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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. Acts as a ligand for frizzled FZD8 and LRP6. May negatively regulate the TGF-beta pathway. Has a essential roles in ovary determination. Regulates Wnt signaling by antagonizing DKK1/KREM1-mediated internalization of LRP6 through an interaction with KREM1.
Gene References into Functions
first report of a RSPO1 missense mutation in association with human disease (familial 46,XX disorder of sexual development) . PMID: 29262419
Rspo1 increases the number of Lgr5(+) liver stem cells in human liver fibrosis tissues, and once they are isolated, these cells are able to form organoids, and treatment with HGF/Rspo1 promotes their expansion PMID: 29079780
RSPOs facilitate HSC activation and promote liver fibrogenesis by enhancing the Wnt pathway PMID: 27572318
Results showed that Rspo1 expression is downregulated in adult follicles but its activation is sufficient in promoting ovarian tumors supporting its direct involvement in the initiation of ovarian cancers. PMID: 27270435
We highlight the cooperation of WNT4, RSPO1 and FOXL2 within a regulatory network and the need for further research to better understand their role in defining and maintaining ovarian identity. PMID: 27604691
Rspo1 glycosylation at Asn137 is essential for secretion and stability but not for heparin binding. PMID: 27314333
DPY19L3-mediated C-mannosylation of Rspo1 at tryptophan(156) is required for Rspo1 secretion. PMID: 26764097
Genetic variants in ZC3H11B, RSPO1, and GJD2 are associated with susceptibility to the development of high myopia in a Han Chinese population. PMID: 26485405
R-Spondin1 has an effect on radiosensitivity of glioma cells PMID: 25865226
ZNRF3 and LGR4-binding sites in RSPO1 are required for Wnt signaling. PMID: 24165923
Changes in the expression levels of IRS1, IRS2, RIPK2, RSPO1, and DNA JC15 genes might contribute to the development of insulin resistance and glucose intolerance in the obese boys. PMID: 26040030
the LGR4-Rspo1 complex crystal structure shows divergent mechanisms of ligand recognition by leucine-rich repeat G-protein-coupled receptors PMID: 25480784
ZNRF3 binds RSPO1 and LGR5-RSPO1 with micromolar affinity via RSPO1 furin-like 1 (Fu1) domain. PMID: 24349440
Loss of RSPO1 expression is associated with invasive ductal carcinoma of the breast. PMID: 24373193
RSPO-LGR4 not only induces the clearance of RNF43/ZNRF3 to increase Wnt receptor levels but also recruits IQGAP1 into the Wnt signaling complex. PMID: 24639526
Crystal structures of the Lgr4 ectodomain alone and bound to Rspo1. PMID: 23891289
In conclusion, present study highlights the role of Rspo 1 in bone remodeling where it activates Wnt signaling to induce differentiation, as shown in human as well murine in vitro osteoblast cell models. PMID: 23617070
Recent developments have demonstrated that ovarian development is an active process (rather than a default process); ovarian development/function requires expression of RSPO1, WNT4, and FOXL2. [REVIEW] PMID: 23044875
R-Spondin potentiates Wnt/beta-catenin signaling through orphan receptors LGR4 and LGR5 PMID: 22815884
study provides new mechanistic insights into the regulation of Wnt receptor turnover, and reveals ZNRF3 as a tractable target for therapeutic exploration PMID: 22575959
R-spondin1 is upregulated during critical stages of early human ovary development and may function as a tissue-specific amplifier of beta-catenin signaling to oppose testis determination. PMID: 21297984
identified a gene, R-spondin1, with potent and specific proliferative effects on intestinal crypt cells PMID: 16109882
Human R-spondin1 (RSPO1) is the gene disrupted in a recessive syndrome characterized by XX sex reversal, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin. PMID: 17041600
RSPO1 regulates Wnt signaling by inhibiting internalization of LRP6. PMID: 17804805
Mutational analysis of the RSPO1 gene in a 46,XX woman with true hermaphroditism, palmoplantar keratoderma, congenital bilateral corneal opacities, onychodystrophy, and hearing impairment, is reported. PMID: 18085567
R-sponin1 (Rspo1) acted synergistically with Wnt3A to activate Wnt/beta-catenin signaling in the uncommitted mesenchymal C2C12 cells. PMID: 18242177
SRY represses the transcriptional of the Rspo1/Wnt target genes involved in ovarian determination. PMID: 19376480
Mice treated with R-spondin1 showed increased intestinal epithelial healing, providing a protective effect against chemotherapy-induced intestinal mucositis. PMID: 16306530
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Involvement in disease
Keratoderma, palmoplantar, with squamous cell carcinoma of skin and sex reversal (PKKSCC)
Subcellular Location
Secreted. Nucleus.
Protein Families
R-spondin family
Tissue Specificity
Abundantly expressed in adrenal glands, ovary, testis, thyroid and trachea but not in bone marrow, spinal cord, stomach, leukocytes colon, small intestine, prostate, thymus and spleen.