| 2018 |
Dkk4 consists of two independent folded domains (CRD1 and CRD2) joined by a highly flexible, nonstructured linker. CRD1 has significant structural homology to CRD2, pointing to multiple gene duplication events during Dkk family evolution. Dkk4 CRD2 mediates high-affinity binding to both the E1E2 region of LRP6 and the Kremen1 (Krm1) extracellular domain, while the N-terminal region binds LRP6 E1E2 with only moderate affinity via the conserved NXI(R/K) motif but does not interact with Krm proteins. Dkk and Krm family proteins function synergistically to inhibit Wnt signaling. |
NMR structural determination, SPR binding assays, mutagenesis, functional Wnt signaling reporter assays |
The Journal of biological chemistry |
High |
29925589
|
| 2016 |
Dkk4 selectively inhibits a subset of Wnts and is further inactivated by proteolytic cleavage. Intact Dkk4 inhibits meibomian gland extension, but the cleaved form progressively increases during meibomian gland development with a concomitant upswing in Wnt activity. Elevation of Lrp6 (a direct Eda target and Wnt co-receptor) eliminates Dkk4 inhibition in cell and organotypic cultures, and Lrp6 upregulation restores meibomian gland formation in Tabby mice. |
Transgenic mouse overexpression, cell culture, organotypic culture, in vivo genetic rescue (Lrp6 overexpression in Tabby mice), protein cleavage assays |
Development (Cambridge, England) |
High |
27864382
|
| 2008 |
Dkk4 is a direct transcriptional target of the Eda-A1/Edar signaling pathway (the most highly induced gene in the microarray screen), and its expression in ectodermal placodes also depends on prior Wnt activity. Dkk4 functions as a Wnt antagonist in ectodermal placodes, acting downstream of Edar to provide lateral inhibition for correct patterning of hair follicles. |
Microarray profiling of Eda-A1-stimulated eda-/- skin explants, in situ hybridization/co-localization with Edar, genetic analysis in NF-kappaB-deficient and eda-/- mice |
Developmental biology |
Medium |
18508042
|
| 2010 |
Dkk4 acts through an Eda-independent pathway to regulate secondary hair follicle development. A Dkk4 transgene blocked secondary follicle induction in Tabby (Eda-/y) mice without affecting primary hair, and Dkk4-regulated secondary hair development, like the Eda-dependent primary hair pathway, is further mediated by selective activation of Shh. |
Transgenic mouse overexpression, genetic epistasis with Tabby (Eda-/y) mice, Shh pathway analysis |
PloS one |
High |
20386733
|
| 2012 |
TFAP2E-dependent chemoresistance to fluorouracil in colorectal cancer is mediated through DKK4. Colorectal cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin. |
Cell line overexpression, cell viability assays, TFAP2E methylation-function correlation in patient cohorts |
The New England journal of medicine |
Medium |
22216841
|
| 2012 |
DKK4 attenuates Wnt/β-catenin signaling in hepatocellular carcinoma cells, reducing β-catenin-responsive luciferase activity, decreasing β-catenin and cyclin D1 protein levels, and its tumor-suppressive effect on β-catenin is masked by proteasome inhibition. |
Ectopic DKK4 expression in HCC cell lines, luciferase reporter assay, western blotting, proteasome inhibitor treatment, xenograft mouse model |
Oncogene |
Medium |
22249261
|
| 2012 |
Restoration of wild-type APC in SW480 colon cancer cells induces secretion of DKK4 via exosomes, associated with reduced DKK4 promoter methylation and downregulation of DNMT-3a. |
Comparative proteomic analysis of exosomes by mass spectrometry, RT-PCR, immunoblotting, immunogold electron microscopy, methylation-specific PCR |
Electrophoresis |
Medium |
22740476
|
| 2016 |
Under hyperglycemic conditions, DKK4 expression is suppressed in HCC cells, leading to activation of canonical Wnt signaling and enhanced proliferation via β-catenin. Knockdown of DKK4 by shRNA promotes proliferation under normoglycemic conditions, which is suppressed by exogenous recombinant DKK4 protein. |
shRNA knockdown, recombinant protein rescue, β-catenin level measurement, cell cycle analysis, NOD/SCID mouse xenograft model |
Scientific reports |
Medium |
27272409
|
| 2017 |
DKK4 knockdown in docetaxel-resistant A549/DTX cells reduces colony formation and invasion and promotes pro-apoptotic effects of docetaxel via caspase 3 activation and BCL-2 inhibition, possibly mediated by activation of the c-Jun N-terminal kinase (JNK) signaling pathway. |
shRNA knockdown, cell viability assay, flow cytometry for apoptosis, caspase 3 and BCL-2 western blotting, invasion assay |
Acta biochimica et biophysica Sinica |
Medium |
28981599
|
| 2019 |
DLX3 regulates DKK4 expression through histone H3 lysine 27 trimethylation (H3K27me3) at the DKK4 promoter; DLX3 knockdown decreases H3K27me3 enrichment at the DKK4 promoter, increasing DKK4 expression and suppressing Wnt/β-catenin signaling during osteogenic differentiation of bone marrow mesenchymal stem cells. |
ChIP-qPCR, lentiviral overexpression/knockdown, RT-qPCR, western blotting, osteogenic differentiation assays (ALP, alizarin red staining) |
Biochemical and biophysical research communications |
Medium |
31202458
|
| 2022 |
DKK4 inhibits colorectal cancer metastasis through a negative feedback mechanism: Wnt3a and LiCl induce DKK4 expression, and DKK4 in turn represses Wnt/β-catenin signaling by suppressing FZD6 and AKT2/s552 β-catenin phosphorylation. RNA-seq after DKK4 knockdown revealed upregulation of AKT2, FZD6, and JUN. |
RNA-seq, luciferase reporter assay, transwell assays, subcutaneous and metastatic mouse tumor models, cell counting kit-8 assays, bioinformatics |
The Journal of biological chemistry |
Medium |
36181792
|
| 2023 |
LARP1 promotes DKK4 mRNA stabilization by competitively interacting with PABPC1 to prevent BTG2-dependent deadenylation and degradation of DKK4 mRNA, leading to elevated DKK4 protein, enhanced β-catenin expression and nuclear import in hepatoblastoma. |
Co-immunoprecipitation, RNA immunoprecipitation, RNA pull-down, mRNA stability assays, poly(A)-tail length assays, RNA-sequencing |
Clinical and translational medicine |
Medium |
37070251
|
| 2024 |
DKK4 secreted from colorectal cancer cells inactivates β-catenin in stromal fibroblasts, inducing formation of stress fiber-containing fibroblasts and myofibroblasts, resulting in restricted expansion of primary tumor masses but enhanced CRC metastasis. Chemical inhibition of β-catenin by MSAB promoted CRC metastasis, supporting that reduced β-catenin activity in the tumor stroma facilitates progression. |
CRC cell-fibroblast co-culture, mouse CRC xenograft models, chemical β-catenin inhibitor (MSAB) treatment, immunofluorescence for stress fibers/myofibroblast markers |
Oncogene |
Medium |
38519641
|
| 2025 |
METTL14 stimulates m6A methylation of DKK4 mRNA, stabilizing DKK4 expression and promoting docetaxel resistance and malignant progression in lung cancer. Downregulation of DKK4 reversed proliferation, cell cycle arrest, apoptosis resistance, migration, and M2 macrophage polarization in DTX-resistant cells. |
MeRIP assay (methylated RNA immunoprecipitation), RT-qPCR, western blot, EdU proliferation assay, flow cytometry, transwell assay, mouse xenograft model |
Journal of biochemical and molecular toxicology |
Medium |
41208390
|