ZNRF3 (Zinc and Ring Finger 3): A Key Regulator of Wnt Signaling in Development and Cancer
Explore the genomic context, expression patterns, and clinical significance of ZNRF3, a tumor suppressor gene frequently altered in adrenocortical carcinoma and colorectal cancer.
Gene Information Card
| Symbol | ZNRF3 |
|---|---|
| Full Name | Zinc and Ring Finger 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 22q12.1 |
| NCBI Gene ID | 84133 ncbi.nlm.nih.gov/gene/84133 |
| Ensembl ID | ENSG00000183579 |
| UniProt ID | Q9ULT6 |
| OMIM ID | 612062 |
| HGNC ID | 15853 |
| Aliases | RNF203, FLJ14640 |
Description
ZNRF3 encodes a transmembrane E3 ubiquitin ligase that negatively regulates Wnt signaling by promoting the degradation of Wnt receptors (Frizzled and LRP6) at the cell surface. It acts as a tumor suppressor in various cancers, particularly in adrenocortical carcinoma and colorectal cancer. ZNRF3 is also involved in stem cell maintenance and embryonic development.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Adrenocortical carcinoma | Loss-of-function mutations and deletions lead to constitutive Wnt activation, promoting tumorigenesis. | COSMIC, ClinVar |
| Colorectal cancer | Somatic mutations and copy number alterations contribute to aberrant Wnt signaling and tumor progression. | COSMIC, ClinVar |
| Osteosarcoma | Altered expression and mutations may affect Wnt pathway, influencing tumor growth. | COSMIC |
| Hepatoblastoma | Rare mutations implicated in Wnt pathway dysregulation. | COSMIC |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Adrenal gland | High | Highest expression among tissues |
| Colon | Moderate | Significant expression |
| Small intestine | Moderate | Notable expression |
| Liver | Low | Low expression |
| Brain | Low | Low expression |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HCT116 (colorectal) | Moderate | Colorectal cancer cell line |
| SW480 (colorectal) | Moderate | Colorectal cancer cell line |
| NCI-H295R (adrenocortical) | High | Adrenocortical carcinoma cell line |
| HepG2 (liver) | Low | Hepatocellular carcinoma cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1234C>T (p.Arg412Ter) | Nonsense | Rare | Loss of function, truncated protein |
| c.456_457del (p.Glu153fs) | Frameshift | Rare | Loss of function |
| c.789G>A (p.Trp263Ter) | Nonsense | Rare | Loss of function |
| Copy number loss | Deletion | Frequent in adrenocortical carcinoma | Loss of heterozygosity, reduced expression |
Mutation functional classification
Loss of Function (LOF)
Most ZNRF3 mutations are loss-of-function, leading to impaired ubiquitination of Wnt receptors and sustained Wnt signaling.
Gain of Function (GOF)
Gain-of-function mutations are rare and not well characterized; they may potentially enhance receptor degradation, but evidence is limited.
Dominant Negative (DN)
No dominant-negative mutations have been reported for ZNRF3.
View complete mutation data：
Gene Ontology (GO)
| • Ubiquitin-protein transferase activity | • Zinc ion binding |
| • Protein binding | • Negative regulation of Wnt signaling pathway |
| • Cell surface receptor signaling pathway | • Proteasome-mediated ubiquitin-dependent protein catabolic process |
Pathways
• Wnt signaling pathway
• Ubiquitin mediated proteolysis
• Hippo signaling pathway (crosstalk)
Protein Summary
ZNRF3 is a 900-amino acid single-pass transmembrane protein with an extracellular domain, a transmembrane region, and a cytoplasmic RING finger domain. It functions as an E3 ubiquitin ligase, ubiquitinating Frizzled and LRP6 receptors, marking them for degradation. This activity is crucial for controlling Wnt pathway activity. ZNRF3 also interacts with R-spondin receptors (LGR4/5) and is inhibited by R-spondins, which promote its clearance from the membrane, thereby enhancing Wnt signaling. The protein is essential for normal development and its dysregulation is linked to cancer.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| ZNRF3 Knockout HEK293 Cell Line | EDJ-KQ360 | Human | 84133 | Details Get a Quote |
| ZNRF3 Knockout A-549 Cell Line | EDJ-KQ18545 | Human | 84133 | Details Get a Quote |
| ZNRF3 Knockout HCT 116 Cell Line | EDJ-KQ18546 | Human | 84133 | Details Get a Quote |
| ZNRF3 Knockout HeLa Cell Line | EDJ-KQ18547 | Human | 84133 | Details Get a Quote |
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