MicroRNA (miR)‑mediated mRNA and multiple signaling pathway dysregulations have been extensively implicated in several cancer types, including gliomas.
Although previous studies have reported that miR‑301a acts as an oncogene, the underlying mechanisms of miR‑301a in the initiation and progression of glioma remain unknown. The present study aimed to investigate the involvement of miR‑301a‑mediated signaling pathway dysregulation in glioma.
The results identified that miR‑301a was significantly upregulated in gliomas and was associated with a poor prognosis based on The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases.
Moreover, zinc and ring finger 3 (ZNRF3) exerted a critical role in the miR‑301a‑mediated effects on the malignant phenotype, such as by affecting proliferation and apoptosis.
Mechanistically, the TOP/FOP luciferase assay, western blotting and immunofluorescence results demonstrated that miR‑301a knockdown inhibited the wnt/β‑catenin signaling pathway, at least partially via ZNRF3, while ZNRF3 was a direct functional target of miR‑301a, as indicated by luciferase reporter assay and western blot analysis.
Furthermore, ZNRF3 could in turn repress miR‑301a expression, which was dependent on the wnt pathway. Collectively, the present study identified a novel miR‑301a/ZNRF3/wnt/β‑catenin signaling feedback loop that serves critical roles in glioma tumorigenesis, and that may represent a potential therapeutic target.
ZNRF3 Regulates Collagen-Induced Arthritis Through NF-kB and Wnt Pathways
Although the E3 ubiquitin ligase Zinc and ring finger 3 (ZNRF3) negatively regulates the Wnt signaling pathway, its function in rheumatoid arthritis (RA) is elusive. Here, the effects and the mechanism of ZNRF3 on a mouse model of collagen-induced arthritis (CIA) and human fibroblast-like synoviocytes (FLS) obtained from RA patients were determined. Our results showed that ZNRF3 was highly expressed in tissues and FLSs compared to trauma patients.
Lentivirus-mediated silencing of ZNRF3 induced apoptosis decreased cell viability and significantly attenuated inflammation in RA-FLSs via tumor necrosis-α (TNF-α).
Additionally, silencing of ZNRF3 reduced knee joint damage and also decreased the level of TNF-α, IL-1β, and IL-6 in the CIA mouse model.
These effects were mediated by the crosstalk between Wnt and NF-κB pathways in RA-FLS.
The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer.
A hallmark of Spemann’s organizer function is its expression of Wnt antagonists that regulate axial embryonic patterning. Here we identify the tumor suppressor Protein tyrosine phosphatase receptor-type kappa (Ptprk), as a Wnt inhibitor of the Spemann organizer.
We show that PTPRK acts via the transmembrane E3 ubiquitin ligase ZNRF3, a negative regulator of Wnt signaling promoting Wnt receptor degradation, which is also expressed in the organizer.
Deficiency of ptprk increases Wnt signaling, leading to reduced expression of Spemann organizer effector genes and inducing head and axial defects.
We identify a ‘4Y’ endocytic signal in ZNRF3, which Ptprk maintains unphosphorylated to promote Wnt receptor depletion. Our discovery of PTPRK as a negative regulator of Wnt receptor turnover provides a rationale for its tumor suppressive function and reveals that in PTPRK-RSPO3 recurrent cancer fusions both fusion partners, in fact, encode ZNRF3 regulators.
Effects of miR‑106b‑3p on cell proliferation and epithelial‑mesenchymal transition, and targeting of ZNRF3 in esophageal squamous cell carcinoma.
Previous studies have demonstrated that the dysregulation of microRNAs (miRs) is frequently associated with cancer progression.
Deregulation of miR‑106b‑3p has been observed in various types of human cancer. However, the biological function of miR‑106b‑3p in esophageal squamous cell carcinoma (ESCC) remains unclear. Thus, the aim of this study was to investigate the role of miR‑106b‑3p in ESCC.
In the current study, the results indicated that miR‑106b‑3p was upregulated in ESCC cell lines and tissues. An increase in miR‑106b‑3p using miR mimics significantly promoted the proliferation of ESCC cells in vitro.
Furthermore, the results demonstrated that miR‑106b‑3p overexpression promoted migration, invasion and epithelial‑mesenchymal transition (EMT) of ESCC cells. In addition, zinc and ring finger 3 (ZNRF3) was identified as a target of miR‑106b‑3p in ESCC cells, and the ZNRF3 expression level was inversely associated with miR‑106b‑3p. It was also demonstrated that miR‑106b‑3p has a role in EMT by regulating Wnt/β‑catenin signaling pathway in ESCC.
In conclusion, these data suggested that miR‑106b‑3p promotes cell proliferation and invasion, partially by downregulating ZNRF3 and inducing EMT via Wnt/β‑catenin signaling in ESCC cells.
Thus, miR‑106b‑3p and ZNRF3 may be novel molecular targets for the future treatment of ESCC.
A ZNRF3-dependent Wnt/β-catenin signaling gradient is required for adrenal homeostasis.
Spatiotemporal control of Wnt signaling is essential for the development and homeostasis of many tissues. The transmembrane E3 ubiquitin ligases ZNRF3 (zinc and ring finger 3) and RNF43 (ring finger protein 43) antagonize Wnt signaling by promoting degradation of frizzled receptors.
ZNRF3 and RNF43 are frequently inactivated in human cancer, but the molecular and therapeutic implications remain unclear. Here, we demonstrate that adrenocortical-specific loss of ZNRF3, but not RNF43, results in adrenal hyperplasia that depends on Porcupine-mediated Wnt ligand secretion.
Furthermore, we discovered a Wnt/β-catenin signaling gradient in the adrenal cortex that is disrupted upon loss of ZNRF3.
Unlike β-catenin gain-of-function models, which induce high Wnt/β-catenin activation and expansion of the peripheral cortex, ZNRF3 loss triggers activation of moderate-level Wnt/β-catenin signaling that drives proliferative expansion of only the histologically and functionally distinct inner cortex.
Genetically reducing β-catenin dosage significantly reverses the ZNRF3-deficient phenotype. Thus, homeostatic maintenance of the adrenal cortex is dependent on varying levels of Wnt/β-catenin activation, which is regulated by ZNRF3.
RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6.
The four R-spondin secreted ligands (RSPO1-RSPO4) act via their cognate LGR4, LGR5 and LGR6 receptors to amplify WNT signalling1-3. Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs.
Functional studies revealed impaired binding to the LGR4/5/6 receptors and the RNF43 and ZNRF3 transmembrane ligases, and reduced WNT potentiation, which correlated with allele severity.
Unexpectedly, however, the triple and ubiquitous knockout of Lgr4, Lgr5 and Lgr6 in mice did not recapitulate the known Rspo2 or Rspo3 loss-of-function phenotypes. Moreover, endogenous depletion or addition of exogenous RSPO2 or RSPO3 in triple-knockout Lgr4/5/6 cells could still affect WNT responsiveness. Instead, we found that the concurrent deletion of rnf43 and znrf3 in Xenopus embryos was sufficient to trigger the outgrowth of supernumerary limbs.
Our results establish that RSPO2, without the LGR4/5/6 receptors, serves as a direct antagonistic ligand to RNF43 and ZNRF3, which together constitute a master switch that governs limb specification. These findings have direct implications for regenerative medicine and WNT-associated cancers.
SCFβ-TRCP E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation.
Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types.
As a key upstream regulator of the Wnt pathway, the transmembrane E3 ligase ZNRF3 has recently been established to play a role in negative regulation of Wnt signaling by targeting Frizzled (FZD) receptor for ubiquitination and degradation. However, the upstream regulation of ZNRF3, in particular the turnover of ZNRF3, is still unclear.
Here we report that ZNRF3 is accumulated in the presence of proteasome inhibitor treatment independent of its E3-ubiquitin ligase activity. Furthermore, the Cullin 1-specific SCF complex containing β-TRCP has been identified to directly interact with and ubiquitinate ZNRF3 thereby regulating its protein stability.
Human E3 ubiquitin-protein ligase ZNRF3 (ZNRF3) |
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| 1-CSB-EP890933HU | Cusabio |
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ZNRF3 siRNA |
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| 20-abx941181 | Abbexa |
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ZNRF3 siRNA |
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| 20-abx941182 | Abbexa |
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ZNRF3 Antibody |
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| 1-CSB-PA890933HA01HU | Cusabio |
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ZNRF3 Antibody |
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| DF14289 | Affbiotech | 100ul | 420 EUR |
ZNRF3 Antibody |
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| DF14289-100ul | Affinity Biosciences | 100ul | 280 EUR |
ZNRF3 Antibody |
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| DF14289-200ul | Affinity Biosciences | 200ul | 350 EUR |
ZNRF3 Antibody |
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| CAC10550-100ug | Biomatik Corporation | 100ug | 314 EUR |
ZNRF3 Antibody |
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| CAC10550-50ug | Biomatik Corporation | 50ug | 199.2 EUR |
ZNRF3 Antibody |
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| MBS7001333-005mg | MyBiosource | 0.05mg | 190 EUR |
ZNRF3 Antibody |
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| MBS7001333-01mg | MyBiosource | 0.1mg | 270 EUR |
ZNRF3 Antibody |
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| MBS7001333-5x01mg | MyBiosource | 5x0.1mg | 1205 EUR |
ZNRF3 Antibody |
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| MBS9631961-1mg | MyBiosource | 1mg | 375 EUR |
ZNRF3 Antibody |
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| MBS9631961-5x1mg | MyBiosource | 5x1mg | 1545 EUR |
ZNRF3 Antibody |
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| MBS9629578-01mL | MyBiosource | 0.1mL | 260 EUR |
ZNRF3 Antibody |
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| MBS9629578-02mL | MyBiosource | 0.2mL | 305 EUR |
ZNRF3 Antibody |
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| MBS9629578-5x02mL | MyBiosource | 5x0.2mL | 1220 EUR |
E3 ubiquitin-protein ligase ZNRF3 protein (ZNRF3) Antibody |
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| abx312167-100g | Abbexa | 100 µg | 362.5 EUR |
E3 ubiquitin-protein ligase ZNRF3 protein (ZNRF3) Antibody |
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| abx312167-20g | Abbexa | 20 µg | 162.5 EUR |
Similar with the degradation of β-catenin by β-TRCP, ZNRF3 is ubiquitinated by β-TRCP in both CKI-phosphorylation- and degron-dependent manners.
Thus, our findings not only identify a novel substrate for β-TRCP oncogenic regulation, but also highlight the dual regulation of Wnt signaling by β-TRCP in a context-dependent manner where β-TRCP negatively regulates Wnt signaling by targeting β-catenin, and positively regulates Wnt signaling by targeting ZNRF3.