Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors. Upon binding to LGR4-6 (LGR4, LGR5 or LGR6), LGR4-6 associate with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. Also regulates the canonical Wnt/beta-catenin-dependent pathway and non-canonical Wnt signaling by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway. During embryonic development, plays a crucial role in limb specification, amplifying the Wnt signaling pathway independently of LGR4-6 receptors, possibly by acting as a direct antagonistic ligand to RNF43 and ZNRF3, hence governing the number of limbs an embryo should form.

1. 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 PMID: 29769720
2. RSPO2 is a novel target gene of the NOBOX key transcription factor, confirming its important role during the follicular growth in ovary. However, RSPO2 mutations are rare or uncommon in women with primary ovarian insufficiency. PMID: 28743298
3. Novel targets ANTXR1 and RSPO2 were confirmed to be suppressed by miR-493 directly. PMID: 28651234
4. RSPOs facilitate HSC activation and promote liver fibrogenesis by enhancing the Wnt pathway PMID: 27572318
5. Role of RSPO2 in gastric cancer PMID: 28219935
6. RSPO2 suppresses colorectal cancer metastasis by counteracting the Wnt5a/Fzd7-driven noncanonical Wnt pathway. PMID: 28600110
7. genetic and functional data indicate that RSPO2 is a susceptibility gene for OPLL (Ossification of the Posterior Longitudinal Ligament of the Spine) PMID: 27374772
8. Rspo2 was found to have a negative regulatory effect during oxidized low density lipoproteininduced macrophage apoptosis by regulating lipid uptake. PMID: 27571704
9. data reveal a RSPO2-induced, LGR5-dependent Wnt signaling-negative feedback loop that exerts a net growth-suppressive effect on CRC cells PMID: 24476626
10. results suggest that the expression of RSPO fusion transcripts is related to a subset of colorectal cancers arising in the Japanese population PMID: 24847761
11. Wnt(high) cells were more likely to give rise to Wnt(high) progeny, tended to be more metastatic, and revealed higher levels of RSPO2 expression. PMID: 25769727
12. These findings suggest that R-Spondin2 may promote hepatic stellate cell activation by enhancing the canonical Wnt pathway. PMID: 24852883
13. Oocyte-derived R-spondin2 is a paracrine factor essential for primary ovarian follicle development PMID: 23407710
14. using RNA-seq data, identification of multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours PMID: 22895193
15. Reduced Rspo-2 levels in osteoarthritis osteoblasts are responsible, at least in part, for their reduced Wnt/beta-catenin signaling and abnormal mineralization. PMID: 22127703
16. There is a role for R-spondin2 in keratinocyte proliferation and epidermal thickening in keloid scarring. PMID: 21160497

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Secreted.

R-spondin family

HGNC: 28583

OMIM: 610575

KEGG: hsa:340419

STRING: 9606.ENSP00000276659

UniGene: Hs.444834