Affinage

RSPO3

R-spondin-3 · UniProt Q9BXY4

Length
272 aa
Mass
30.9 kDa
Annotated
2026-06-10
46 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RSPO3 is a secreted Wnt-pathway potentiator that acts as a niche-derived ligand to sustain tissue-specific stem cell compartments and to control vascular and metabolic homeostasis (PMID:29559533, PMID:26766444). It engages two principal signaling modes: a syndecan-4 (SDC4)-dependent route that drives clathrin-mediated endocytosis of Wnt-receptor complexes to transduce non-canonical Wnt/PCP signaling through Wnt5a/Fz7/Dvl/JNK (PMID:21397842), and a route through its cognate receptor LGR4 (and LGR5) that amplifies canonical Wnt/β-catenin signaling (PMID:29559533, PMID:32559496). Through LGR4, RSPO3 couples to multiple downstream cascades in a context-dependent manner — Gab1–Gαi1/3–ERK in endothelium and neurons (PMID:37805583), IQGAP1-dependent LRP6/β-catenin activation in lung adenocarcinoma (PMID:25531322, PMID:42203310), AMPKα–SREBP2 suppression of hepatic cholesterol synthesis (PMID:32926477), NF-κB activation in gastric stem cells (PMID:35767364), and ILK/Akt in pulmonary endothelial regeneration (PMID:38677673). In the intestinal niche RSPO3 is produced principally by PDGFRα+ pericryptal myofibroblasts and is far more potent than RSPO1 in stimulating crypt Wnt/β-catenin signaling, stem cell expansion, and Paneth cell differentiation (PMID:29559533, PMID:27511199). RSPO3 supports comparable stem/progenitor functions in other compartments via dedicated stromal sources, including adrenal capsule cells that imprint zona glomerulosa fate (PMID:27313319) and osteoblasts that regulate trabecular bone mass (PMID:34389713). In endothelium it maintains vascular remodeling through non-canonical WNT/Ca2+/NFAT signaling, with RNF213-mediated degradation of NFAT1 and filamin A as a regulatory node (PMID:26766444). Recurrent PTPRK-RSPO3 gene fusions act as oncogenic drivers in colorectal cancer, where the lesion sustains a Wnt-dependent stem-cell compartment and anti-RSPO3 antibody treatment inhibits tumor growth and forces differentiation (PMID:26700806, PMID:27511199). RSPO3 can also act through non-LGR receptors, including GNG7-mediated Akt/GSK-3β/β-catenin signaling in gastric cancer stem cells (PMID:38581123).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2011 High

    Establishing how RSPO3 transmits a non-canonical Wnt signal answered whether R-spondins act only by stabilizing Wnt receptors or by actively remodeling receptor trafficking.

    Evidence Binding assays, Xenopus loss-of-function and epistasis with Wnt5a/Fz7/Dvl/JNK, and clathrin inhibition

    PMID:21397842

    Open questions at the time
    • Whether the SDC4/PCP route operates in mammalian adult tissues was not addressed
    • Structural basis of the RSPO3-SDC4 interaction not defined
  2. 2012 Medium

    Single Rspo3 deletion versus Rspo2/Rspo3 double mutants resolved whether RSPO3 has a unique developmental role or is functionally redundant with paralogs.

    Evidence Conditional Rspo3 allele and Rspo2/Rspo3 double-knockout genetic epistasis in limb

    PMID:22610508

    Open questions at the time
    • Did not identify the receptors or downstream pathway underlying limb redundancy
    • No molecular distinction between RSPO2 and RSPO3 contributions
  3. 2014 Medium

    Identifying LGR4 and IQGAP1 as effectors in Keap1-deficient lung adenocarcinoma extended RSPO3 signaling from development into a tumor-promoting proliferation/migration axis.

    Evidence shRNA knockdown of RSPO3/LGR4/IQGAP1 with proliferation, migration, and in vivo metastasis assays

    PMID:25531322

    Open questions at the time
    • IQGAP1 not shown to bind RSPO3 directly
    • Mechanism linking LGR4-IQGAP1 to proliferation not reconstituted
  4. 2015 High

    Anti-RSPO3 treatment of PTPRK-RSPO3 fusion-positive xenografts tested whether the fusion is a therapeutic dependency and which cell compartment drives tumor growth.

    Evidence Anti-RSPO3 antibody treatment of patient-derived xenografts with stem cell and expression assays

    PMID:26700806

    Open questions at the time
    • Receptor and downstream signaling for the fusion-driven growth not dissected here
    • Durability of response and resistance not addressed
  5. 2016 High

    Tissue-specific knockouts defined RSPO3 as a niche-derived maintenance signal in distinct organs, clarifying that its developmental role persists into adult homeostasis.

    Evidence Inducible endothelial-specific and adrenal conditional knockouts with pathway and phenotypic readouts (vascular pruning, NFAT, β-catenin, SHH)

    PMID:26766444 PMID:27313319

    Open questions at the time
    • Endothelial and adrenal studies used distinct downstream readouts (WNT/Ca2+/NFAT vs β-catenin) without a unifying mechanism
    • Upstream regulation of stromal RSPO3 production not defined
  6. 2016 High

    Gain-of-function Rspo3 expression in vivo showed RSPO3 is sufficient to expand intestinal stem cells and drive tumorigenesis, linking its niche role to oncogenesis.

    Evidence Conditional Rspo3 transgenic mice with stem cell marker flow cytometry and Kras synergy

    PMID:27511199

    Open questions at the time
    • Only modest β-catenin increase observed, leaving the proliferative driver partly unexplained
    • Receptor dependence not formally tested in this model
  7. 2017 Medium

    Studies in bone progenitors and colorectal resistance refined RSPO3 signaling outputs as both ERK-modulatory and dependent on intact downstream Wnt machinery.

    Evidence RSPO3/LGR4 manipulation with ERK inhibitors in hASCs; LGK974 resistance selection and AXIN1 RNAi in fusion-positive CRC cells

    PMID:28100566 PMID:28220828

    Open questions at the time
    • RSPO3 as a negative ERK regulator in stem cells contrasts with ERK-driving roles elsewhere, unresolved
    • AXIN1 loss conferring porcupine-inhibitor resistance not mechanistically linked to RSPO3 itself
  8. 2018 High

    Endothelial barrier and intestinal niche-source studies sharpened both the cellular origin and a permeability function of RSPO3.

    Evidence PDGFRα-Cre conditional knockout with organoid rescue; ECIS barrier assays with VE-cadherin/β-catenin imaging and IL-1β co-treatment

    PMID:29559533 PMID:30157748

    Open questions at the time
    • Barrier-disrupting role appears to oppose vascular-maintenance role, leaving net endothelial function context-dependent
    • Receptor mediating junction disruption not identified
  9. 2020 Medium

    Discovery of RSPO3-LGR4 outputs in AML, hepatocytes, and adipose depots established defined downstream cascades and metabolic/oncogenic roles beyond canonical Wnt.

    Evidence Anti-RSPO3 antibody in AML PDX with HOXA9 epistasis; AMPKα-SREBP2 epistasis in hepatocytes; depot-specific adipose progenitor assays and zebrafish rspo3 mutant

    PMID:32493999 PMID:32559496 PMID:32926477

    Open questions at the time
    • AML finding is High-confidence but hepatic and adipose cascades rest on single-lab knockdown epistasis
    • How a single ligand selects between SREBP2, NF-κB, and Wnt outputs not defined
  10. 2021 High

    Osteoblast-specific knockout identified the cellular source and cell-autonomous bone function of RSPO3, and a later study placed it relative to estrogen signaling.

    Evidence Runx2-Cre conditional knockout with bone densitometry and strength testing; OVX/estradiol epistasis

    PMID:34389713 PMID:35068191

    Open questions at the time
    • Receptor mediating osteoblast-autonomous effect not pinned down
    • Why estrogen-dependence differs between cortical and trabecular bone unexplained
  11. 2022 High

    Gastric stem cell studies revealed RSPO3-LGR4 can activate NF-κB, coupling the pathway to inflammation and pathogen-driven hyperplasia.

    Evidence Lgr4- and Lgr5-specific conditional knockouts with H. pylori infection, NF-κB and chemokine/neutrophil readouts

    PMID:35767364

    Open questions at the time
    • Molecular link from LGR4 to NF-κB not reconstituted
    • Whether RSPO3 ligand itself, versus other RSPOs, drives this in vivo not isolated
  12. 2023 Medium

    Mechanistic studies defined a Gab1-Gαi1/3-ERK signaling complex and mapped RSPO3 receptor-targeting domains, and identified epigenetic control of the RSPO3 promoter.

    Evidence Co-IP for LGR4-Gab1-Gαi, Gαi KO MEFs and MCAO neuroprotection; FuFu-domain liposome uptake in LGR5-high cells; dCas9-TET1/DNMT3a promoter editing in cholangiocarcinoma

    PMID:36813038 PMID:37805583 PMID:37932819

    Open questions at the time
    • Gab1-Gαi-ERK complex shown by Co-IP in single lab without structural validation
    • Relationship between FuFu-domain LGR5 binding and the LGR4-Gab1 cascade not integrated
  13. 2024 Medium

    Newer studies broadened RSPO3 effectors to ILK/Akt, GNG7, and pyroptosis pathways and tested complex-disruption as a therapeutic strategy.

    Evidence EC-specific genetic models with ILK/Akt readout; Co-IP/LC-MS identification of GNG7 with knockdown epistasis; NSCLC radiosensitivity with NLRP3 readouts; MHP1-AcN peptide disruption of LGR4-IQGAP1

    PMID:38581123 PMID:38677673 PMID:39245068 PMID:42203310

    Open questions at the time
    • GNG7-mediated, LGR-independent route rests on a single Co-IP/MS study
    • Pyroptosis/radiosensitivity finding is Low-confidence and not reconstituted
  14. 2025 Medium

    Inter-organ and additional niche studies extended RSPO3 to neurally relayed metabolic control and to non-Wnt-dependent stem cell maintenance.

    Evidence Hepatic Rspo3 OE/KO with vagal denervation and metabolic phenotyping; XAV939-resistant hLESC proliferation; H3K4me3 regulation of RSPO3 in dermal papilla cells

    PMID:39760688 PMID:39854351 PMID:40775776

    Open questions at the time
    • The signal carried from liver to nerves to peripheral tissues is undefined
    • β-catenin-independent stem cell route lacks an identified downstream effector

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single secreted RSPO3 molecule selects among SDC4/PCP, LGR4-canonical Wnt, LGR4-Gab1-Gαi-ERK, NF-κB, GNG7-Akt, and β-catenin-independent outputs in different cell types.
  • No structural or quantitative model integrates the receptor/co-receptor repertoire that dictates pathway choice
  • Direct binding partners beyond SDC4, LGR4/LGR5, and GNG7 not systematically mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
GNG7IQGAP1LGR4LGR5SDC4

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 RSPO3 binds syndecan 4 (SDC4) and together they activate Wnt/PCP signaling; RSPO3 functions by inducing SDC4-dependent, clathrin-mediated endocytosis of Wnt-receptor complexes, which is essential for PCP signal transduction. In Xenopus embryos, RSPO3/PCP signaling during gastrulation requires Wnt5a and is transduced via Fz7, Dvl, and JNK. Binding assays, Xenopus embryo loss-of-function, epistasis with Wnt5a/Fz7/Dvl/JNK, clathrin inhibition experiments Developmental cell High 21397842
2016 Endothelial RSPO3 controls vascular remodeling via non-canonical WNT/Ca2+/NFAT signaling. Inducible endothelial-specific Rspo3 deletion caused endothelial apoptosis and vascular pruning. RSPO3 co-regulates genes including Rnf213, Usp18, and Trim30α; RNF213 targets filamin A and NFAT1 for proteasomal degradation, attenuating non-canonical WNT/Ca2+ signaling. NFAT protein levels were decreased in endothelial cells of Rspo3-iECKO mice, and pharmacological NFAT inhibition phenocopied Rspo3-iECKO mice. Inducible endothelial-specific conditional knockout, endothelial gene expression screen, pharmacological NFAT inhibition, protein degradation assays Developmental cell High 26766444
2016 Capsular RSPO3 signals to the underlying steroidogenic compartment of the adrenal gland to induce β-catenin signaling and imprint zona glomerulosa cell fate. Deletion of RSPO3 leads to loss of SHH signaling and impaired organ growth. RSPO3 function is required in adult life to ensure replenishment of lost cells and maintain zona glomerulosa properties. Conditional knockout mouse models, immunohistochemistry, β-catenin signaling readout, SHH pathway analysis Genes & development High 27313319
2018 PDGFRα+ pericryptal stromal myofibroblasts are the principal source of RSPO3 in the intestinal stem cell niche in vivo. RSPO3 is several orders of magnitude more potent than RSPO1 in stimulating Wnt/β-catenin signaling and organoid growth. Stromal Rspo3 ablation in PdgfRα+ cells decreased intestinal crypt Wnt/β-catenin signaling and Paneth cell differentiation, and was rescued by exogenous RSPO3 protein. Cell-type-specific Cre-mediated conditional knockout (PdgfRα-Cre;Rspo3fl/fl), organoid growth assays, exogenous protein rescue, β-catenin signaling measurements Proceedings of the National Academy of Sciences of the United States of America High 29559533
2015 Targeting RSPO3 in PTPRK-RSPO3 fusion-positive colorectal tumor xenografts inhibits tumor growth and promotes differentiation, with stem cell compartment genes being most sensitive to anti-RSPO3 treatment, indicating that a stem-cell compartment drives PTPRK-RSPO3 colorectal tumor growth. Anti-RSPO3 antibody treatment of patient-derived xenografts, gene expression profiling, functional stem cell assays Nature High 26700806
2016 In vivo RSPO3 expression expands Lgr5+ stem cells, Paneth cells, non-Paneth label-retaining cells, and Lgr4+ niche cells, and drives rapid intestinal tumorigenesis. Wnt/β-catenin signaling was modestly increased, and mutant Kras synergized with Rspo3 in hyperplastic growth. Conditional Rspo3 transgenic mouse model (Lgr5-GFP-CreERT2 × Rspo3 transgene), histological analysis, flow cytometry for stem cell markers Gut High 27511199
2020 RSPO3-LGR4 signaling upregulates key self-renewal genes and is essential for leukemia stem cell (LSC) self-renewal in AML. Blocking the RSPO3-LGR4 interaction with clinical-grade anti-RSPO3 antibody (OMP-131R10/rosmantuzumab) impairs self-renewal and induces differentiation in AML patient-derived xenografts without affecting normal hematopoietic stem cells. LGR4 is epigenetically upregulated and works through cooperation with HOXA9. Anti-RSPO3 antibody (OMP-131R10), patient-derived xenograft (PDX) experiments, gene expression analysis, epigenetic characterization of LGR4 Cancer cell High 32559496
2014 RSPO3 aberrantly expressed in Keap1-deficient lung adenocarcinomas signals via LGR4 and the mediator IQGAP1 to promote tumor cell proliferation and migration. Knockdown of RSPO3, LGR4, or IQGAP1 reduced cell proliferation and migration in vitro, and KD of LGR4 or IQGAP1 decreased tumor growth and metastasis in vivo. shRNA knockdown of RSPO3/LGR4/IQGAP1, cell proliferation and migration assays, in vivo xenograft metastasis models Oncogene Medium 25531322
2017 RSPO3 is a negative regulator of ERK/FGF signaling downstream of LGR4 in human adipose-derived stem cells (hASCs). RSPO3 knockdown increased osteogenic potential, an effect blocked by ERK1/2 inhibition. LGR4 silencing inhibited ERK signaling and osteogenic differentiation, and abrogated RSPO3-regulated osteogenesis and RSPO3-induced ERK1/2 inhibition. RSPO3 shRNA knockdown, LGR4 siRNA silencing, ERK pathway inhibitors, osteogenic differentiation assays in hASCs Scientific reports Medium 28220828
2020 RSPO3 limits gluteofemoral adipose tissue expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis, while stimulating abdominal adipose progenitor proliferation. The distinct biological responses in abdominal versus gluteal adipose progenitors are associated with differential changes in WNT signaling. Zebrafish with a nonsense rspo3 mutation display altered fat distribution. Human cellular studies with RSPO3 treatment/knockdown in adipose progenitors from different depots, zebrafish nonsense mutant, WNT signaling measurements Nature communications Medium 32493999
2021 Osteoblast-derived RSPO3 is the principal source of RSPO3 in bone. RSPO3 increases osteoblast proliferation and differentiation in a cell-autonomous manner, and is an important regulator of vertebral trabecular bone mass and bone strength in adult mice. Osteoblast-specific conditional knockout (Runx2-Cre;Rspo3fl/fl), bone densitometry, bone strength testing, cell proliferation and differentiation assays Nature communications High 34389713
2022 RSPO3 signaling via LGR4 drives proliferation of gastric stem cells and induces NF-κB activity in proliferative stem cells. LGR4-driven NF-κB activation is responsible for H. pylori-induced gland hyperplasia and chemokine expression in stem cells, resulting in neutrophil recruitment. LGR4 also regulates LGR5 expression in this context. Conditional knockout mice (Lgr4-specific and Lgr5-specific), H. pylori infection model, NF-κB activity assays, chemokine/neutrophil recruitment measurements The EMBO journal High 35767364
2020 RSPO1/RSPO3-LGR4 signaling in hepatocytes suppresses cholesterol synthesis via the AMPKα-SREBP2 pathway. RSPO3 increased phosphorylation of AMPKα Thr172, reduced SREBP2 nuclear translocation and Srebf2 mRNA. LGR4 knockdown increased hepatic cholesterol synthesis and decreased AMPKα phosphorylation; AMPKα knockdown abrogated Rspo-induced inhibition of cholesterol synthesis. LGR4/Rspo1/Rspo3 knockdown in mice and hepatocytes, AMPKα agonist/antagonist/shRNA experiments, SREBP2 nuclear translocation assays FASEB journal Medium 32926477
2023 Endothelial cell-derived RSPO3 activates LGR4-Gab1-Gαi1/3 complex formation to drive Erk activation and protect neurons from ischemia/reperfusion injury. Only Erk (not Akt or β-catenin) inhibitors reversed RSPO3-induced neuroprotection. Silencing or knockout of Gαi1 and Gαi3 abolished RSPO3-induced neuroprotection. Endothelial RSPO3 knockdown/KO increased ischemic injury in MCAO mice. Co-IP (LGR4-Gab1-Gαi association), MEF Gαi1/3 KO, Erk/Akt/β-catenin inhibitors, endothelial-specific RSPO3 KO/KD/OE mice, MCAO model Cell death & disease Medium 37805583
2024 RSPO3 mediates pulmonary endothelial regeneration in a LGR4-dependent manner. Beyond β-catenin, integrin-linked kinase (ILK)/Akt was identified as a novel downstream effector of RSPO3/LGR4 signaling. EC-specific RSPO3 knockdown inhibited endothelial cell proliferation and exacerbated injury, while EC-specific overexpression promoted recovery. EC-specific RSPO3 KD, inducible EC-specific KO, EC-specific OE mice, LGR4-dependence assays, ILK/Akt signaling measurements in sepsis model International journal of biological macromolecules Medium 38677673
2017 Loss of AXIN1 confers resistance to WNT pathway blockade (porcupine inhibitor LGK974) in RSPO3-fusion-positive colorectal cancer cells. Suppression of AXIN1 by RNA interference in parental VACO6 cells (carrying PTPRK-RSPO3 fusion) markedly increased resistance to LGK974, establishing AXIN1 loss as a mechanism of acquired resistance. Long-term LGK974 treatment to generate resistant cells, whole-genome sequencing to identify AXIN1 frameshifts, AXIN1 RNAi in parental cells, transcriptional and morphological WNT pathway readouts EMBO molecular medicine Medium 28100566
2024 RSPO3 promotes gastric cancer stem cell properties through direct interaction with transmembrane protein GNG7, leading to phosphorylation of Akt and GSK-3β and accumulation of β-catenin. GNG7 knockdown blocked RSPO3-induced β-catenin activation and CSC-like properties. This pathway is distinct from canonical LGR-mediated Wnt signaling. Co-immunoprecipitation (CoIP) and LC-MS/MS to identify RSPO3-interacting proteins, GNG7 siRNA knockdown, recombinant RSPO3 protein treatment, western blot for Akt/GSK-3β/β-catenin, in vivo peritoneal seeding model Cancer medicine Medium 38581123
2023 The Furin (FuFu) domains of RSPO3 mediate specific, LGR5-dependent cellular uptake when conjugated to liposomes. Full-length RSPO1 mediates aspecific LGR5-independent uptake largely via heparan sulfate proteoglycan binding, whereas RSPO3 FuFu domain-coated liposomes selectively target LGR5-high cells. Fluorescence-loaded liposome uptake assays, LGR5-high vs LGR5-low cell comparison, domain-specific conjugation, doxorubicin-loaded FuFuRSPO3 liposome growth inhibition Journal of controlled release Medium 36813038
2018 RSPO3 impairs vascular endothelial barrier function by inducing inter-endothelial gap formation through disruption of β-catenin and VE-cadherin alignment at adherens junctions, and synergizes with pro-inflammatory IL-1β to enhance endothelial hyperpermeability. Electric Cell-substrate Impedance Sensing (ECIS) of primary endothelial monolayers, RSPO3 protein treatment, immunofluorescence of β-catenin/VE-cadherin at junctions, IL-1β co-treatment Molecular medicine Medium 30157748
2022 RSPO3 is expressed in osteoblasts and regulates vertebral trabecular bone mass in a cell-autonomous manner; osteoblast-derived RSPO3 is required for a full estrogenic response on cortical (but not trabecular) bone. Estradiol and RSPO3 regulate vertebral trabecular bone mass independently of each other. Osteoblast-specific Rspo3 conditional KO (Runx2-Cre), OVX mouse model with estradiol treatment, bone densitometry and bone strength testing American journal of physiology. Endocrinology and metabolism Medium 35068191
2024 RSPO3 overexpression increases NSCLC radiosensitivity through induction of pyroptosis mediated by the β-catenin–NF-κB signaling pathway and NLRP3 inflammasome. Anti-RSPO3 antibody (OMP-131R10) blocked radiation-induced pyroptosis and anti-tumor immunity in vivo. RSPO3 overexpression/knockdown in NSCLC cell lines, β-catenin/NF-κB pathway inhibitors, NLRP3 inflammasome assays, in vivo anti-RSPO3 antibody treatment with radiation Radiotherapy and oncology Low 39245068
2023 The RSPO3 promoter is regulated by the balance between DNA methyltransferase DNMT3a and DNA demethylase TET1 in cholangiocarcinoma. Targeted RSPO3 promoter demethylation using dCas9-TET1CD inhibited CCA tumorigenicity, while targeted methylation using dCas9-DNMT3a promoted it. Targeted epigenetic editing (dCas9-DNMT3a and dCas9-TET1CD), in vitro and in vivo CCA models, methylation analysis Clinical epigenetics Medium 37932819
2026 MHP1-AcN (a RANKL-derived peptide) directly interacts with LGR4 and disrupts RSPO3-induced LGR4-IQGAP1 complex formation, inhibiting RSPO3-enhanced phosphorylation of LRP6 and accumulation of β-catenin, and suppressing tumor growth and metastatic potential in lung adenocarcinoma. Immunoprecipitation for LGR4-IQGAP1 complex, immunoblotting for LRP6 phosphorylation and β-catenin, A549 xenograft model, cell migration/invasion assays Anticancer research Medium 42203310
2012 Rspo3 single conditional knockout in the limb did not produce limb defects, but combining Rspo3 and Rspo2 mutations caused severe hindlimb truncations, demonstrating redundant function of these R-spondin paralogs during limb development. Conditional Rspo3 allele (loxP-flanked exons 2-4), Cre-mediated deletion, Rspo2/Rspo3 double knockout genetic epistasis Genesis Medium 22610508
2025 H3K4me3 histone modification regulates the transcription of RSPO3 in dermal papilla cells. Increasing H3K4me3 levels enhanced DPC proliferation and Wnt signaling pathway gene expression, partly through elevated RSPO3. RSPO3 itself promotes DPC proliferation, inhibits apoptosis, and increases Wnt pathway gene expression. CUT&Tag for H3K4me3 mapping, H3K4me3 inhibitor (BCL-121) and agonist (PBIT) treatment, RNA-seq, RSPO3 functional assays in DPCs Epigenetics & chromatin Low 40775776
2025 Hepatic Rspo3 regulates systemic glucose metabolism and body composition via inter-organ communication involving afferent vagal and efferent sympathetic nerves. Viral-mediated hepatic Rspo3 induction improved insulin resistance in obese mice; hepatic vagal denervation suppressed these remote effects on adipose tissue and skeletal muscle. Hepatic Rspo3 suppression (Cre-LoxP) exacerbated diabetes and obesity. Viral-mediated hepatic Rspo3 overexpression, Cre-LoxP hepatic conditional KO, hepatic vagus denervation, metabolic phenotyping (glucose tolerance, insulin sensitivity, body composition) PLoS biology Medium 39854351
2025 RSPO3 promotes proliferation and self-renewal of human limbal epithelial stem cells (LESCs) through a WNT/β-catenin-independent signaling pathway, as demonstrated by the lack of impairment when β-catenin activation was blocked by XAV939. Exogenous RSPO3 treatment of hLESCs, β-catenin inhibitor XAV939, EdU proliferation assay, stemness marker assessment (ΔNp63, ABCG2), in vivo corneal wound healing model Investigative ophthalmology & visual science Low 39760688
2026 Chondrocyte-derived RSPO3 acts in an autocrine manner to enhance chondrocyte anabolism and in a paracrine manner to directly drive M2 macrophage polarization. The pro-M2 macrophage effect is specifically mediated through activation of the LGR4/LRP6/β-catenin signaling axis in macrophages. NsPEFs-ADSCs-EV treatment, RSPO3 neutralization, macrophage polarization assays (M1/M2 markers), LGR4/LRP6/β-catenin signaling assays, OA mouse model Bioactive materials Low 41624077

Source papers

Stage 0 corpus · 46 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 PDGFRα pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo. Proceedings of the National Academy of Sciences of the United States of America 234 29559533
2015 Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function. Nature 204 26700806
2011 Rspo3 binds syndecan 4 and induces Wnt/PCP signaling via clathrin-mediated endocytosis to promote morphogenesis. Developmental cell 194 21397842
2016 Endothelial RSPO3 Controls Vascular Stability and Pruning through Non-canonical WNT/Ca(2+)/NFAT Signaling. Developmental cell 152 26766444
2016 Frequent PTPRK-RSPO3 fusions and RNF43 mutations in colorectal traditional serrated adenoma. The Journal of pathology 107 26924569
2020 Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia. Cancer cell 96 32559496
2016 The adrenal capsule is a signaling center controlling cell renewal and zonation through Rspo3. Genes & development 76 27313319
2016 RSPO3 expands intestinal stem cell and niche compartments and drives tumorigenesis. Gut 65 27511199
2014 Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness. Oncogene 64 25531322
2017 Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions. EMBO molecular medicine 56 28100566
2020 RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro. Nature communications 49 32493999
2017 RSPO3-LGR4 Regulates Osteogenic Differentiation Of Human Adipose-Derived Stem Cells Via ERK/FGF Signalling. Scientific reports 47 28220828
2017 RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations. Scientific reports 41 29127379
2012 A conditional allele of Rspo3 reveals redundant function of R-spondins during mouse limb development. Genesis (New York, N.Y. : 2000) 35 22610508
2021 RSPO3 is important for trabecular bone and fracture risk in mice and humans. Nature communications 29 34389713
2022 Gastric stem cells promote inflammation and gland remodeling in response to Helicobacter pylori via Rspo3-Lgr4 axis. The EMBO journal 25 35767364
2019 RSPO3 promotes the aggressiveness of bladder cancer via Wnt/β-catenin and Hedgehog signaling pathways. Carcinogenesis 20 30329043
2020 Rspo1/Rspo3-LGR4 signaling inhibits hepatic cholesterol synthesis through the AMPKα-SREBP2 pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 32926477
2018 RSPO3 impairs barrier function of human vascular endothelial monolayers and synergizes with pro-inflammatory IL-1. Molecular medicine (Cambridge, Mass.) 17 30157748
2023 Endothelial cell-derived RSPO3 activates Gαi1/3-Erk signaling and protects neurons from ischemia/reperfusion injury. Cell death & disease 16 37805583
2020 RSPO3 is a marker candidate for predicting tumor aggressiveness in ovarian cancer. Annals of translational medicine 16 33313096
2024 Endothelial RSPO3 mediates pulmonary endothelial regeneration by LGR4-dependent activation of β-catenin and ILK signaling pathways after inflammatory vascular injury. International journal of biological macromolecules 13 38677673
2024 RSPO3 regulates the radioresistance of Non-Small cell lung cancer cells via NLRP3 Inflammasome-Mediated pyroptosis. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 12 39245068
2021 Rspo3 regulates the abnormal differentiation of small intestinal epithelial cells in diabetic state. Stem cell research & therapy 8 34099046
2022 Estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other. American journal of physiology. Endocrinology and metabolism 6 35068191
2022 RSPO3 is a novel contraction-inducible factor identified in an "in vitro exercise model" using primary human myotubes. Scientific reports 6 35995979
2025 Rspo3-mediated metabolic liver zonation regulates systemic glucose metabolism and body mass in mice. PLoS biology 5 39854351
2018 Cynoglossus semilaevis Rspo3 Regulates Embryo Development by Inhibiting the Wnt/β-Catenin Signaling Pathway. International journal of molecular sciences 5 29966290
2017 The RSPO3 gene as genetic markers for bone mass assessed by quantitative ultrasound in a population of young adults. Annals of human genetics 5 29230809
2024 RSPO3 induced by Helicobacter pylori extracts promotes gastric cancer stem cell properties through the GNG7/β-catenin signaling pathway. Cancer medicine 4 38581123
2023 RSPO3 Furin domain-conjugated liposomes for selective drug delivery to LGR5-high cells. Journal of controlled release : official journal of the Controlled Release Society 4 36813038
2023 Amniotic fluid stem cell attenuated necrotizing enterocolitis progression by promoting Rspo3/AMPKα axis. Immunobiology 4 37173190
2023 Upregulation of RSPO3 via targeted promoter DNA demethylation inhibits the progression of cholangiocarcinoma. Clinical epigenetics 4 37932819
2025 RSPO3 Promotes Proliferation and Self-Renewal of Limbal Epithelial Stem Cells Through a WNT/β-Catenin-Independent Signaling Pathway. Investigative ophthalmology & visual science 2 39760688
2025 H3K4me3 regulates the transcription of RSPO3 in dermal papilla cells to influence hair follicle morphogenesis and development. Epigenetics & chromatin 2 40775776
2022 Investigation of cell signalings and therapeutic targets in PTPRK-RSPO3 fusion-positive colorectal cancer. PloS one 2 36129915
2025 Lonicerin targets ADRA1D and RSPO3 to ameliorate diabetes-induced vascular injury through Ca2+/Calcineurin/NFAT1-dependent anti-EndMT pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 1 40398181
2024 Decreased RSPO3 and β-Catenin in Preeclampsia: Correlation with Blood Pressure and Pregnancy Outcomes. Medical science monitor : international medical journal of experimental and clinical research 1 39568191
2023 Rspo1 and Rspo3 are required for sensory lineage neural crest formation in mouse embryos. Developmental dynamics : an official publication of the American Association of Anatomists 1 37767857
2026 Deletion of Rspo1 or Rspo3 in the mesenchyme does not affect Wolffian duct maintenance or morphogenesis. microPublication biology 0 41573670
2026 NsPEFs-enriched ADSCs-EVs alleviate osteoarthritis via RSPO3-mediated dual pro-chondrogenic and pro-M2 macrophage properties. Bioactive materials 0 41624077
2026 A RANKL-derived Peptide Inhibits RSPO3-LGR4-Wnt Signaling and Lung Adenocarcinoma in Mice. Anticancer research 0 42203310
2026 Deciphering the RSPO3-NFATC1 switch in the bone-cartilage paradox: Genetic liability to osteoporosis protects against osteoarthritis by modulating subchondral bone compliance. Osteoarthritis and cartilage 0 42218990
2025 Protein interaction network drive more group integrated analytic larynx hub protein markers: LYVE1/FBLN5/INMT/DCN/ZFY/RSPO3 protein macromolecule collaborative diagnosis of a new era. International journal of biological macromolecules 0 40419046
2025 Unveiling CTRB2, RSPO3, KLOTB, and ROR1 as obesity-pancreatic disease association proteins: a comprehensive Mendelian randomization study. Gastroenterology report 0 40860620
2025 RSPO3 rearrangements in advanced colorectal cancer patients and their relationship with disease characteristics. World journal of gastrointestinal oncology 0 41281482

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