RSPO3, also known as PWTSR or THSD2, is a protein containing a TSP1-type repeat sequence. It acts as an activator of the canonical Wnt signaling pathway, functioning as a ligand for the LGR4-6 receptor, a key regulator of angiogenesis. It also regulates both the canonical Wnt/β-catenin-dependent pathway and the non-canonical Wnt signaling pathway by acting as an inhibitor of NRF3, a crucial regulator of the Wnt signaling pathway.
RSPO3 expression distribution
RSPO3 is mainly expressed in fibroblasts, smooth muscle cells, stromal cells, endometrial stromal cells, endothelial cells, and inhibitory neurons.
(Data source: unprot)
Structure of RSPO3 and its receptor
The RSPO3 protein contains multiple functional domains that determine its biological activity and specific recognition of interacting molecules. The human RSPO3 protein consists of 272 amino acids and has a molecular weight of 28.3 kDa. Like other members of the R-spondin family, RSPO3 contains two cysteine-rich furin-like domains responsible for binding to cell surface receptors. Furthermore, protein sequence analysis shows that the C-terminal region of RSPO3 is highly conserved.
(Data source: He Z, et al. Ann Med. 2023)
(Data source: Alphafold)
RSPO3 signaling pathway and regulation
The primary function of RSPOs is to synergize with the canonical Wnt/β-catenin signaling pathway. The operation of the canonical Wnt/β-catenin signaling pathway depends on the activation of the upstream Wnt/FZD/LRP complex. Canonical Wnt ligands induce DVL activation and inhibit the activity of the disruption complex, leading to β-catenin accumulation, nuclear translocation, and transcription of Wnt target genes. RSPOs enhance the canonical Wnt/β-catenin signaling pathway by eliminating the negative regulator ZNRF3/RNF43, thereby increasing the availability of membrane Wnt receptors and Wnt ligand-mediated pathway activation. In the absence of canonical Wnt ligands, disruption of the complex induces β-catenin phosphorylation. Phosphorylated β-catenin is degraded by the cytoplasmic proteasome.
(Data source: He Z, et al. Ann Med. 2023)
Targeted therapy for RSPO3
Rosmantuzumab (OMP-131R10) is a monoclonal antibody targeting RSPO3 for the treatment of solid tumors. Its highest development stage is Phase 1 clinical trials, and no new progress information has been found at present.
DBPR117 is a monoclonal antibody targeting RSPO3, developed by the National Institutes of Health and currently in preclinical research. It possesses a novel amino acid sequence in its complementarity-determining regions (CDRs) that specifically bind to human RSPO3. DBPR117 may target a novel epitope (56-75 aa) in the RSPO3 Furin region to neutralize the RSPO-WNT pathway. DBPR117 can be used alone or in combination with other drugs to treat tumors with RPSO3 fusions/overexpression. In the B16F10 syngeneic mouse model, DBPR117 combined with an anti-PD-1 antibody synergistically combats melanoma.
(Data source: National Health Research Institutes website)
