Affinage

DKK1

Dickkopf-related protein 1 · UniProt O94907

Length
266 aa
Mass
28.7 kDa
Annotated
2026-06-09
100 papers in source corpus 36 papers cited in narrative 36 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

DKK1 is a secreted glycoprotein that acts as a context-dependent antagonist of canonical Wnt/β-catenin signaling, patterning embryonic axes and tuning Wnt output in bone, cartilage, vasculature, immune cells, and epithelia (PMID:10625541, PMID:20858621, PMID:25080367). In development it is expressed in the Spemann organizer and prechordal plate, where its secreted Wnt-antagonist activity patterns the anterior nervous system and axial mesendoderm; this expression is driven directly by OTX2 binding the H1 regulatory region and is required, together with Wnt restraint, for anterior head and peri-cloacal anorectal/genitourinary morphogenesis (PMID:10625541, PMID:25231759, PMID:24479159). High-affinity Kremen receptors clear DKK1 from the cell surface through clathrin- and AP-2-dependent endocytosis governed by an atypical Kremen1 dileucine motif (PMID:23251700). In bone, osteoblast/osteocyte-derived DKK1 suppresses Wnt-driven osteoblast differentiation and new bone formation while promoting osteoclast activity, and its conditional loss is buffered by compensatory upregulation of sclerostin, such that combined Dkk1/Sost ablation yields synergistic anabolic bone gain; this axis underlies inflammatory bone erosion, periodontal bone loss, and protection of cartilage in osteoarthritis (PMID:20858621, PMID:19304568, PMID:29875318, PMID:31921182, PMID:25080367). DKK1 transcription is regulated by Osterix and C/EBPβ at the proximal promoter, by epigenetic activation through CBX7/p300 histone acetylation, EGFR-driven nuclear PKM2/p300-mediated H3 phospho-acetylation, and hypoxia-driven CREB/MMSET H3K36me2, and is silenced by CpG promoter hypermethylation in colon cancer (PMID:22459449, PMID:31963554, PMID:25351982, PMID:33172955, PMID:33420361, PMID:16491118). Beyond canonical Wnt inhibition, DKK1 drives β-catenin-independent oncogenic signaling: it binds CKAP4 to sustain hepatocellular carcinoma proliferation, signals through AKT and TGF-β1 to promote tumor growth and invasion, and through NF-κB and non-canonical Wnt/JNK to promote prostate cancer growth and suppress apoptosis (PMID:36718957, PMID:30906632, PMID:31568519, PMID:38067123). In the tumor microenvironment, stroma-derived DKK1 suppresses β-catenin in myeloid-derived suppressor cells to enforce immune suppression, and in migrating epithelial cells it disrupts directional polarity by mislocalizing Cdc42 and displacing Par6 from the leading edge (PMID:27045006, PMID:19776352).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 High

    Establishing DKK1 as a secreted Wnt antagonist that patterns the anterior nervous system answered what its core embryonic activity is and where it acts.

    Evidence Ectopic mRNA expression and genetic epistasis across zebrafish mutants with in situ hybridization

    PMID:10625541

    Open questions at the time
    • Receptor identity at the time undefined
    • Did not address mammalian organogenesis roles
  2. 2006 High

    Discovery of CpG promoter hypermethylation silencing DKK1 in colon cancer, with Wnt-independent tumor-suppressor effects upon re-expression, revealed both an epigenetic control mode and a β-catenin-independent function.

    Evidence Methylation-specific PCR, demethylation, colony/xenograft assays and TCF reporter in colon cancer lines

    PMID:16491118

    Open questions at the time
    • Mechanism of Wnt-independent suppression not defined
    • Receptor mediating the effect unknown
  3. 2009 High

    Linking extracellular DKK1 to mislocalized Cdc42 and Par6 displacement explained how it disrupts directional epithelial cell migration.

    Evidence Wound healing with reciprocal recombinant treatment/siRNA and immunofluorescence of polarity machinery in intestinal epithelial cells

    PMID:19776352

    Open questions at the time
    • Receptor coupling DKK1 to Cdc42 not identified
    • Relationship to canonical Wnt not resolved
  4. 2010 High

    In vivo neutralization in inflammatory and metastatic models established DKK1 as a driver of pathological bone remodeling acting on both osteoblasts and osteoclasts, and through canonical and non-canonical (JNK) Wnt arms.

    Evidence Anti-Dkk-1 antibody in TNFtg mice, prostate cancer bone metastasis models, histomorphometry, TCF reporter, phospho-JNK blots

    PMID:19304568 PMID:20858621 PMID:20957670

    Open questions at the time
    • Cell-intrinsic vs paracrine contributions not separated
    • Direct receptors in osteoclast lineage unclear
  5. 2012 High

    Identifying Osterix as a direct activator and Kremen-mediated clathrin endocytosis defined transcriptional control and surface clearance of DKK1.

    Evidence ChIP, promoter deletion luciferase, Osx-null calvaria; Kremen1 dileucine mutagenesis with AP-2 siRNA and pitstop 2

    PMID:22459449 PMID:23251700

    Open questions at the time
    • How endocytosis quantitatively tunes Wnt inhibition unclear
    • Other promoter inputs not mapped
  6. 2012 High

    Demonstrating DKK1 protection of cartilage and angiogenic regulation expanded its role into joint disease and vascular biology.

    Evidence Chondrocyte transgenic/adenoviral OA models with Wnt-3a catabolic gene assays; synovial fibroblast HIF-1α/angiogenic axis and tumor vascular models

    PMID:22488261 PMID:22736200 PMID:24091497

    Open questions at the time
    • Context-dependent pro- vs anti-angiogenic switch mechanism unclear
    • Distinct from DKK2 opposing role unexplained
  7. 2014 High

    OTX2 binding the H1 element and conditional Dkk1 deletion in peri-cloacal mesenchyme established direct upstream control and a developmental requirement in head and anorectal/genitourinary morphogenesis.

    Evidence Conditional Otx2/Dkk1 knockouts, ChIP, luciferase, compound-mutant epistasis, BrdU proliferation

    PMID:24479159 PMID:25231759

    Open questions at the time
    • Cross-tissue generalization of OTX2 control untested
    • Other transcriptional inputs in non-neural tissues unmapped
  8. 2014 Medium

    Identifying CBX7/p300 histone acetylation as a DKK1 activator and CA9 as a binding partner broadened the regulatory and interaction landscape.

    Evidence ChIP for promoter acetylation, CBX7-p300 co-IP, stem-cell marker rescue; CA9 co-IP and domain mapping with mTOR/angiogenesis readouts

    PMID:22430125 PMID:25351982

    Open questions at the time
    • CA9 interaction is single-lab without reciprocal validation in vivo
    • Physiological significance of CA9 binding unclear
  9. 2016 High

    Showing stroma-derived DKK1 suppresses β-catenin in MDSCs answered how it contributes to tumor immune suppression beyond tumor-cell-autonomous effects.

    Evidence Antibody neutralization, myeloid β-catenin conditional KO epistasis, MDSC depletion, recombinant DKK1 in mouse and human cells

    PMID:27045006

    Open questions at the time
    • Receptor on MDSCs not identified
    • Breadth across tumor types not established
  10. 2018 High

    Conditional Dkk1/Sost double deletion revealed sclerostin as the compensatory mechanism limiting the bone phenotype of DKK1 loss, explaining why single inhibition is buffered.

    Evidence Bone-specific Dkk1 KO, Sost KO epistasis, dual antibody co-treatment, μCT/DXA/biomechanics

    PMID:29875318

    Open questions at the time
    • Molecular basis of Sost upregulation upon DKK1 loss undefined
  11. 2019 Medium

    Dissection of Wnt-axis-independent oncogenic signaling through AKT and TGF-β1 clarified how DKK1 promotes proliferation and invasion without engaging β-catenin.

    Evidence siRNA knockdown and recombinant treatment in esophageal and hepatocellular carcinoma cells with AKT/β-catenin and TGF-β1 reciprocal readouts

    PMID:30906632 PMID:31568519

    Open questions at the time
    • Receptor linking DKK1 to AKT/TGF-β1 not resolved in these studies
    • Single-lab, single-line findings
  12. 2020 High

    Mapping EGFR-driven nuclear PKM2/p300 H3 phospho-acetylation and C/EBPβ induction defined signal-responsive transcriptional activation of DKK1.

    Evidence Site-directed mutagenesis of PKM2-Ser37/p300-Ser1834, ChIP at DKK1 promoter, in vivo HCC; C/EBPβ ChIP and 1,25D3 secretion/mineralization assays

    PMID:31963554 PMID:33172955

    Open questions at the time
    • Integration of multiple promoter inputs in vivo unclear
    • Cell-type specificity of each pathway not delineated
  13. 2021 Medium

    Hypoxia-driven CREB/MMSET H3K36me2 and DKK1-WWP2-GLI2 crosstalk linked DKK1 induction and downstream Hedgehog activation to myeloma bone disease and drug resistance.

    Evidence p38/CREB/MMSET knockdown, ChIP for H3K36me2; WWP2/GLI2 ubiquitination assays and bortezomib resistance models

    PMID:33420361 PMID:34546340

    Open questions at the time
    • WWP2-GLI2 axis single-lab without independent confirmation
    • Generalizability beyond myeloma untested
  14. 2023 High

    Identifying CKAP4 as a required receptor for DKK1-driven HCC proliferation and NF-κB/JNK signaling in prostate cancer pinned down β-catenin-independent receptor mechanisms.

    Evidence DKK1/CKAP4 deletion and domain-deletion rescue, anti-CKAP4 antibody with lenvatinib; prostate cancer DKK1 transduction with NF-κB/caspase and OPG/RANKL assays

    PMID:36718957 PMID:38067123

    Open questions at the time
    • Whether CKAP4 mediates AKT/TGF-β1 effects in other tumors untested
    • Structural basis of receptor selectivity unclear
  15. 2024 Medium

    Defining DKK1 loss as a driver of endometrial fibrosis via autophagy suppression and exosomal IL-8 extended its role into tissue fibrosis and stromal-immune crosstalk.

    Evidence DKK1 conditional KO mice, stromal cell siRNA/overexpression, autophagic flux and exosome IL-8 assays, rapamycin rescue

    PMID:38961399

    Open questions at the time
    • Single-lab study
    • Receptor/pathway selectivity in stromal cells not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The receptor logic distinguishing canonical Wnt-inhibitory DKK1 (via LRP5/6-Kremen) from β-catenin-independent signaling (CKAP4, AKT, NF-κB/JNK, TGF-β1) and how cells select between these outputs remains unresolved.
  • No unifying model linking receptor engagement to downstream pathway choice
  • Structural determinants of partner selection not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005576 extracellular region 3 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 1
Partners
CA9CKAP4KREMEN1LRP5LRP6

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 DKK1 is expressed in the Spemann organizer/prechordal plate and functions as a secreted Wnt antagonist; ectopic expression in zebrafish enlarged forebrain, eyes, and axial mesendoderm, and rescued forebrain/notochord defects in bozozok mutants, establishing that Dkk1 acts in dorsal mesendoderm to pattern the anterior nervous system and axial mesendoderm independently of dorso-anterior mesendoderm. Ectopic expression (mRNA injection), genetic epistasis in zebrafish mutants (boz, sqt, oep), in situ hybridization Developmental biology High 10625541
1999 Dkk-1 is expressed in interdigital mesenchyme during mouse limb development (E9.0–E14.5), with posterior expression initially overlapping Shh, suggesting a role in digit patterning downstream of key limb signaling molecules. Whole-mount in situ hybridization, double whole-mount in situ hybridization with Shh Mechanisms of development Medium 10559490
2006 DKK-1 gene is transcriptionally silenced by CpG island promoter hypermethylation in colon cancer cell lines; treatment with 5-aza-2'-deoxycytidine restored expression. Restoration of DKK-1 in non-expressing cells with truncated APC had no effect on β-catenin/TCF-dependent transcription but induced tumor suppressor-like features (reduced colony formation, tumor growth inhibition in nude mice), indicating DKK-1 functions independently of canonical Wnt signaling in this context. Bisulfite sequencing/methylation-specific PCR, 5-aza-2'-deoxycytidine demethylation, colony formation assay, nude mouse xenograft, luciferase TCF reporter assay Oncogene High 16491118
2007 DKK1 secreted by dermal fibroblasts suppresses melanocyte function and growth by downregulating MITF and β-catenin, and increases keratinocyte proliferation while decreasing melanin uptake; treatment of reconstructed skin with DKK1 induced a thicker, less pigmented epidermis, reproducing the palmoplantar phenotype through Wnt/β-catenin pathway modulation. Recombinant DKK1 treatment of keratinocytes and reconstructed skin, DNA microarray, RT-PCR, Western blotting FASEB journal High 17984176
2009 Dkk-1 inhibits intestinal epithelial cell migration by inducing mislocalized activation of Cdc42, displacing the polarity protein Par6 from the leading edge, and persistently inhibiting relocation of the microtubule organizing center and Golgi apparatus in the direction of migration; siRNA knockdown of Dkk-1 confirmed that extracellular Dkk-1 was required for this polarity defect. Wound healing assay, recombinant Dkk-1 treatment, siRNA knockdown, immunofluorescence of Cdc42, Par6, MTOC, and Golgi Molecular biology of the cell High 19776352
2010 Neutralization of Dkk-1 in TNF-transgenic mice completely protected from inflammatory bone loss by preventing TNF-mediated impairment of osteoblast function and enhanced osteoclast activity; TNF rapidly increased Dkk-1 expression in primary osteoblasts in vitro, blocking osteoblast differentiation; Dkk-1 blockade also reduced sclerostin expression in differentiated osteoblasts in vitro and in vivo, and reduced osteocyte death. Anti-Dkk-1 neutralizing antibody in hTNFtg mice, bone histomorphometry, β-catenin/osteocalcin/OPG immunohistochemistry, in vitro primary osteoblast stimulation with TNF Annals of the rheumatic diseases High 20858621
2010 Blockade of DKK1 in TNF-transgenic mice reduced bone erosions and osteoclast counts, promoted hypertrophic chondrocyte formation (collagen type X expression), and induced ankylosis of sacroiliac joints, without affecting inflammation; this demonstrates DKK1 normally suppresses Wnt-driven new bone formation in inflammatory joint disease. Anti-DKK1 antibody treatment in TNFtg mice, histology, immunohistochemistry for collagen X, β-catenin, osteoclast counting Annals of the rheumatic diseases High 19304568
2010 DKK-1 overexpression in Ace-1 prostate cancer cells increased subcutaneous tumor mass and incidence of bone metastases associated with increased phospho-JNK (non-canonical Wnt pathway), while decreasing the osteoblastic phenotype of bone metastases by inhibiting TCF activity in osteoblast precursors (canonical Wnt pathway). Stable DKK-1 overexpression, intracardiac/intratibial injection in athymic mice, bioluminescent imaging, micro-CT, histopathology, TCF luciferase assay in ST2 cells, Western blot for phospho-JNK The Prostate High 20957670
2010 Dkk-1 and Dkk-2 redundantly inhibit Wnt signaling to regulate myocardial proliferation during mouse heart development; double null embryos show myocardial hypertrophy with increased cell proliferation and epicardial hypercellularity with broadened Connexin 43 expression from proepicardial precursors. Double Dkk1/Dkk2 null mouse genetics, histology, immunohistochemistry, BrdU proliferation assay International journal of cardiology Medium 20439124
2012 DKK1 overexpression in chondrocytes (Col2a1-Dkk1 transgenic mice or intraarticular AdDkk-1 injection) inhibited DMM-induced experimental osteoarthritis; Wnt-3a-induced expression of Mmp13 and Adamts4 in chondrocytes was blocked by Dkk-1 pretreatment, establishing that Dkk-1 protects cartilage by suppressing Wnt-mediated catabolic factor expression. Chondrocyte-specific transgenic mice, intraarticular adenoviral injection, OA scoring, recombinant Wnt-3a/Dkk-1 treatment of primary chondrocytes, RT-PCR for Mmp13/Adamts4 Arthritis and rheumatism High 22488261
2012 Dkk-1 in synovial fibroblasts upregulates HIF-1α and angiogenic factors (SDF-1, CSF-1) and proteinases (ADAMTS-5, MMP-3) through stabilization of GSK3β-Ser9, β-catenin, TCF4, and ERK signaling; IL-1β-induced Dkk-1 promotes angiogenesis in endothelial cells. Knockdown of HIF-1α decreased Dkk-1–driven angiogenic factor expression. Anti-Dkk-1 antibody, siRNA knockdown, IL-1β stimulation, HIF-1α siRNA, ELISA, RT-PCR, in vitro angiogenesis assay, in vivo Dkk-1 antisense oligonucleotide in rat OA Arthritis and rheumatism High 22736200
2012 Osteoblast-specific transcription factor Osterix (Osx) directly binds to two GC-rich sites in the proximal 250 bp of the Dkk1 promoter and activates Dkk1 transcription; Dkk1 expression was downregulated in Osx-null calvaria and after Osx siRNA knockdown, and upregulated upon Osx overexpression. ChIP-qPCR, promoter deletion luciferase assays, siRNA knockdown, Osx overexpression in Tet-off C2C12 cells, Osx-null embryo calvaria RT-PCR Biochemical and biophysical research communications High 22459449
2012 Kremens (high-affinity DKK1 receptors) internalize DKK1 from the cell surface via clathrin-mediated endocytosis; Kremen1 contains an atypical dileucine motif (DXXXLV) required for internalization, and mutation of LV to AA blocked internalization; AP-2 inhibition or pitstop 2 (clathrin inhibitor) also blocked Kremen1 internalization. Mutagenesis of Kremen1 dileucine motif, AP-2 siRNA knockdown, clathrin inhibitor pitstop 2, flow cytometry/cell surface assay PloS one High 23251700
2013 DKK1 inhibits tumor angiogenesis and reduces pericyte coverage of tumor blood vessels in B16F10 melanoma-bearing mice, while DKK2 has opposite pro-angiogenic effects; these differential roles were confirmed in endothelial-specific DKK1/DKK2 transgenic mice and in an oxygen-induced retinopathy model. Adenoviral DKK1/DKK2 expression in tumor-bearing mice, endothelial-specific transgenic mice, tumor vascular density/perfusion quantification, pericyte coverage, oxygen-induced retinopathy model Angiogenesis High 24091497
2014 OTX2 directly activates Dkk1 expression by binding to the H1 regulatory region of Dkk1 in the anterior mesendoderm; tissue-specific ablation of Otx2 in the AME disrupted Dkk1 expression and phenocopied head truncation; compound Otx2;Dkk1 mutants showed enhanced head defects. Conditional Otx2 knockout, ChIP-qPCR, RT-qPCR, luciferase reporter assay, cross-species comparative analysis, genetic epistasis (compound mutants) Development (Cambridge, England) High 25231759
2014 Dkk-1 overexpression in bone (Col1a1-Dkk1 transgenic mice) ameliorated OA severity after meniscectomy by reducing subchondral bone Wnt/β-catenin activation, decreasing VEGF in osteoblasts, and thereby reducing MMP expression in chondrocytes; direct cartilage exposure to Dkk-1 caused proteoglycan loss and increased NITEGE expression, indicating distinct bone-mediated vs. direct cartilage effects. Col1a1-Dkk1 transgenic mice, meniscectomy OA model, X-Gal staining (Topgal reporter), micro-CT, histomorphometry, cartilage explant culture, VEGF/MMP mRNA analysis Arthritis & rheumatology (Hoboken, N.J.) High 25080367
2014 DKK-1 interacts with carbonic anhydrase IX (CA9) via the Val60-Tyr168 site of DKK-1 binding to the N-terminal domain of CA9 in vitro and in vivo; DKK-1 overexpression inhibited CA9-mediated mTOR phosphorylation and endothelial cell angiogenesis in tumorigenesis. Co-immunoprecipitation, domain mapping, mTOR phosphorylation assay, endothelial cell angiogenesis assay Cellular signalling Medium 22430125
2014 Dkk1 expression in peri-cloacal mesenchyme regulates anorectal and genitourinary tract formation; conditional Dkk1 deletion causes imperforate anus with rectourinary fistula and preputial hypospadias, associated with ectopic expansion of dorsal peri-cloacal mesenchyme (increased proliferation/survival) and elevated Wnt/β-catenin, Shh, Fgf8, and Bmp4 activity; genetic hyperactivation of Wnt/β-catenin in cloacal mesenchyme partially recapitulates Dkk1 mutant phenotypes. Conditional Dkk1 knockout mouse, β-catenin activation transgenic epistasis, histology, immunohistochemistry, BrdU proliferation assay Developmental biology High 24479159
2014 ox-LDL induces DKK1 expression in macrophages; DKK1 in turn decreases LOX-1 via Wnt/β-catenin pathway and increases ABCA/G1 via STAT3 pathway, thereby inhibiting cholesterol loading in macrophages. ox-LDL stimulation of macrophages, Western blot for LOX-1/ABCA1/ABCG1/β-catenin, STAT3 pathway analysis FEBS letters Medium 25436422
2014 CBX7 inhibits Wnt/β-catenin/TCF pathway by enhancing DKK-1 transcription through cooperation with p300 acetyltransferase, increasing histone acetylation at the DKK-1 promoter; pharmacologic DKK-1 inhibition in CBX7-overexpressing cells restored Wnt signaling and the CD44+/CD24−/ESA+ stem cell population. ChIP for histone acetylation at DKK-1 promoter, co-IP of CBX7 with p300, luciferase reporter, DKK-1 pharmacological inhibition, flow cytometry for stem cell markers FASEB journal High 25351982
2015 TNF strongly induces DKK-1 production in fibroblast-like synoviocytes, whereas IL-6 suppresses DKK-1 production and abrogates TNF-induced DKK-1 upregulation; the inverse correlation between DKK-1 and IL-6 levels in synovial fluid was confirmed in vitro in FLS cultures. FLS cell culture stimulation with TNF/IL-1β/IL-6, ELISA for DKK-1, correlation analysis in synovial fluid samples Arthritis & rheumatology (Hoboken, N.J.) Medium 25941031
2016 Stroma-derived DKK1 targets β-catenin in MDSCs to suppress their immune function and promote tumor growth; DKK1 neutralization decreases MDSC numbers by rescuing β-catenin; recombinant DKK1 suppressed β-catenin target genes in MDSCs from mice and humans; anti-DKK1 antitumor effects were lost in mice lacking β-catenin in myeloid cells or after MDSC depletion. DKK1 neutralizing antibody in tumor-bearing mice, myeloid-specific β-catenin conditional knockout epistasis, MDSC depletion, recombinant DKK1 treatment, flow cytometry, gene expression analysis The Journal of experimental medicine High 27045006
2018 Conditional deletion of Dkk1 from bone has negligible effects on bone mass unless sclerostin (Sost) is also removed; Dkk1 inhibition increases Sost expression as a compensatory mechanism. Combined deletion of Dkk1 and Sost, or co-administration of anti-Dkk1 and anti-sclerostin antibodies, produced synergistic anabolic bone gain exceeding individual or additive effects. Conditional Dkk1 bone-specific knockout, Sost osteocyte-specific knockout epistasis, sclerostin neutralizing antibody, DXA, μCT, histomorphometry, biomechanical testing JCI insight High 29875318
2018 Atorvastatin downregulates DKK-1 protein and mRNA through inhibition of Cdc42, Rho, and Rac geranylgeranylated proteins; DKK-1 itself mediates ~21% of statin-modulated proteins in endothelial cells, including clusterin/apoJ, PAI-1, MARCKS, and PTX3, establishing DKK-1 as a downstream effector of statin action. Label-free quantitative mass spectrometry proteomics, DKK-1 siRNA gene silencing, mRNA quantification, statin treatment ± geranylgeranyl pathway inhibitors, in vivo rabbit model Scientific reports High 30420710
2019 Osteocyte-specific deletion of Dkk-1 prevented alveolar bone loss in experimental periodontitis in mice, increasing bone volume/density, reducing osteoclast numbers, increasing bone formation markers (Runx2, Osteocalcin), decreasing RANKL expression, and reducing local inflammatory infiltrates; serum Dkk-1 was reduced and TCF-7 expression increased in these mice. Dkk-1fl/fl;Dmp1:Cre osteocyte-specific conditional knockout, experimental periodontitis ligature model, micro-CT, histomorphometry, RT-PCR, ELISA for Dkk-1/CTX/P1NP Frontiers in immunology High 31921182
2019 DKK1 knockdown in OE33 esophageal adenocarcinoma cells attenuated viability, proliferation, migration, and invasion; these effects were not mediated through the canonical β-catenin pathway but through downstream Akt phosphorylation; Wnt3a restored Akt phosphorylation in DKK1-depleted cells without further stimulating β-catenin transcription, indicating a Wnt-axis-independent oncogenic role for DKK1 via Akt. siRNA DKK1 knockdown, recombinant DKK1/Wnt3a treatment, Akt phosphorylation Western blot, β-catenin reporter assay, proliferation/migration/invasion assays American journal of cancer research Medium 30906632
2019 DKK1 promotes invasion and migration of hepatocellular carcinoma cells through a TGF-β1–dependent mechanism; knockdown of TGF-β1 negatively affected the DKK1 proinvasive effect; the canonical Wnt/β-catenin pathway was not responsible for the proinvasive effect as active β-catenin levels were unchanged upon DKK1 treatment. Recombinant DKK1 treatment, DKK1 siRNA knockdown, TGF-β1 siRNA knockdown, Boyden chamber invasion assay, zymography, MMP-2/MMP-9 Western blot, ELISA PloS one Medium 31568519
2020 EGF receptor activation promotes DKK1 transcription in HCC via parallel MEK-ERK and PI3K-Akt pathways: ERK phosphorylates PKM2 at Ser37 promoting its nuclear translocation, and Akt phosphorylates p300 at Ser1834; nuclear PKM2 and p300 then cooperatively mediate phosphorylation and acetylation of histone H3 at the DKK1 promoter to synergistically enhance DKK1 transcription. Mutational analysis of PKM2-Ser37 and p300-Ser1834, nuclear fractionation, ChIP for histone H3 phosphorylation/acetylation at DKK1 promoter, MEK/PI3K inhibition, chemically-induced HCC rat model Science signaling High 33172955
2020 1,25-dihydroxyvitamin D3 (1,25D3) promotes DKK1 expression in osteoblasts by inducing C/EBPβ, which directly binds the human DKK1 promoter; 1,25D3 also stimulates secretion of DKK1 from the endoplasmic reticulum to the extracellular space; blocking DKK1 attenuated calcified nodule formation in mineralized osteoblasts without affecting ALP activity or collagen synthesis, establishing a required role for DKK1 in osteoblast mineralization. C/EBPβ siRNA knockdown and overexpression, ChIP for C/EBPβ at DKK1 promoter, 1,25D3 treatment, DKK1 secretion/ER trafficking assay, DKK1 blocking antibody in mineralization assay Cells High 31963554
2021 Under hypoxia, p38 kinase phosphorylates CREB driving its nuclear import to activate DKK1 transcription in myeloma cells; CREB recruits MMSET (a downstream target of HIF-1α induced by hypoxia), stabilizing HIF-1α protein and increasing H3K36me2 at the DKK1 promoter; combined CREB inhibition and hypoxia-activated prodrug reduced MM-induced bone destruction in vivo. p38 inhibition, CREB knockdown, MMSET knockdown, ChIP for H3K36me2 at DKK1 promoter, nuclear import assay, in vivo MM bone destruction model Oncogene High 33420361
2021 DKK1 suppresses WWP2 (an E3 ubiquitin ligase) expression via canonical Wnt/β-catenin signaling; loss of WWP2 stabilizes GLI2 (a Hedgehog transcription factor) by preventing its ubiquitination and proteasomal degradation, thereby activating Hedgehog signaling and promoting bortezomib resistance in multiple myeloma cells. WWP2 knockdown and overexpression, DKK1 manipulation, GLI2 ubiquitination assay, Hh pathway reporter, in vitro and in vivo bortezomib resistance assays Carcinogenesis Medium 34546340
2022 hAMSC-derived DKK-1 (along with IGFBP-3 and DKK-3) inhibits hepatic stellate cell activation by blocking the canonical Wnt/β-catenin signaling pathway; siRNA silencing of DKK-1 in hAMSCs reversed this inhibitory effect, attenuating the anti-fibrotic action; this was confirmed via GSK3β/β-catenin pathway assessment. hAMSC transplantation in CCl4-induced liver fibrosis mice, antibody array for secreted cytokines, siRNA knockdown of DKK-1/DKK-3/IGFBP-3, Western blot for Wnt/β-catenin components Stem cell research & therapy Medium 35659360
2023 DKK1 binding to CKAP4 is required for HCC cell proliferation; DKK1 lacking the CKAP4 binding region did not rescue phenotypes caused by DKK1 depletion; deletion of either DKK1 or CKAP4 inhibited HCC cell growth; anti-CKAP4 antibody inhibited HCC growth and showed enhanced antitumor effect when combined with lenvatinib. DKK1/CKAP4 deletion in HCC cells, domain-deletion rescue experiment, anti-CKAP4 antibody treatment, in vivo HCC tumor growth assay, co-treatment with lenvatinib Cancer science High 36718957
2023 DKK1 in prostate cancer cells promotes growth and migration independently of canonical Wnt signaling via upregulation of NF-κB/p65 signaling, inhibition of caspase-dependent apoptosis through downregulation of non-canonical Wnt/JNK signaling, and upregulation of EMT genes; DKK1 also inhibits osteoblast differentiation and promotes osteoclast activity by decreasing the OPG/RANKL ratio in the bone microenvironment. Stable DKK1 transduction in Probasco PCa cells, intratibial/intracardiac injection in nude mice, in vitro proliferation/migration assays, NF-κB/p65 and caspase Western blot, primary osteoblast/osteoclast co-culture assays, OPG/RANKL measurement Cells High 38067123
2023 NR2F2 silencing in endothelial cells induces DKK1 production; co-silencing DKK1 and NR2F2 prevents NR2F2-loss-induced STAT and AKT activation and reverses endothelial-to-mesenchymal transition, establishing DKK1 as a downstream effector of NR2F2 loss that drives pathologic endothelial signaling. NR2F2 siRNA silencing, co-silencing of NR2F2 and DKK1, STAT/AKT phosphorylation Western blot, EndMT marker analysis, serum DKK1 ELISA in PAH patients American journal of physiology. Lung cellular and molecular physiology Medium 37039367
2024 DKK1 loss in endometrial stromal cells promotes endometrial fibrosis by suppressing autophagic flux through Wnt/β-catenin and PI3K/AKT/mTOR pathways, and by promoting secretion of IL-8 in exosomes that drives macrophage proliferation and macrophage-to-myofibroblast transition; rapamycin partially restored the fibrotic phenotype in DKK1 conditional knockout mice. DKK1 conditional knockout mice, DKK1 siRNA/overexpression in endometrial stromal cells, autophagic flux assay, exosome IL-8 measurement, rapamycin rescue experiment, immunohistochemistry for α-SMA/macrophages Journal of translational medicine Medium 38961399

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene 292 16491118
2010 Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression. Annals of the rheumatic diseases 169 20858621
2009 Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints. Annals of the rheumatic diseases 167 19304568
2000 Zebrafish Dkk1 functions in forebrain specification and axial mesendoderm formation. Developmental biology 159 10625541
2005 SK channels in excitability, pacemaking and synaptic integration. Current opinion in neurobiology 148 15922588
2016 Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer. The Journal of experimental medicine 140 27045006
2015 Sclerostin and DKK1: new players in renal bone and vascular disease. Kidney international 123 26083653
2007 Dickkopf 1 (DKK1) regulates skin pigmentation and thickness by affecting Wnt/beta-catenin signaling in keratinocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 122 17984176
2012 Gremlin 1, frizzled-related protein, and Dkk-1 are key regulators of human articular cartilage homeostasis. Arthritis and rheumatism 114 22576962
2014 Dkk-1-mediated inhibition of Wnt signaling in bone ameliorates osteoarthritis in mice. Arthritis & rheumatology (Hoboken, N.J.) 106 25080367
2010 Dickkopf-1 (DKK-1) stimulated prostate cancer growth and metastasis and inhibited bone formation in osteoblastic bone metastases. The Prostate 106 20957670
2007 Dickkopf-1 (DKK1) is a widely expressed and potent tumor-associated antigen in multiple myeloma. Blood 101 17515399
2012 Dkk-1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice. Arthritis and rheumatism 99 22488261
2010 Control of Dkk-1 ameliorates chondrocyte apoptosis, cartilage destruction, and subchondral bone deterioration in osteoarthritic knees. Arthritis and rheumatism 83 20131282
2013 GREM1, FRZB and DKK1 mRNA levels correlate with osteoarthritis and are regulated by osteoarthritis-associated factors. Arthritis research & therapy 69 24286177
2009 Functions and modulation of neuronal SK channels. Cell biochemistry and biophysics 69 19655101
2018 Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition. JCI insight 66 29875318
2017 MicroRNA-433-3p promotes osteoblast differentiation through targeting DKK1 expression. PloS one 66 28628652
2022 Drug Discovery of DKK1 Inhibitors. Frontiers in pharmacology 64 35355709
2014 CBX7 inhibits breast tumorigenicity through DKK-1-mediated suppression of the Wnt/β-catenin pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 63 25351982
2021 Expression and Role of Dickkopf-1 (Dkk1) in Tumors: From the Cells to the Patients. Cancer management and research 60 33536782
2015 Tumor necrosis factor and interleukin-6 differentially regulate Dkk-1 in the inflamed arthritic joint. Arthritis & rheumatology (Hoboken, N.J.) 60 25941031
2008 SK-NEP-1 and Rh1 are Ewing family tumor lines. Pediatric blood & cancer 58 17154184
2013 Sclerostin and DKK1 in primary hyperparathyroidism. Calcified tissue international 55 23430197
2022 Human amniotic mesenchymal stem cells-derived IGFBP-3, DKK-3, and DKK-1 attenuate liver fibrosis through inhibiting hepatic stellate cell activation by blocking Wnt/β-catenin signaling pathway in mice. Stem cell research & therapy 54 35659360
2012 Functional expression of SK channels in murine detrusor PDGFR+ cells. The Journal of physiology 54 23148317
2020 Wnt signaling modulator DKK1 as an immunotherapeutic target in ovarian cancer. Gynecologic oncology 53 32192732
2012 The role of BMPs in bone anabolism and their potential targets SOST and DKK1. Current molecular pharmacology 51 21787290
2009 Regulation of skin pigmentation and thickness by Dickkopf 1 (DKK1). The journal of investigative dermatology. Symposium proceedings 51 19675559
2018 Dickkopf-1 (Dkk-1) serum levels in systemic sclerosis and rheumatoid arthritis patients: correlation with the Trabecular Bone Score (TBS). Clinical rheumatology 49 30291470
2018 Dkk1 involvement and its potential as a biomarker in pancreatic ductal adenocarcinoma. Clinica chimica acta; international journal of clinical chemistry 48 30452897
2013 RANKL/OPG ratio and DKK-1 expression in primary osteoblastic cultures from osteoarthritic and osteoporotic subjects. The Journal of rheumatology 45 23457386
2012 Dickkopf-1 (DKK1) promotes invasion and metastasis of hepatocellular carcinoma. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 44 23266194
2012 Dkk-1 promotes angiogenic responses and cartilage matrix proteinase secretion in synovial fibroblasts from osteoarthritic joints. Arthritis and rheumatism 42 22736200
1999 Expression pattern of Dkk-1 during mouse limb development. Mechanisms of development 42 10559490
2013 Distinct roles of DKK1 and DKK2 in tumor angiogenesis. Angiogenesis 41 24091497
2017 In psoriatic arthritis Dkk-1 and PTH are lower than in rheumatoid arthritis and healthy controls. Clinical rheumatology 40 28634697
2019 DKK1 promotes hepatocellular carcinoma inflammation, migration and invasion: Implication of TGF-β1. PloS one 39 31568519
2020 EGF promotes DKK1 transcription in hepatocellular carcinoma by enhancing the phosphorylation and acetylation of histone H3. Science signaling 38 33172955
2021 Perspectives on miRNAs Targeting DKK1 for Developing Hair Regeneration Therapy. Cells 37 34831180
2019 LncRNA XIST facilitates cell growth, migration and invasion via modulating H3 histone methylation of DKK1 in neuroblastoma. Cell cycle (Georgetown, Tex.) 37 31208278
2015 SK channels and calmodulin. Channels (Austin, Tex.) 37 25942650
2010 Dkk1 and Dkk2 regulate epicardial specification during mouse heart development. International journal of cardiology 37 20439124
2022 New Emerging Biomarkers for Bone Disease: Sclerostin and Dickkopf-1 (DKK1). Calcified tissue international 35 36165920
2009 Clinical significance of serum DKK-1 in patients with gynecological cancer. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 35 19820386
2019 Changes in Dkk-1, sclerostin, and RANKL serum levels following discontinuation of long-term denosumab treatment in postmenopausal women. Bone 34 30910600
2018 Identification of DKK-1 as a novel mediator of statin effects in human endothelial cells. Scientific reports 33 30420710
2017 CSN5/JAB1 suppresses the WNT inhibitor DKK1 in colorectal cancer cells. Cellular signalling 33 28229932
2014 Preliminary mechanism on the methylation modification of Dkk-1 and Dkk-3 in hepatocellular carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 31 25344678
2009 Dkk-1 inhibits intestinal epithelial cell migration by attenuating directional polarization of leading edge cells. Molecular biology of the cell 31 19776352
2019 Dickkopf-1 (DKK1) promotes tumor growth via Akt-phosphorylation and independently of Wnt-axis in Barrett's associated esophageal adenocarcinoma. American journal of cancer research 30 30906632
2010 The regulation of Dkk1 expression during embryonic development. Developmental biology 30 20144607
2020 SOX9-activated PXN-AS1 promotes the tumorigenesis of glioblastoma by EZH2-mediated methylation of DKK1. Journal of cellular and molecular medicine 29 32329150
2018 DKK1 and Kremen Expression Predicts the Osteoblastic Response to Bone Metastasis. Translational oncology 29 29772510
2014 Sclerostin and Dkk-1 in patients with ankylosing spondylitis. Acta reumatologica portuguesa 29 25111416
2014 Head formation: OTX2 regulates Dkk1 and Lhx1 activity in the anterior mesendoderm. Development (Cambridge, England) 29 25231759
2005 Comparative genomics on Dkk1 orthologs. International journal of oncology 29 15942669
2019 Loss of Dkk-1 in Osteocytes Mitigates Alveolar Bone Loss in Mice With Periodontitis. Frontiers in immunology 28 31921182
2017 Dkk1: A key molecule in joint remodelling and fibrosis. Mediterranean journal of rheumatology 28 32185280
2016 miR-522 contributes to cell proliferation of hepatocellular carcinoma by targeting DKK1 and SFRP2. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 28 26960688
2013 Dickkopf-1 (DKK1) phosphatase and tensin homolog on chromosome 10 (PTEN) crosstalk via microRNA interference in the diabetic heart. Basic research in cardiology 28 23636253
2012 Potential role for therapies targeting DKK1, LRP5, and serotonin in the treatment of osteoporosis. Current osteoporosis reports 28 22210558
2019 Wnt Pathway Inhibitor DKK1: A Potential Novel Biomarker for Adiposity. Journal of the Endocrine Society 27 30746507
2017 In vitro effect of microRNA-107 targeting Dkk-1 by regulation of Wnt/β-catenin signaling pathway in osteosarcoma. Medicine 27 28682874
2014 Dkk1 in the peri-cloaca mesenchyme regulates formation of anorectal and genitourinary tracts. Developmental biology 27 24479159
2007 Neurospora spore killers Sk-2 and Sk-3 suppress meiotic silencing by unpaired DNA. Genetics 27 17339226
2020 Biomarkers in WNT1 and PLS3 Osteoporosis: Altered Concentrations of DKK1 and FGF23. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 26 31968132
2018 IL-1β Enhances Wnt Signal by Inhibiting DKK1. Inflammation 26 29956067
2023 Asprosin promotes feeding through SK channel-dependent activation of AgRP neurons. Science advances 25 36812308
2011 Specific inhibitory protein Dkk-1 blocking Wnt/β-catenin signaling pathway improve protectives effect on the extracellular matrix. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 25 22038356
2022 TGF-β1/Smad3 upregulates UCA1 to promote liver fibrosis through DKK1 and miR18a. Journal of molecular medicine (Berlin, Germany) 24 36001113
2022 Wnt signaling pathway inhibitors, sclerostin and DKK-1, correlate with pain and bone pathology in patients with Gaucher disease. Frontiers in endocrinology 24 36506070
2020 Wnt antagonist DKK-1 levels in systemic sclerosis are lower in skin but not in blood and are regulated by microRNA33a-3p. Experimental dermatology 23 32592422
2015 Expression of Wnt3a, Wnt10b, β-catenin and DKK1 in periodontium during orthodontic tooth movement in rats. Acta odontologica Scandinavica 23 26414930
2014 Induction of DKK1 by ox-LDL negatively regulates intracellular lipid accumulation in macrophages. FEBS letters 23 25436422
2021 Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma. Oncogene 22 33420361
2019 miR-29a promotes osteoblast proliferation by downregulating DKK-1 expression and activating Wnt/β-catenin signaling pathway. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 22 31538414
2018 Elevated Expression of Dkk-1 by Glucocorticoid Treatment Impairs Bone Regenerative Capacity of Adipose Tissue-Derived Mesenchymal Stem Cells. Stem cells and development 22 29084466
2014 Expanding role of SK channels in cardiac electrophysiology. Heart rhythm 22 24681007
2020 DKK1 Induced by 1,25D3 Is Required for the Mineralization of Osteoblasts. Cells 21 31963554
2020 LncRNA Linc-PINT inhibits miR-523-3p to hamper retinoblastoma progression by upregulating Dickkopf-1 (DKK1). Biochemical and biophysical research communications 20 32828314
2020 Artesunate promotes osteoblast differentiation through miR-34a/DKK1 axis. Acta histochemica 20 33066846
2022 DKK1 drives immune suppressive phenotypes in intrahepatic cholangiocarcinoma and can be targeted with anti-DKK1 therapeutic DKN-01. Liver international : official journal of the International Association for the Study of the Liver 19 35924447
2021 ZBTB38 suppresses prostate cancer cell proliferation and migration via directly promoting DKK1 expression. Cell death & disease 19 34697293
2012 Characterization of Dkk1 gene regulation by the osteoblast-specific transcription factor Osx. Biochemical and biophysical research communications 19 22459449
2010 Differential expression of DKK-1 binding receptors on stromal cells and myeloma cells results in their distinct response to secreted DKK-1 in myeloma. Molecular cancer 19 20846389
2023 Effects of Dickkopf-1 (DKK-1) on Prostate Cancer Growth and Bone Metastasis. Cells 18 38067123
2022 DKK-1 Is Underexpressed in Mesenchymal Stem Cells from Patients with Ankylosing Spondylitis and Further Downregulated by IL-17. International journal of molecular sciences 18 35743102
2017 sFRP3 and DKK1 Regulate Fibroblast-Like Synoviocytes Markers and Wnt Elements Expression Depending on Cellular Context. Immunological investigations 18 28151034
2005 Dkk1, -2, and -3 expression in mouse craniofacial development. Journal of molecular histology 18 16195809
2016 Dkk1: A promising molecule to connect Alzheimer's disease and osteoporosis. Medical hypotheses 17 26880631
2012 High-affinity Dkk1 receptor Kremen1 is internalized by clathrin-mediated endocytosis. PloS one 17 23251700
2023 DKK1-CKAP4 signal axis promotes hepatocellular carcinoma aggressiveness. Cancer science 16 36718957
2023 Inflammation and DKK1-induced AKT activation contribute to endothelial dysfunction following NR2F2 loss. American journal of physiology. Lung cellular and molecular physiology 16 37039367
2017 DKK1 and sclerostin are early markers of relapse in multiple myeloma. Bone 16 28993177
2021 DKK1 suppresses WWP2 to enhance bortezomib resistance in multiple myeloma via regulating GLI2 ubiquitination. Carcinogenesis 15 34546340
2021 Niacinamide Down-Regulates the Expression of DKK-1 and Protects Cells from Oxidative Stress in Cultured Human Dermal Papilla Cells. Clinical, cosmetic and investigational dermatology 15 34703266
2012 Dickkopf-1 (DKK-1) interrupts FAK/PI3K/mTOR pathway by interaction of carbonic anhydrase IX (CA9) in tumorigenesis. Cellular signalling 15 22430125
2024 DKK1 loss promotes endometrial fibrosis via autophagy and exosome-mediated macrophage-to-myofibroblast transition. Journal of translational medicine 14 38961399
2021 Differential modulation of SK channel subtypes by phosphorylation. Cell calcium 14 33422768

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