25/AO7 E3 ubiquitin ligase physically interacts with both Nkd1 and Axin in an E3 ligase-independent manner, disrupting the Nkd1-Axin inhibitory complex and thereby positively regulating Wnt signaling; this interaction distinguishes Nkd1 from Nkd2 in their feedback regulation of Wnt signaling. Co-immunoprecipitation, Wnt target gene expression assay, morpholino knockdown in zebrafish Oncotarget Medium 27007149
2022 NKD1 binds APC protein and promotes its ubiquitination degradation by restraining expression of the deubiquitinating enzyme USP15 and blocking the USP15-APC interaction, thereby enhancing beta-catenin nuclear accumulation and promoting colon cancer cell proliferation and migration. Co-immunoprecipitation, ubiquitination assay, USP15 interaction analysis, luciferase reporter assay, loss-of-function/overexpression experiments Cancer science Medium 36445120
2023 NKD1 protein binds to the YWHAE gene promoter region and activates its transcription, thereby promoting glucose uptake in colon cancer cells; NKD1 and YWHAE proteins also co-localize in colon cancer cells. ChIP assay, dual-luciferase reporter gene assay, NKD1 overexpression/knockout, immunofluorescence, glucose uptake assay Nan fang yi ke da xue xue bao Medium 37202194
2023 NKD1 interacts with PCM1 and promotes PCM1 degradation through the ubiquitin-proteasome pathway; this NKD1/PCM1 interaction mediates NKD1-regulated cell proliferation and cell cycle progression in colorectal cancer cells. Quantitative proteomics, co-immunoprecipitation, immunofluorescence, siRNA knockdown, cell cycle analysis Molecular biology reports Medium 37338734
2024 YTHDF3, an m6A reader, suppresses NKD1 transcription and translation in an m6A-dependent manner; reduced NKD1 expression activates the WNT/beta-catenin signaling pathway, promoting HCC cell migration and invasion, establishing NKD1 as a downstream target of YTHDF3-mediated m6A modification. RNA-seq, meRIP-seq, Lace-seq, Western blot, in vitro and in vivo functional assays Experimental cell research Medium 39127439
2024 Nkd1 functions downstream of Axin2 in Wnt signaling feedback; genetic epistasis in axin2/nkd1 double-mutant zebrafish demonstrated that the double mutant phenotype (including Wnt target gene expression profile by qRT-PCR/RNA-seq and protein expression by mass spectrometry) resembles nkd1 single mutant, placing Nkd1 downstream of Axin2 in the pathway. CRISPR/Cas9 double-mutant zebrafish generation, qRT-PCR, RNA-seq, mass spectrometry protein expression, Wnt sensitivity assays Molecular biology of the cell High 38656801
2025 NKD1 binds MYC protein through its EF-hand domain, inhibits autophagic degradation of MYC by suppressing the LC3B-MYC interaction, and facilitates MYC nuclear entry; PPARdelta acts as a transcription factor for NKD1; this PPARdelta/NKD1/MYC axis promotes colon cancer cell proliferation, migration, and angiogenesis. Differential protein expression profiling (SW620 vs SW620-nkd1-/-), Co-IP, autophagy pathway analysis, EF-hand domain mutant analysis, ChIP for PPARdelta on NKD1 promoter, NKD1 knockout cell line Cell death & disease Medium 40675969
2026 Wnt3a specifically induces NKD1 expression and triggers NKD1 membrane detachment; NKD1 then directly interacts with MSX1 (identified as a key transcription factor via SCENIC analysis), facilitating MSX1 nuclear translocation to promote odontogenic gene activation; MSX1 occupancy at odontogenic gene promoters was validated by CUT&Tag, and Wnt3a-activated NKD1-MSX1 signaling enhances reparative dentin formation in vivo. Single-cell transcriptomics, SCENIC gene regulatory network analysis, CUT&Tag, co-localization assay, in vivo murine pulp exposure model, overexpression experiments International journal of oral science Medium 41526338

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Molecular cloning, gene structure, and expression analyses of NKD1 and NKD2. International journal of oncology 115 11604995
2017 miR-532 promoted gastric cancer migration and invasion by targeting NKD1. Life sciences 54 28356225
2019 Exosome-mediated transfer of miR-1290 promotes cell proliferation and invasion in gastric cancer via NKD1. Acta biochimica et biophysica Sinica 42 31435644
2009 Mutations in the human naked cuticle homolog NKD1 found in colorectal cancer alter Wnt/Dvl/beta-catenin signaling. PloS one 42 19956716
2018 The lncRNA H19 positively affects the tumorigenic properties of glioblastoma cells and contributes to NKD1 repression through the recruitment of EZH2 on its promoter. Oncotarget 41 29643989
2004 A targeted mutation of Nkd1 impairs mouse spermatogenesis. The Journal of biological chemistry 38 15546883
2010 Zebrafish Nkd1 promotes Dvl degradation and is required for left-right patterning. Developmental biology 35 20858476
2013 Nkd1 functions as a passive antagonist of Wnt signaling. PloS one 34 24009776
2017 Long non-coding RNA HNF1A-AS1 promotes hepatocellular carcinoma cell proliferation by repressing NKD1 and P21 expression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 33 28292020
2015 Wnt ligand-dependent activation of the negative feedback regulator Nkd1. Molecular biology of the cell 31 25904337
2007 Viable mice with compound mutations in the Wnt/Dvl pathway antagonists nkd1 and nkd2. Molecular and cellular biology 31 17438140
2015 FGF2 mediates hepatic progenitor cell formation during human pluripotent stem cell differentiation by inducing the WNT antagonist NKD1. Genes & development 30 26637527
2014 NKD1 marks intestinal and liver tumors linked to aberrant Wnt signaling. Cellular signalling 23 25446263
2016 The NKD1/Rac1 feedback loop regulates the invasion and migration ability of hepatocarcinoma cells. Scientific reports 20 27231134
2022 Let-7b-5p inhibits colon cancer progression by prohibiting APC ubiquitination degradation and the Wnt pathway by targeting NKD1. Cancer science 16 36445120
2015 Expression pattern and clinicopathologic significance of NKD1 in human primary hepatocellular carcinoma. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 12 25706354
2006 Expression and regulation of Nkd-1, an intracellular component of Wnt signalling pathway in the chick embryo. Anatomy and embryology 9 16763811
2024 YTHDF3-mediated m6A modification of NKD1 regulates hepatocellular carcinoma invasion and metastasis by activating the WNT/β-catenin signaling axis. Experimental cell research 8 39127439
2016 Rnf25/AO7 positively regulates wnt signaling via disrupting Nkd1-Axin inhibitory complex independent of its ubiquitin ligase activity. Oncotarget 8 27007149
2017 Downregulation of NKD1 in human osteosarcoma and its clinical significance. Molecular medicine reports 7 29115501
2024 Nkd1 functions downstream of Axin2 to attenuate Wnt signaling. Molecular biology of the cell 6 38656801
2023 Clinical Significance of NKD Inhibitor of WNT Signaling Pathway 1 (NKD1) in Glioblastoma. Genetics research 3 36969985
2025 NKD1 enhances colon cancer progression by inhibiting the autophagic degradation of MYC. Cell death & disease 1 40675969
2023 [NKD1 promotes glucose uptake in colon cancer cells by activating YWHAE transcription]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 1 37202194
2023 NKD1 targeting PCM1 regulates the therapeutic effects of homoharringtonine on colorectal cancer. Molecular biology reports 1 37338734
2019 miR-532 promotes colorectal cancer invasion and metastasis by targeting NKD1. Cellular and molecular biology (Noisy-le-Grand, France) 1 31472047
2026 Wnt3a promotes in situ dentin formation through NKD1-MSX1 axis-mediated odontogenic differentiation of dental pulp stem cells. International journal of oral science 0 41526338

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