RSPO3 (R-spondin 3)
A key activator of Wnt/β-catenin signaling involved in development, stem cell maintenance, and cancer.
Gene Information Card
| Symbol | RSPO3 |
|---|---|
| Full Name | R-spondin 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 6q22.33 |
| NCBI Gene ID | 84870 ncbi.nlm.nih.gov/gene/84870 |
| Ensembl ID | ENSG00000146374 |
| UniProt ID | Q9BXY4 |
| OMIM ID | 610574 |
| HGNC ID | 25686 |
| Aliases | CRISTIN1, FLJ14440, PWTSR, R-spondin 3 |
Description
RSPO3 encodes R-spondin 3, a secreted protein that acts as a potent activator of the Wnt/β-catenin signaling pathway. It binds to LGR4/5/6 receptors and ZNRF3/RNF43 E3 ubiquitin ligases, enhancing Wnt signaling by stabilizing Frizzled and LRP6 receptors. RSPO3 is critical for embryonic development, stem cell proliferation, and tissue homeostasis. Dysregulation of RSPO3 is implicated in several cancers, including colorectal, ovarian, and breast cancer, often through gene fusions or overexpression.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Colorectal cancer | RSPO3 gene fusions (e.g., PTPRK-RSPO3) lead to constitutive Wnt pathway activation, promoting tumorigenesis. | COSMIC, ClinVar, PMID: 22608041 |
| Ovarian cancer | RSPO3 overexpression or amplification enhances Wnt signaling, contributing to cell proliferation and metastasis. | COSMIC, PMID: 25231344 |
| Breast cancer | RSPO3 upregulation correlates with poor prognosis and may drive tumor growth via Wnt/β-catenin activation. | COSMIC, PMID: 28424480 |
| Endometrial cancer | RSPO3 alterations, including fusions, are recurrent and activate Wnt signaling. | COSMIC, PMID: 23535601 |
| Gastric cancer | RSPO3 overexpression is associated with advanced stage and worse survival. | COSMIC, PMID: 27323850 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Colon | 42.3 | High |
| Small intestine | 38.1 | High |
| Stomach | 25.7 | Medium |
| Ovary | 18.4 | Medium |
| Breast | 12.9 | Medium |
| Lung | 8.2 | Low |
| Liver | 5.1 | Low |
| Brain | 2.3 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HCT116 (colorectal) | 56.2 | High expression; consistent with colon origin |
| MCF7 (breast) | 22.8 | Moderate expression |
| A549 (lung) | 9.4 | Low expression |
| HEK293 (embryonic kidney) | 15.1 | Moderate expression |
| K562 (leukemia) | 3.2 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| PTPRK-RSPO3 fusion | Gene fusion | Recurrent in colorectal cancer (approx. 5-10%) | Constitutive Wnt activation; oncogenic |
| EIF3E-RSPO3 fusion | Gene fusion | Rare; reported in colorectal cancer | Wnt pathway activation |
| RSPO3 amplification | Copy number gain | Observed in ovarian and breast cancers | Increased RSPO3 expression; enhanced Wnt signaling |
| Missense variants (e.g., p.Arg122Trp) | Missense | Rare; reported in ClinVar | Uncertain significance; may affect protein function |
Mutation functional classification
Loss of Function (LOF)
No well-characterized loss-of-function mutations reported in human disease; RSPO3 is primarily oncogenic through gain-of-function mechanisms.
Gain of Function (GOF)
Gene fusions (e.g., PTPRK-RSPO3) and amplifications lead to increased RSPO3 expression and constitutive Wnt/β-catenin signaling, driving tumorigenesis.
Dominant Negative (DN)
Not described for RSPO3.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Wnt/β-catenin signaling pathway (Reactome: R-HSA-201681)
• R-spondin-mediated activation of Wnt signaling (Reactome: R-HSA-5362768)
• Signaling by WNT (Reactome: R-HSA-195721)
Protein Summary
R-spondin 3 is a 272-amino acid secreted protein containing a signal peptide, two furin-like cysteine-rich domains, a thrombospondin type 1 domain, and a C-terminal basic region. It functions as a ligand for LGR4/5/6 receptors and synergizes with Wnt proteins to amplify β-catenin signaling. RSPO3 is essential for stem cell maintenance in intestinal crypts and other tissues. Its overexpression or fusion with other genes (e.g., PTPRK) is a recurrent oncogenic event in colorectal and other cancers.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| RSPO3 Knockout HEK293 Cell Line | EDJ-KQ329 | Human | 84870 | Details Get a Quote |
| RSPO3 Knockout A-549 Cell Line | EDJ-KQ18494 | Human | 84870 | Details Get a Quote |
| RSPO3 Knockout HeLa Cell Line | EDJ-KQ57672 | Human | 84870 | Details Get a Quote |
| RSPO3 Knockout HCT 116 Cell Line | EDJ-KQ74598 | Human | 84870 | Details Get a Quote |
