R-spondin 3 (RSPO3) is a member of the R-Spondin (RSPO) family in vertebrates that activate Wnt/beta-catenin signaling, plays a key role in these processes. The RSPO family of secreted Wnt modulators is involved in development and disease and holds therapeutic promise as stem cell growth factors. The four members have high structural homology. RSPO2 and RSPO3 are more potent than RSPO1, whereas RSPO4 is relatively inactive. All RSPO members require Wnt ligands and LRP6 for activity and amplify signaling of Wnt3A, Wnt1, and Wnt7A, suggesting that RSPO proteins are general regulators of canonical Wnt signaling. RSPO3/PCP signaling during gastrulation requires Wnt5a and is transduced via Fz7, Dvl, and JNK. RSPO3 functions by inducing Sdc4-dependent, clathrin-mediated endocytosis. RSPO3 is a novel, evolutionarily conserved angiogenic factor in embryogenesis. RSPO3 has a key role in the interaction between chorion and allantois in labyrinthine development.

R-spondin-3 (RSPO3), also known as Protein with TSP type-1 repeat, Roof plate-specific spondin-3, Thrombospondin type-1 domain-containing protein 2, PWTSR, THSD2 and CRISTIN1, is a member of the thrombospondin type 1 repeat supergene family. RSPO3 is a secreted protein and widely expressed in many tissues. RSPO3 contains two Furin-like repeats which have been found in a variety of eukaryotic proteins involved in the mechanism of signal transduction by receptor tyrosine kinases, and one TSP type-1 domain, RSPO3 founctions as a activator of the beta-catenin signaling cascade, leading to TCF-dependent gene activation. Otherwise, RSPO3 may negatively regulate the TGF-beta pathway.

Thrombospondin Type-1 Domain-Containing Protein 1 (THSD1) is a single-pass type I membrane protein. THSD1 contains a signal peptide and one TSP type-1 domain that is found in thrombospondin. THSD1 is a good novel candidate for TSG as it has been mapped to 13q14. Alternatively spliced transcript variants encoding distinct isoforms have been observed. THSD1 may be involved in the complement pathway.