Affinage

RSPO2

R-spondin-2 · UniProt Q6UXX9

Length
243 aa
Mass
28.3 kDa
Annotated
2026-06-10
53 papers in source corpus 22 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RSPO2 is a secreted modulator of cell-surface signaling that potentiates canonical Wnt/β-catenin signaling by engaging the LGR4/5/6 receptor family through its furin-like domains (PMID:41954225), with receptor binding being separable from signaling output by mutagenesis (PMID:41954225) and the RSPO2–LGR4 interaction required for Wnt potentiation (PMID:40179630). Mechanistically, RSPO2 binds LGR5 and stabilizes membrane ZNRF3, and engages Frizzled receptors: it promotes ZNRF3-mediated ubiquitination and degradation of Fzd7 to dampen PKC/ERK signaling and antagonizes Wnt5a by competing for Fzd7 (PMID:24476626, PMID:28600110). Beyond Wnt, RSPO2 acts context-dependently as a BMP-pathway repressor—maintaining AML self-renewal independently of Wnt by inhibiting BMP receptor signaling (PMID:34407399) and de-repressing SMAD1/5/9 signaling when lost during chondrogenesis (PMID:34778258)—and as an FGF antagonist via its thrombospondin (TSP1) domain acting upstream of Mek1, a function distinct from the Wnt-mediating furin domains (PMID:32366679); it can also antagonize Wnt by blocking TCF3/TCF7L1 phosphorylation independently of LGR4/5 and RNF43/ZNRF3 binding (PMID:34183732). RSPO2 additionally signals through LGR4 and integrin β3 to stabilize receptors and activate FAK/Src in cancer (PMID:36217544). These activities underlie defined physiological roles: neuromuscular junction formation and AChR clustering via Lgr5/MuSK (PMID:30206360, PMID:38233267), suppression of adipogenesis and chondrogenesis (PMID:35027768, PMID:27374772), osteoclastic pre-metastatic niche formation with RANKL via LGR4 (PMID:34847079), cooperation with Wnt9b in facial and tracheal cartilage development (PMID:33328171, PMID:32457899), oocyte–granulosa cell coordination with GDF9:BMP15 (PMID:40492505), and hippocampal synaptic plasticity downstream of KAT6A (PMID:38758792). RSPO2 expression is controlled transcriptionally by C/EBPβ, E2F1 (through promoter methylation), VDR, and NF-κB, and a variant reducing C/EBPβ binding confers susceptibility to ossification of the posterior longitudinal ligament (OPLL) (PMID:27374772, PMID:34175894, PMID:38233267, PMID:35984875).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2014 High

    Established that RSPO2 engages LGR5 and stabilizes ZNRF3, defining a receptor-level mechanism that can feed back negatively on Wnt signaling in colorectal cancer.

    Evidence Reciprocal Co-IP plus LGR5-knockdown epistasis in CRC cells

    PMID:24476626

    Open questions at the time
    • Does not resolve how the same RSPO2-LGR5-ZNRF3 axis switches between Wnt potentiation and suppression
    • No structural detail of the ternary complex
  2. 2016 Medium

    Connected RSPO2 to human disease and chondrocyte biology by showing a promoter SNP altering C/EBPβ binding controls RSPO2 levels and that RSPO2 inhibits early chondrocyte differentiation via Wnt/β-catenin.

    Evidence GWAS fine-mapping, ChIP/EMSA, luciferase reporter, chondrocyte differentiation assays for OPLL

    PMID:27374772

    Open questions at the time
    • Does not establish causal mutation in patient tissue
    • Mechanism linking reduced RSPO2 to OPLL pathology not fully dissected
  3. 2016 Medium

    Revealed a Wnt-independent metabolic role: RSPO2 limits macrophage lipid uptake by modulating PPARγ nuclear translocation and CD36 expression.

    Evidence Overexpression/knockdown with ChIP of PPARγ-CD36 promoter and oxLDL uptake assays

    PMID:27571704

    Open questions at the time
    • Receptor mediating this effect not identified
    • Single-lab; in vivo relevance to atherosclerosis untested
  4. 2017 Medium

    Extended the receptor repertoire to Frizzled, showing RSPO2 drives ZNRF3-dependent Fzd7 degradation and competes with Wnt5a, suppressing noncanonical Wnt-driven migration.

    Evidence Co-IP, ubiquitination assay, PKC/ERK readouts, competitive binding in CRC cells

    PMID:28600110

    Open questions at the time
    • No reciprocal in vivo validation of Fzd7 competition
    • Relationship to LGR-dependent mechanism unclear
  5. 2018 High

    Defined a neuromuscular role, with motor-neuron-derived Rspo2 driving AChR clustering and NMJ organization primarily through Lgr5.

    Evidence Tissue-specific rescue of Rspo2-/- mice with ultrastructural and molecular readouts

    PMID:30206360

    Open questions at the time
    • Downstream coupling of Lgr5 to AChR clustering machinery not detailed
  6. 2018 Medium

    Showed RSPO2 can positively activate β-catenin signaling through LGR4 in thyroid cancer, contrasting with its suppressive CRC role.

    Evidence Exogenous RSPO2 treatment, LGR4 knockdown, phospho-ERK/LRP6/GSK3β western blots, proliferation/migration assays

    PMID:29383135

    Open questions at the time
    • Does not explain context-dependent directionality of RSPO2 signaling
    • Single cell-line based
  7. 2020 High

    Separated RSPO2's signaling functions by domain, mapping FGF/ERK antagonism to the TSP1 domain distinct from the Wnt-mediating furin domains.

    Evidence Xenopus explant elongation, ERK phosphorylation, domain-deletion mutants, CA-Mek1 epistasis

    PMID:32366679

    Open questions at the time
    • Direct FGF-pathway binding target of TSP1 domain not identified
    • Proposed intramolecular regulation not structurally resolved
  8. 2020 Medium

    Placed Rspo2 within developmental signaling hierarchies as a downstream effector of HH-Foxf1 and a cooperative partner of Wnt9b in cartilage and facial morphogenesis.

    Evidence Multiple HH/Gli and compound Wnt9b;Rspo2 mutant mice with lineage tracing and explants

    PMID:32457899 PMID:33328171

    Open questions at the time
    • Whether Wnt9b:RSPO2 cooperation uses LGR-independent mechanism unresolved
    • Receptor for facial cooperation not defined
  9. 2021 High

    Demonstrated a Wnt-independent oncogenic mechanism in which autocrine RSPO2 sustains AML self-renewal by inhibiting BMP receptor signaling.

    Evidence KO/knockdown, BMP readouts, Wnt-independent epistasis, AML xenograft survival

    PMID:34407399

    Open questions at the time
    • BMP receptor subtype and binding interface not identified
    • How RSPO2 physically blocks BMP signaling unknown
  10. 2021 Medium

    Reinforced RSPO2 as a dual Wnt-activator/BMP-repressor in chondrogenesis and identified miR-181a as a post-transcriptional regulator.

    Evidence miR-181a luciferase targeting, mimic transfection, SMAD1/5/9 phospho-readouts in MSCs

    PMID:34778258

    Open questions at the time
    • BMP-repression mechanism not molecularly defined
    • Single-lab readouts
  11. 2021 Medium

    Identified an epigenetic input controlling RSPO2 transcription via E2F1 binding to a hypomethylated promoter in granulosa cells.

    Evidence Bisulfite sequencing, DNMT1 knockdown, E2F1 ChIP, luciferase reporter, in vivo/in vitro knockdown

    PMID:34175894

    Open questions at the time
    • Generality of E2F1/methylation control beyond granulosa cells untested
  12. 2022 High

    Established RSPO2 as a metastasis-promoting niche signal that, with RANKL, acts via LGR4/Gαq/β-catenin to regulate DKK1, with decoy LGR4-ECD therapeutically alleviating bone metastasis.

    Evidence GPCR ligand screening, receptor-ligand assays, in vivo mouse bone metastasis with decoy LGR4-ECD

    PMID:34847079

    Open questions at the time
    • Specificity of decoy for RSPO2 versus RANKL not fully partitioned
  13. 2022 High

    Defined a suppressive role for RSPO2 in adipogenesis through LGR4 in CD142+ progenitor cells.

    Evidence scRNA-seq, loss/gain-of-function mice, receptor identification

    PMID:35027768

    Open questions at the time
    • Downstream effectors of LGR4 in adipogenic blockade not detailed
  14. 2022 Medium

    Uncovered a Wnt-independent dual-receptor signaling mode in which RSPO2 stabilizes LGR4 and integrin β3 to activate FAK/Src in ovarian cancer.

    Evidence Co-IP (LGR4, integrin β3), internalization, Src translocation, FAK/Src phospho-assays

    PMID:36217544

    Open questions at the time
    • Integrin β3 binding interface on RSPO2 not mapped
    • Single-lab Co-IP without structural validation
  15. 2022 Medium

    Showed RSPO2 marks a Prg4+ tendon progenitor population and suppresses ectopic ossification, with NF-κB driving its inflammation/load-induced expression.

    Evidence scRNA-seq, Achilles tendon puncture mouse model with Rspo2 overexpression, human chondrogenesis assay, NF-κB analysis

    PMID:35984875

    Open questions at the time
    • Direct NF-κB binding to Rspo2 regulatory elements not shown
  16. 2021 Medium

    Distinguished RSPO2's anti-Wnt activity at TCF3 from its receptor-level actions, showing it inhibits TCF3 phosphorylation independently of LGR4/5 and RNF43/ZNRF3 binding.

    Evidence Xenopus gain/loss-of-function, TCF3 phospho-assays, binding-defective domain mutants, Dishevelled phospho-assay

    PMID:34183732

    Open questions at the time
    • Mechanism by which RSPO2 reaches intracellular TCF3 phosphorylation unresolved
    • Receptor or mediator for this effect unidentified
  17. 2024 High

    Linked RSPO2 to brain function, showing KAT6A transcriptionally drives hippocampal Rspo2 to support Wnt signaling, synaptic plasticity, and memory.

    Evidence Conditional Kat6a/Rspo2 KO, AAV RSPO2 rescue in CA3, synaptic/behavioral/Wnt readouts

    PMID:38758792

    Open questions at the time
    • Receptor mediating CA3 RSPO2 Wnt signaling not specified
  18. 2024 High

    Defined a VDR→Rspo2→MuSK transcriptional axis at the NMJ via a distal VDR enhancer.

    Evidence RNA-seq, VDR ChIP-seq, CRISPR deletion of the VDR site, MuSK phosphorylation and AChR clustering assays, Chrne KO mice

    PMID:38233267

    Open questions at the time
    • Direct molecular coupling of Rspo2 to MuSK activation not detailed
  19. 2025 Medium

    Provided structure-function proof that the furin domain mediates LGR4/5/6 binding and that binding is separable from Wnt signaling, enabling engineered signaling-dead binders.

    Evidence Furin-domain mutagenesis, biolayer interferometry, TOPFLASH reporter, in vivo tumor assays

    PMID:41954225

    Open questions at the time
    • Structural basis of signaling uncoupling not solved
  20. 2025 Medium

    Extended RSPO2 biology to ovarian reproduction, showing oocyte RSPO2 coordinates with GDF9:BMP15 via CTNNB1/SMAD2 crosstalk to regulate granulosa cells.

    Evidence Oocyte-specific Rspo2 KO, transcriptomics, RSPO2-GDF9:BMP15 interaction assays, pathway readouts

    PMID:40492505

    Open questions at the time
    • Determinants of synergy versus antagonism on different target genes unresolved
  21. 2025 Low

    Identified a secretion partner, PALMD, that promotes RSPO2 release and paracrine Wnt activation.

    Evidence Co-IP, secretion assay, Wnt reporter, organoid models (preprint)

    Open questions at the time
    • Preprint, not peer-reviewed
    • Single-lab Co-IP without reciprocal in vivo validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what molecular determinants dictate whether RSPO2 potentiates or antagonizes a given pathway in a given cell type, and the receptors/effectors for several Wnt-independent activities (TCF3 inhibition, BMP repression, FGF antagonism) are not identified.
  • No unifying structural/biochemical model of context-switching
  • BMP and FGF antagonism receptors unidentified
  • Mechanism reaching intracellular TCF3 unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0048018 receptor ligand activity 4
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 3
Partners
BMP15FZD7GDF9ITGB3LGR4LGR5RANKLZNRF3

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 RSPO2 interacts with LGR5 to stabilize membrane-associated ZNRF3, and this RSPO2-LGR5-ZNRF3 interaction mediates a negative feedback loop on Wnt/β-catenin signaling in colorectal cancer cells, suppressing cell proliferation. Co-immunoprecipitation, LGR5 knockdown epistasis, overexpression/depletion in CRC cells Nature communications High 24476626
2017 RSPO2 physically interacts with Fzd7, promoting ZNRF3-mediated ubiquitination and degradation of cell-surface Fzd7, which suppresses downstream PKC/ERK signaling. RSPO2 also antagonizes Wnt5a by blocking Wnt5a binding to Fzd7, thereby suppressing noncanonical Wnt-driven CRC cell migration and invasion. Co-immunoprecipitation (RSPO2-Fzd7 interaction), ubiquitination assay, PKC/ERK pathway readouts, competitive binding assay (RSPO2 vs Wnt5a for Fzd7) Cancer letters Medium 28600110
2022 RSPO2 and RANKL signal through their receptor LGR4 on osteoclast precursors to modulate DKK1 expression via Gαq and β-catenin signaling, promoting osteoclastic premetastatic niche formation. Soluble LGR4 extracellular domain acting as a decoy receptor for RSPO2 and RANKL significantly alleviated bone metastasis in mouse models. Unbiased GPCR ligand/agonist screening, receptor-ligand interaction assays, genetic knockdown, in vivo mouse bone metastasis model with decoy LGR4-ECD The Journal of clinical investigation High 34847079
2022 RSPO2 is secreted by a subset of CD142+ adipogenic progenitor cells and inhibits maturation of early adipogenic progenitors through the receptor LGR4, suppressing de novo adipogenesis. Single-cell RNA-sequencing, loss-of-function and gain-of-function in mice, receptor identification (LGR4) Nature metabolism High 35027768
2021 RSPO2 maintains acute myeloid leukemia (AML) cell self-renewal and prevents differentiation independently of WNT signaling, by inhibiting BMP receptor signaling in an autocrine manner. Loss-of-function knockdown/knockout, BMP signaling pathway readouts, WNT-independent epistasis, AML mouse xenograft survival models, primary AML cell assays Cell reports High 34407399
2020 In Xenopus, Rspo2 antagonizes FGF signaling upstream of Mek1 by inhibiting Erk1 activation in response to FGF; the FGF inhibitory activity was mapped to the thrombospondin type 1 (TSP1) domain of Rspo2, distinct from the Furin-like domains that mediate Wnt signaling. An intramolecular interaction within Rspo2 may control its signaling output. Xenopus ectoderm explant elongation assay, ERK phosphorylation assays, domain deletion/mutant constructs, constitutively active Mek1 epistasis, Rspo2 morpholino depletion Development (Cambridge, England) High 32366679
2021 During Xenopus anteroposterior axis specification, Rspo2 functions as a Wnt antagonist by inhibiting TCF3/TCF7L1 phosphorylation (which normally leads to Wnt target gene activation), independently of binding to RNF43/ZNRF3 and LGR4/5, and without affecting Dishevelled phosphorylation, indicating Frizzled activity is not altered. Xenopus gain-of-function/loss-of-function, TCF3 phosphorylation assays, domain binding mutants (RNF43/ZNRF3 and LGR4/5 binding-defective), Dishevelled phosphorylation assay, rescue of TCF3-depleted embryos Scientific reports Medium 34183732
2018 RSPO2 activates the β-catenin pathway in thyroid cancer cells through GPR48/LGR4, inducing phosphorylation of ERK, LRP6, and GSK3β (at serine 9); LGR4 knockdown decreases proliferation and migration by inhibiting the β-catenin pathway. Treatment with exogenous RSPO2 in thyroid cancer cell lines, LGR4 knockdown, western blot for ERK/LRP6/GSK3β phosphorylation, proliferation/migration assays Oncotarget Medium 29383135
2018 Rspo2 promotes acetylcholine receptor (AChR) clustering and NMJ formation primarily via its receptor Lgr5; spinal motor neuron-derived Rspo2 has the major role in AChR clustering and NMJ postsynaptic organization, while muscle-derived Rspo2 normalizes ultrastructural NMJ features but does not affect AChR clustering at the light microscopy level. Tissue-specific rescue of Rspo2-/- mice (SMN-specific or muscle-specific Rspo2 expression), AChR cluster morphology, NMJ ultrastructural analysis, gene expression profiling Scientific reports High 30206360
2022 RSPO2 promotes ovarian cancer cell growth and metastasis through a dual-receptor mechanism: (1) RSPO2-LGR4 interaction prevents LGR4 endocytic degradation and promotes LGR4-mediated translocation of Src to the plasma membrane; (2) RSPO2 directly binds integrin β3 to enhance integrin stability, both actions potentiating autophosphorylation of FAK and/or Src. Co-immunoprecipitation (RSPO2-LGR4, RSPO2-integrin β3), receptor internalization assays, Src membrane translocation assay, FAK/Src phosphorylation assays, loss-of-function with knockdown iScience Medium 36217544
2024 KAT6A histone acetyltransferase transcriptionally regulates Rspo2 expression in hippocampal CA3 neurons; loss of KAT6A reduces RSPO2 levels, impairs Wnt signaling, and causes synaptic and memory deficits. Restoring RSPO2 expression in CA3 neurons rescues Wnt signaling deficits and learning-associated behaviors in Kat6a mutant mice. Conditional knockout of Kat6a and Rspo2 in excitatory neurons, AAV-mediated RSPO2 rescue in CA3, synaptic structure/plasticity assays, behavioral tests, Wnt signaling readouts Science advances High 38758792
2022 RSPO2 is specifically expressed in a distinct Prg4+ (lubricin+) tendon/ligament stem/progenitor cell cluster; RSPO2 overexpression suppresses ectopic ossification by inhibiting chondrogenic differentiation; RSPO2 expression is induced by inflammatory stimulation and mechanical loading via NF-κB signaling. Single-cell transcriptomics, in vivo Achilles tendon puncture mouse model with Rspo2 overexpression, human ligament cell chondrogenesis assay, NF-κB pathway analysis Science advances Medium 35984875
2021 In porcine granulosa cells, hypomethylation of -758/-749 and -563/-553 regions in the RSPO2 promoter facilitates binding of transcription factor E2F1, enhancing RSPO2 transcription. Increased RSPO2 promotes GC proliferation, E2 secretion, and inhibits apoptosis through Wnt signaling (LGR4/CTNNB1). Bisulfite sequencing, DNMT1 knockdown, E2F1 ChIP/binding assay, luciferase reporter assay, RSPO2 knockdown in vivo and in vitro, granulosa cell functional assays Cell death & disease Medium 34175894
2025 RSPO2 is primarily expressed in oocytes and coordinates with the GDF9:BMP15 heterodimer to regulate granulosa cell development; RSPO2 interacts with GDF9:BMP15 and exhibits gene-specific synergistic or antagonistic effects involving crosstalk between CTNNB1- and SMAD2-dependent pathways. Conditional knockout of Rspo2 in oocytes disrupts key granulosa cell genes and impairs oocyte mitochondrial function. Conditional oocyte-specific Rspo2 knockout, transcriptomic analysis, protein-protein interaction assay (RSPO2-GDF9:BMP15), CTNNB1 and SMAD2 pathway readouts Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 40492505
2020 A HH-Foxf1-Rspo2 signaling axis governs tracheal cartilage development: HH/Gli signaling maintains Foxf1 expression in splanchnic mesoderm, and Foxf1 supports Sox9+ chondrocyte progenitors and Rspo2 expression; loss of Rspo2 (downstream of disrupted HH/Gli) reduces Wnt signaling required for chondrogenesis. Multiple HH/Gli mouse mutant models, lineage tracing of Sox9+ chondrocytes, epistasis analysis of HH→Foxf1→Rspo2 axis Disease models & mechanisms Medium 33328171
2020 Compound Wnt9b;Rspo2 double-mutant mice display more severe facial defects than either single mutant, demonstrating that RSPO2 cooperates with WNT9b to potentiate canonical WNT/β-catenin signaling during mouse facial development. Evidence suggested LGR4/5/6 receptors may play less critical roles in this WNT9b:RSPO2 cooperation. Compound Wnt9b and Rspo2 gene knockout mice, ex vivo facial explants, gene expression analysis Frontiers in cell and developmental biology Medium 32457899
2016 RSPO2 was identified as a susceptibility gene for OPLL; a transcription factor C/EBPβ specifically binds to the RSPO2 core promoter region containing SNP rs374810, and the risk allele of rs374810 reduces C/EBPβ binding and decreases RSPO2 transcription. R-spondin 2 inhibits early chondrocyte differentiation marker expression by activating Wnt-β-catenin signaling. GWAS locus fine-mapping, ChIP/EMSA for C/EBPβ binding, luciferase reporter assay, chondrocyte differentiation assays, in vitro and in vivo transcription assays American journal of human genetics Medium 27374772
2016 Rspo2 negatively regulates oxLDL-induced lipid uptake in macrophages by inhibiting CD36 expression through regulation of PPARγ nuclear translocation; ChIP analysis revealed that Rspo2 manipulation affects direct binding between PPARγ and the CD36 promoter, thereby suppressing oxLDL-induced apoptosis. Rspo2 overexpression/knockdown, flow cytometry (apoptosis), western blot (PPARγ, CD36, ER stress markers), ChIP assay (PPARγ-CD36 promoter binding), Dil-oxLDL uptake assay Molecular medicine reports Medium 27571704
2024 Calcitriol (active vitamin D) induces Rspo2 expression via VDR binding to a region ~15 kbp upstream of Rspo2; biallelic CRISPR deletion of this VDR-binding site abolished calcitriol-mediated Rspo2 induction and MuSK phosphorylation, establishing a VDR→Rspo2→MuSK signaling axis at the NMJ. RNA-seq, ChIP-seq (VDR binding), CRISPR/Cas9 deletion of VDR-binding site, MuSK phosphorylation assay, AChR clustering assay, in vivo Chrne KO mouse model Neurotherapeutics High 38233267
2021 miR-181a targets RSPO2 mRNA in human mesenchymal stromal cells (MSC); loss of RSPO2 via miR-181a reduces canonical WNT signaling and activates BMP signaling (increased SMAD1/5/9 phosphorylation and SOX9 accumulation), demonstrating that RSPO2 functions as a WNT activator and BMP signaling repressor during chondrogenesis. miR reporter/luciferase assay confirming miR-181a targeting of RSPO2, mimic transfection, SMAD1/5/9 phosphorylation assay, WNT signaling readouts in MSC chondrogenesis Frontiers in cell and developmental biology Medium 34778258
2025 A mutant RSPO2 furin domain that retains high-affinity binding to LGR4/5/6 but lacks Wnt/β-catenin signaling activity was engineered; this demonstrates that the furin domain is responsible for LGR4/5/6 receptor binding and that signaling can be uncoupled from binding by mutagenesis. Mutagenesis of RSPO2 furin domain, biolayer interferometry (binding affinity), TOPFLASH Wnt reporter assay, cytotoxicity and in vivo tumor assays Journal of medicinal chemistry Medium 41954225
2025 PALMD (palmdelphin) interacts with RSPO2 and facilitates its secretion; loss of PALMD reduces RSPO2 secretion and Wnt/β-catenin signaling, while overexpression of PALMD enhances paracrine Wnt activation in a RSPO2-dependent manner in colorectal cancer cells and organoids. Co-immunoprecipitation (PALMD-RSPO2), RSPO2 secretion assay, Wnt reporter assay, PALMD knockdown/overexpression, RSPO2-specific antibody inhibition, patient-derived organoid models bioRxivpreprint Low
2025 Nanobodies developed against RSPO2 via phage display inhibit RSPO2-LGR4 interactions and block RSPO2-induced Wnt/β-catenin signaling in human renal epithelial cells, validating that the RSPO2-LGR4 protein-protein interaction is required for Wnt pathway potentiation. Phage display, biolayer interferometry (KD measurement), TOPFLASH Wnt reporter assay, protein blotting Veterinary immunology and immunopathology Low 40179630

Source papers

Stage 0 corpus · 53 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 RSPO2-LGR5 signaling has tumour-suppressive activity in colorectal cancer. Nature communications 107 24476626
2022 RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis. The Journal of clinical investigation 76 34847079
2015 RSPO2 Enhances Canonical Wnt Signaling to Confer Stemness-Associated Traits to Susceptible Pancreatic Cancer Cells. Cancer research 67 25769727
2017 RSPO2 suppresses colorectal cancer metastasis by counteracting the Wnt5a/Fzd7-driven noncanonical Wnt pathway. Cancer letters 60 28600110
2022 Identification of a regulatory pathway inhibiting adipogenesis via RSPO2. Nature metabolism 58 35027768
2012 Rspo2/Int7 regulates invasiveness and tumorigenic properties of mammary epithelial cells. Journal of cellular physiology 47 21732367
2018 Identification of RSPO2 Fusion Mutations and Target Therapy Using a Porcupine Inhibitor. Scientific reports 41 30250044
2016 Identification and Functional Characterization of RSPO2 as a Susceptibility Gene for Ossification of the Posterior Longitudinal Ligament of the Spine. American journal of human genetics 40 27374772
2021 DNA methylation mediated RSPO2 to promote follicular development in mammals. Cell death & disease 36 34175894
2022 RSPO2 defines a distinct undifferentiated progenitor in the tendon/ligament and suppresses ectopic ossification. Science advances 33 35984875
2023 RSPO2 as Wnt signaling enabler: Important roles in cancer development and therapeutic opportunities. Genes & diseases 27 37692504
2019 RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours. Gut 27 30901310
2017 MicroRNA-493 suppresses hepatocellular carcinoma tumorigenesis through down-regulation of anthrax toxin receptor 1 (ANTXR1) and R-Spondin 2 (RSPO2). Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 25 28651234
2021 RSPO2 inhibits BMP signaling to promote self-renewal in acute myeloid leukemia. Cell reports 22 34407399
2018 RSPO2 enhances cell invasion and migration via the WNT/β-catenin pathway in human gastric cancer. Journal of cellular biochemistry 21 30362605
2020 Ablation of PKM2 ameliorated ER stress-induced apoptosis and associated inflammation response in IL-1β-treated chondrocytes via blocking Rspo2-mediated Wnt/β-catenin signaling. Journal of cellular biochemistry 20 31916291
2020 Disruption of a hedgehog-foxf1-rspo2 signaling axis leads to tracheomalacia and a loss of sox9+ tracheal chondrocytes. Disease models & mechanisms 20 33328171
2020 miR-196b-5p Promotes Proliferation, Migration and Invasion of Lung Adenocarcinoma Cells via Targeting RSPO2. Cancer management and research 20 33402849
2010 An insertion in the RSPO2 gene correlates with improper coat in the Portuguese water dog. The Journal of heredity 20 20562213
2022 Suppression of Wnt/β-Catenin Signaling Is Associated with Downregulation of Wnt1, PORCN, and Rspo2 in Alzheimer's Disease. Molecular neurobiology 18 36215026
2016 RSPO2 enriches LGR5(+) spheroid colon cancer stem cells and promotes its metastasis by epithelial-mesenchymal transition. American journal of translational research 16 27158331
2024 KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3. Science advances 14 38758792
2019 Identification of a novel PRR15L-RSPO2 fusion transcript in a sigmoid colon cancer derived from superficially serrated adenoma. Virchows Archiv : an international journal of pathology 14 31209633
2020 Canonical WNT/β-Catenin Signaling Activated by WNT9b and RSPO2 Cooperation Regulates Facial Morphogenesis in Mice. Frontiers in cell and developmental biology 13 32457899
2020 Rspo2 antagonizes FGF signaling during vertebrate mesoderm formation and patterning. Development (Cambridge, England) 12 32366679
2020 A 50-kb deletion disrupting the RSPO2 gene is associated with tetradysmelia in Holstein Friesian cattle. Genetics, selection, evolution : GSE 12 33176673
2019 T5224, RSPO2 and AZD5363 are novel drugs against functional pituitary adenoma. Aging 12 31655798
2017 Upregulation of RSPO2-GPR48/LGR4 signaling in papillary thyroid carcinoma contributes to tumor progression. Oncotarget 12 29383135
2021 MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein - WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal Cells. Frontiers in cell and developmental biology 11 34778258
2018 Differential effects of spinal motor neuron-derived and skeletal muscle-derived Rspo2 on acetylcholine receptor clustering at the neuromuscular junction. Scientific reports 11 30206360
2025 RSPO2 Coordinates with GDF9:BMP15 Heterodimers to Promote Granulosa Cell and Oocyte Development in Mice. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 10 40492505
2022 miR-497-5p-RSPO2 axis inhibits cell growth and metastasis in glioblastoma. Journal of Cancer 10 35281864
2023 Astaxanthin prevents osteoarthritis by blocking Rspo2-mediated Wnt/β-catenin signaling in chondrocytes and abolishing Rspo2-related inflammatory factors in macrophages. Aging 9 37354487
2021 Bone marrow mesenchymal stem cell-derived extracellular vesicles containing miR-497-5p inhibit RSPO2 and accelerate OPLL. Life sciences 9 33857573
2016 Rspo2 suppresses CD36-mediated apoptosis in oxidized low density lipoprotein-induced macrophages. Molecular medicine reports 9 27571704
2022 RSPO2 promotes progression of ovarian cancer through dual receptor-mediated FAK/Src signaling activation. iScience 8 36217544
2023 Rspo2 exacerbates rheumatoid arthritis by targeting aggressive phenotype of fibroblast-like synoviocytes and disrupting chondrocyte homeostasis via Wnt/β-catenin pathway. Arthritis research & therapy 7 37946278
2021 RSPO2 silence inhibits tumorigenesis of nasopharyngeal carcinoma by ZNRF3/Hedgehog-Gli1 signal pathway. Life sciences 7 34273374
2023 Rspo2-LGR4 exacerbates hepatocellular carcinoma progression via activation of Wnt/β-catenin signaling pathway. Gastroenterologia y hepatologia 5 37437654
2024 Calcitriol ameliorates motor deficits and prolongs survival of Chrne-deficient mouse, a model for congenital myasthenic syndrome, by inducing Rspo2. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 4 38233267
2021 Rspo2 inhibits TCF3 phosphorylation to antagonize Wnt signaling during vertebrate anteroposterior axis specification. Scientific reports 4 34183732
2022 Tracing the Origin of the RSPO2 Long-Hair Allele and Epistatic Interaction between FGF5 and RSPO2 in Sapsaree Dog. Genes 3 35052442
2021 Evaluation of WNT Signaling Pathway Gene Variants WNT7B rs6519955, SFRP4 rs17171229 and RSPO2 rs611744 in Patients with Dupuytren's Contracture. Genes 3 34573275
2025 The RSPO2 gene is associated with bilateral anterior amelia in Chihuahuas. Mammalian genome : official journal of the International Mammalian Genome Society 2 40131457
2025 Leucine Attenuates Osteoarthritis via mTORC1/LXRα-Mediated Macrophage Reprogramming and Rspo2/β-Catenin Axis Suppression. Cartilage 2 41200799
2025 Screening, expression, and functional validation of camelid-derived nanobodies targeting RSPO2. Veterinary immunology and immunopathology 1 40179630
2025 Hierarchical clustering defines hypermethylated RSPO2 as early-stage potential biomarker in colorectal cancer. Global medical genetics 1 41142323
2024 RETRACTED: RSPO2-associated mitochondrial metabolism defines molecular subtypes with distinct clinical and immune features in esophageal cancer. Environmental toxicology 1 38491805
2024 Identification of Rare EIF3E::RSPO2 Fusion in Recurrent and Aggressive Urachal Adenocarcinoma. Genes, chromosomes & cancer 1 38884183
2026 RSPO2-Based Peptibodies Conjugated with Pyrrolobenzodiazepine Dimer or Camptothecin Analogs Demonstrate Potent Antitumor Activity by Targeting the Three Receptors LGR4/5/6 in Colorectal Cancer and Neuroblastoma. Journal of medicinal chemistry 0 41954225
2026 Multifaceted role of RSPO2: Epigenetics, immunoregulatory, and therapeutic insights in colorectal cancer. Biochimica et biophysica acta. Reviews on cancer 0 42031178
2025 RSPO2-based peptibodies conjugated with pyrrolobenzodiazepine dimer or camptothecin analogs demonstrate potent anti-tumor activity by targeting the three receptors LGR4/5/6. bioRxiv : the preprint server for biology 0 40894780
2025 Association Between Gene Polymorphisms of RSPO2 of the Wnt Signaling Pathway and Schizophrenia in the Korean Population. Psychiatry investigation 0 41382343

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