Affinage

RSPO1

R-spondin-1 · UniProt Q2MKA7

Length
263 aa
Mass
29.0 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RSPO1 is a secreted glycoprotein that amplifies canonical Wnt/β-catenin signaling by acting as a molecular bridge between two receptor classes, and through this activity governs gonadal sex determination, stem cell maintenance, and tissue morphogenesis (PMID:21909076, PMID:18250098, PMID:18400942). Its tandem furin-like cysteine-rich domains carry out distinct binding functions: Fu2 engages the concave leucine-rich-repeat surface of the LGR4/5/6 receptors, while Fu1 clamps into equivalent grooves on the transmembrane E3 ubiquitin ligases ZNRF3/RNF43, and both interfaces are required to assemble a ternary complex, clear ZNRF3/RNF43 from the cell surface, and activate signaling (PMID:23756651, PMID:24225776, PMID:24165923, PMID:25480784). Within this architecture LGR4/5/6 serve as engagement receptors that increase RSPO1 affinity for the effector receptors ZNRF3/RNF43, and RSPO1's comparatively weak ZNRF3 binding makes it the least potent family member (PMID:23756651, PMID:24050775, PMID:25504990); this ZNRF3/RNF43-directed lysosomal degradation activity is sufficiently modular that signaling-disabled RSPO chimeras can be repurposed to degrade unrelated transmembrane targets (PMID:37321224). RSPO1 requires Wnt ligands and LRP6 for Wnt amplification and provides a self-renewal signal non-interchangeable with that of Wnt in Lgr5+ intestinal stem cells (PMID:18400942, PMID:28467820). In vivo, RSPO1 is an essential driver of XX ovarian differentiation, activating β-catenin and Wnt4 to oppose testis fate and to promote germ cell entry into meiosis, and it cooperates with WNT4 in gonadal progenitor proliferation (PMID:18250098, PMID:21991325, PMID:23095882). RSPO1 additionally supports developmental angiogenesis and hematopoietic stem cell specification, and it operates partly through LGR-independent and TGFβ/SMAD cross-talk routes in nephron progenitor maintenance and intestinal adenomas (PMID:22007135, PMID:28087636, PMID:32324134, PMID:32941878).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2004 Low

    Established RSPO1 as a secreted Wnt-responsive protein, placing it within the Wnt circuitry before its receptor mechanism was known.

    Evidence Expression analysis and epitope-tag fractionation in cell lines and Wnt-1/3a double-knockout mice

    PMID:14732490

    Open questions at the time
    • Single localization experiment with ambiguous nuclear/secreted partition
    • No receptor or biochemical mechanism defined
    • Functional role inferred only from expression dependence
  2. 2008 High

    Defined the minimal signaling unit and an early mechanistic model, showing the furin domains are sufficient and essential for Wnt amplification across all four family members.

    Evidence Domain deletion analysis and TOPFLASH/DKK1 antagonism assays for all R-spondins

    PMID:18400942

    Open questions at the time
    • DKK1-inhibition model later superseded by the LGR/ZNRF3 receptor mechanism
    • Did not identify the engagement receptor
  3. 2008 High

    Demonstrated the central in vivo role of RSPO1 in female sex determination, linking it to β-catenin/Wnt4 activation opposing testis fate.

    Evidence Rspo1 knockout mouse with gonadal histology and Wnt4 expression analysis

    PMID:18250098

    Open questions at the time
    • Receptor mediating the gonadal effect not identified at this stage
    • Cell-autonomy within germ vs somatic cells not resolved here
  4. 2011 High

    Identified LGR4/5/6 as the facultative Wnt-receptor components required for RSPO signaling, resolving how RSPO is sensed at the membrane.

    Evidence Mass spectrometry of receptor complexes, conditional deletion and rescue in mouse gut and HEK293, organoid culture; binding and clathrin-dependence assays in cells and Xenopus

    PMID:21727895 PMID:21909076

    Open questions at the time
    • Effector that translates LGR engagement into Wnt potentiation not yet defined
    • Did not explain differential potency among RSPO family members
  5. 2011 High

    Placed β-catenin signaling cell-autonomously within germ cells, refining the gonadal model to show RSPO1 promotes oogonial differentiation and meiotic entry.

    Evidence Rspo1-/- XX gonad analysis with Stra8 and meiosis markers and epistasis to somatic differentiation

    PMID:21991325

    Open questions at the time
    • Direct germ-cell receptor not identified
    • Quantitative contribution of germ vs somatic signaling unresolved
  6. 2012 High

    Independently confirmed LGR4 as a specific, G-protein-independent RSPO receptor via unbiased screening.

    Evidence siRNA screen, binding, overexpression, reporter, and G-protein coupling assays

    PMID:22815884

    Open questions at the time
    • Mechanism downstream of LGR4 binding still unexplained
    • Effector receptor not yet incorporated
  7. 2012 High

    Revealed cooperative, sex-independent function of RSPO1 with WNT4 in gonadal progenitor proliferation, exposed only by combined loss.

    Evidence Wnt4-/-;Rspo1-/- double knockout with proliferation and histology

    PMID:23095882

    Open questions at the time
    • Molecular basis of WNT4/RSPO1 cooperativity not dissected
    • Receptor usage in progenitors not defined
  8. 2013 High

    Established the two-receptor mechanism structurally and functionally: RSPO1 bridges LGR (engagement) and ZNRF3/RNF43 (effector) E3 ligases through distinct Fu2 and Fu1 interfaces, clearing the ligases to protect Wnt receptors.

    Evidence Multiple crystal structures of binary and ternary complexes plus mutagenesis, biophysics, membrane-clearance and reporter assays

    PMID:23756651 PMID:23756652 PMID:23809763 PMID:24050775 PMID:24165923 PMID:24225776 PMID:24349440

    Open questions at the time
    • Stoichiometric differences between ZNRF3 and RNF43 complexes not yet resolved
    • Family-wide potency determinants only partially quantified
  9. 2014 High

    Defined potency determinants quantitatively, showing signaling strength scales with ternary-complex formation and that RSPO1 has the weakest ZNRF3 binding of the family.

    Evidence Purified-protein binding, chimera ('Superspondin') engineering, and cell signaling assays; LGR4 single-site structure

    PMID:25480784 PMID:25504990

    Open questions at the time
    • Why RSPO1 evolved lower ZNRF3 affinity not addressed
    • In vivo consequence of potency differences not tested here
  10. 2015 High

    Resolved complex stoichiometry, showing RSPO cross-links LGR and ZNRF3 into a 2:2:2 assembly versus 1:1:1 with RNF43.

    Evidence Crystal structures of binary and ternary LGR5-Rspo-ZNRF3/RNF43 complexes

    PMID:26123262

    Open questions at the time
    • Functional consequence of distinct ZNRF3 vs RNF43 stoichiometry not fully defined
  11. 2017 High

    Distinguished RSPO and Wnt ligand functions, showing they are non-interchangeable in Lgr5+ intestinal stem cell self-renewal.

    Evidence In vivo ISC fate analysis with RSPO and non-lipidated Wnt analogue and organoid culture

    PMID:28467820

    Open questions at the time
    • Molecular basis of qualitative difference between RSPO and Wnt inputs not resolved
  12. 2017 Medium

    Extended RSPO1 function to hematopoietic stem cell specification and angiogenesis, placing it upstream of parallel Wnt/Notch and Vegf signaling.

    Evidence Zebrafish genetics and epistasis with Wnt16/DeltaC/DeltaD, Vegfa/Tgfβ1 and Vegfc/Vegfr3

    PMID:22007135 PMID:28087636

    Open questions at the time
    • Receptor mediating these effects not defined in zebrafish
    • Conservation of HSC role in mammals not established here
  13. 2020 High

    Uncovered LGR-independent and TGFβ-crosstalk functions, showing RSPO1 maintains nephron progenitors and restrains adenoma growth through non-canonical routes.

    Evidence Conditional Rspo1/Rspo3 and Lgr4/5/6 knockouts with phospho-SMAD analysis; AAV-RSPO1 delivery to ApcMin/+ mice with organoid TGFBR inhibition

    PMID:32324134 PMID:32941878

    Open questions at the time
    • Receptor mediating LGR-independent activity unidentified
    • Direct link between RSPO1 and SMAD signaling not biochemically defined
  14. 2023 Medium

    Demonstrated the modularity and physiological breadth of RSPO1's ZNRF3/RNF43-directed degradation activity, from engineered target degradation to metabolic regulation.

    Evidence Bispecific ROTAC PD-L1 degradation with ZNRF3/RNF43 dependency; humanized R219W knockin obesity model; AMPKα-SREBP2 epistasis in hepatocytes; cellular LGR4 vs LGR5 complex-architecture binding

    PMID:32926477 PMID:36755192 PMID:37321224 PMID:37402772

    Open questions at the time
    • Several metabolic findings rely on overexpression/administration rather than endogenous manipulation
    • Single-lab observations awaiting independent confirmation
    • Mechanistic link between LGR4 engagement and AMPKα not biochemically resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the receptor(s) mediating RSPO1's LGR-independent and TGFβ/SMAD-coupled functions, and the basis of the reported nuclear localization, remain unresolved.
  • No receptor identified for LGR-independent activity
  • Nuclear localization role and processing not mechanistically resolved
  • Crosstalk to TGFβ/AMPK pathways lacks a defined biochemical intermediary

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005576 extracellular region 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1474165 Reproduction 2
Partners
LGR4LGR5LGR6LRP6RNF43WNT4ZNRF3
Complex memberships
RSPO1–LGR4/5/6–ZNRF3/RNF43 ternary complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 LGR4 and LGR5 associate with the Frizzled/LRP Wnt receptor complex and mediate RSPO1-dependent enhancement of canonical WNT3A signaling; removal of LGR4 abrogates RSPO1-mediated signal enhancement, which is rescued by re-expression of LGR4, -5, or -6, establishing LGR4/5/6 as facultative Wnt receptor components required for R-spondin signaling. Mass spectrometry (complex identification), conditional gene deletion in mouse gut, HEK293 cell rescue experiments, intestinal crypt culture organoids Nature High 21727895
2011 RSPO1 binds to LGR4 and LGR5 through its Furin domains, and LGR4/LGR5 promote RSPO1-mediated Wnt/β-catenin signaling; internalization via Clathrin (but not Caveolin) is required for R-spondin-triggered β-catenin signaling, distinguishing its endocytic mechanism from Wnt3a-mediated signaling. Gain- and loss-of-function experiments in mammalian cells and Xenopus embryos, Clathrin/Caveolin inhibition assays, binding assays EMBO reports High 21909076
2008 RSPO1 controls ovarian differentiation in XX gonads by activating the canonical β-catenin signaling pathway; Rspo1 knockout mice show masculinized gonads with absent female-specific Wnt4 activation, XY-like vascularization/steroidogenesis, and failure of germ cells to enter meiosis, demonstrating that RSPO1 is an essential regulator of canonical β-catenin signaling for female development. Rspo1 knockout mouse model, molecular analyses of Wnt4 expression, histological analysis of gonad phenotype Human molecular genetics High 18250098
2013 Crystal structures of RSPO1 in complex with LGR5 and RNF43 ectodomains reveal that RSPO1 is sandwiched between LGR5 and RNF43: its cysteine-rich domain rod module contacts LGR5 while a hairpin inserts into RNF43; LGR5 does not contact RNF43 but increases RSPO1 affinity for RNF43, supporting LGR5 as an engagement receptor and RNF43 as an effector receptor. X-ray crystallography of ternary complex Genes & development High 23756651
2013 Multiple crystal structures of the ZNRF3 ectodomain, the Fu1-Fu2 fragment of Rspo2, and their complexes with ZNRF3 and RNF43 ectodomains show that a prominent loop in Fu1 clamps into equivalent grooves in ZNRF3/RNF43; Rspo binding enhances dimerization of ZNRF3 but not RNF43; signaling potency depends on ability to recruit ZNRF3/RNF43 via Fu1 into a complex with LGR receptors that interact via Fu2. X-ray crystallography, biophysical binding assays, cellular signaling assays, mutagenesis Nature communications High 24225776
2013 Crystal structure of R-spondin 1 in complex with the LGR5 ectodomain (2.0 Å and 3.2 Å resolution) shows ecto-LGR5 binds Rspo1 at its concave LRR surface forming a 2:2 complex; a phenylalanine clamp (Phe106/Phe110 of Rspo1 pinching Ala190 of LGR5) is critical for binding; anonychia-related mutations reduce Rspo1 signaling but not LGR5 binding. X-ray crystallography, binding assays, mutagenesis, signaling assays Cell reports High 23809763
2013 Crystal structure of LGR4 ECD with RSPO1 N-terminal fragment (containing both FU-CRD1 and FU-CRD2) shows that LGR4 uses its concave surface to bind RSPO1-2F; both furin-like cysteine-rich domains of RSPO1 contribute to LGR4 interaction; all RSPO1-binding residues are conserved in LGR4-6, explaining promiscuous R-spondin binding. X-ray crystallography, binding assays, mutagenesis Genes & development High 23756652
2013 R-spondin interacts with ZNRF3/RNF43 and LGR4 through distinct motifs; both LGR4-binding and ZNRF3-binding motifs of R-spondin are required for LGR4/ZNRF3 interaction, membrane clearance of ZNRF3, and Wnt signaling activation; R-spondin primarily functions by binding and inhibiting ZNRF3, with LGR4/5 serving as engagement receptors and ZNRF3/RNF43 as effector receptors. Mutational analysis of R-spondin binding motifs, ZNRF3 membrane clearance assay, Wnt signaling reporter assays EMBO reports High 24165923
2012 RSPO1 potentiates Wnt/β-catenin signaling through LGR4 and LGR5; siRNA screen identified LGR4 as a specific receptor for RSPO; depletion of LGR4 completely abolished RSPO-induced β-catenin signaling; RSPO binds the extracellular domain of LGR4 and LGR5; LGR4 overexpression sensitizes cells to RSPO; no G-protein coupling of LGR4 was detected in RSPO-treated cells. Unbiased siRNA screen, binding assays, overexpression rescue, signaling reporter assays, G-protein coupling assay PloS one High 22815884
2008 All four R-spondin family members activate canonical Wnt signaling via a common mechanism requiring Wnt ligands and LRP6; the cysteine-rich furin domains are sufficient and essential for Wnt amplification; RSPOs antagonize DKK1 by interfering with DKK1-mediated LRP6/Kremen association, suggesting that Wnt amplification by RSPOs may occur through DKK1 inhibition. Deletion mutant analysis, TOPFLASH reporter assay, DKK1 antagonism assays, LRP6/Kremen interaction assays Molecular biology of the cell High 18400942
2011 RSPO1 activates the WNT/β-catenin signaling pathway in germ cells of XX gonads; in Rspo1(-/-) XX gonads, germ cell proliferation, Stra8 expression (early meiotic marker), and entry into meiosis are all impaired, and germ cell sex reversal occurs prior to Sertoli cell differentiation, indicating β-catenin signaling acts within germ cells to promote oogonial differentiation. Mouse knockout model (Rspo1-/-), meiosis markers, histological analysis, epistasis with somatic cell differentiation PloS one High 21991325
2012 Simultaneous ablation of Rspo1 and Wnt4 impairs proliferation of coelomic epithelium cells in early XY gonads, reducing progenitors of Sertoli cells and resulting in hypoplastic testis; individual knockouts do not show this phenotype, establishing RSPO1 and WNT4 as functionally cooperative regulators of gonadal progenitor proliferation independent of sex. Double knockout mouse model (Wnt4-/-;Rspo1-/-), histological and cell proliferation analysis Development (Cambridge, England) High 23095882
2013 RSPO1 reconstitutes a ternary complex with LGR4 and ZNRF3; RSPO proteins bind LGR4 with nanomolar affinities in decreasing order RSPO4 > RSPO2 > RSPO3 > RSPO1; RSPO2 and RSPO3 form detectable ternary RSPO:LGR4:ZNRF3 complexes, while RSPO4:ZNRF3 complexes were not detected; stronger signaling potency of RSPO2/3 correlates with their stronger binding of both receptors. In vitro reconstitution with bacterially expressed proteins, TR-FRET binding assay, native gel electrophoresis, cell-based signaling assay Biochemistry High 24050775
2017 RSPO ligands and Wnt ligands have qualitatively distinct, non-interchangeable roles in Lgr5+ intestinal stem cell self-renewal; Wnt proteins maintain RSPO receptor expression (basal competency) while RSPO ligands actively drive stem cell self-renewal and expansion; the default fate of Lgr5+ ISCs is to differentiate unless both RSPO and Wnt ligands are present. In vivo Lgr5+ ISC fate analysis, gain-of-function with RSPO ligands and non-lipidated Wnt analogue, intestinal organoid culture Nature High 28467820
2011 RSPO1/Wnt signaling promotes developmental angiogenesis via a Vegfc/Vegfr3 pathway; zebrafish rspo1 mutation impairs angiogenesis without affecting primary vasculogenesis; endothelial cell-autonomous inhibition of canonical Wnt signaling blocks angiogenesis; Vegfc expression is dependent on Rspo1 and Wnt; Vegfc and Vegfr3 are necessary downstream of Rspo1-Wnt for angiogenesis. Zebrafish forward genetic screen, morpholino knockdown, endothelial cell-autonomous Wnt inhibition, epistasis with Vegfc/Vegfr3 Development (Cambridge, England) High 22007135
2013 Crystal structures of ZNRF3 ectodomain alone and in complex with RSPO1 show ZNRF3 binds RSPO1 via its Fu1 domain with micromolar affinity; the ZNRF3-binding site on RSPO1 Fu2 overlaps with trans-interactions in 2:2 LGR5-RSPO1 complexes, suggesting ZNRF3/RNF43 binding would disrupt such arrangements; anonychia-related mutations in RSPO4 map to the observed interface. X-ray crystallography, affinity measurements, mutagenesis analysis PloS one High 24349440
2014 Crystal structure of LGR4-Rspo1 complex identifies the concave surface of LGR4 as the sole binding site for R-spondins; Rspo1 adopts a flat β-fold architecture bound through electrostatic and hydrophobic interactions; all Rspo1-binding residues are conserved in LGR4-6; this one-site binding model is mechanistically distinct from LGR1-3 and LGR7-8 ligand recognition. X-ray crystallography using hybrid LRR technique, binding and cellular assays The Journal of biological chemistry High 25480784
2015 Crystal structure of LGR5 complexed with Rspo2 (at high resolution) shows engagement almost identical to RSPO1; LGR5 ectodomain exhibits nearly 9° plasticity in horseshoe fold; low-resolution ternary LGR5-Rspo2-ZNRF3 structure confirms Rspo proteins cross-link LGRs and ZNRF3 into a 2:2:2 complex with ZNRF3, whereas a 1:1:1 complex is formed with RNF43. X-ray crystallography of binary and ternary complexes Journal of structural biology High 26123262
2014 Signaling potency of RSPOs is determined by ternary complex formation ability (dependent on combined LGR4 and ZNRF3 binding); efficacy depends on ZNRF3 recruitment; RSPO2/3/4 have stronger signaling potencies than RSPO1; engineering RSPO2 ZNRF3-binding region onto RSPO4's LGR4-binding region creates a 'Superspondin' with 10-fold enhanced potency; RSPO1 has the weakest ZNRF3 binding among the four members. Purified protein binding assays, chimeric protein engineering, cell-based signaling assays, mutagenesis Molecular pharmacology High 25504990
2020 RSPO1 expression in Rspo1(-/-) nephron progenitors (cap mesenchymal cells) is required for mesenchyme-to-epithelial transition (MET) linked to Bmp7 expression, SMAD1/5 phosphorylation, and activation of Lef1, Fgf8, and Wnt4; RSPO1 and RSPO3 act redundantly to permit WNT/β-catenin signaling and nephron progenitor maintenance; surprisingly, full knockout of LGR4/5/6 only mildly affects progenitor numbers but does not interfere with MET, revealing LGR-independent functions for R-spondins. Tissue-specific conditional knockout (Rspo1/Rspo3 and Lgr4/5/6 in cap mesenchyme), phospho-SMAD analysis, gene expression analysis eLife High 32324134
2023 RSPO1 inhibits beige adipocyte thermogenesis via LGR4-Wnt/β-catenin signaling; humanized knockin mice with RSPO1 p.R219W mutation show suppressed thermogenesis and obesity; the R219W mutation disrupts RSPO1's electrostatic interaction with the extracellular matrix, causing excessive RSPO1 release that hyperactivates LGR4-Wnt/β-catenin and attenuates mitochondrial respiration and thermogenic capacity in beige adipocytes. Whole-exome sequencing, knockin mouse model, adipose-specific overexpression, Rspo1 ablation, mechanistic RSPO1 administration to differentiated adipocytes Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 36755192
2020 In response to hormonal signaling, Amphiregulin (Areg) secreted by ER-positive luminal mammary cells induces RSPO1 expression in ER-negative luminal cells in a paracrine, EGFR-dependent manner, establishing an Estrogen-Areg-Rspo1 regulatory axis controlling RSPO1 expression in the mammary gland. Conditional cell-type specific analysis, paracrine co-culture experiments, EGFR inhibition, expression analysis Developmental biology Medium 31610144
2017 RSPO1 is required for hematopoietic stem cell (HSC) specification in zebrafish through control of two parallel signaling pathways: Wnt16/DeltaC/DeltaD and Vegfa/Tgfβ1; Rspo1 acts upstream of both pathways to coordinate HSC specification with vessel patterning. Zebrafish genetic analysis, epistasis experiments with Wnt16 and Vegfa pathways Development (Cambridge, England) Medium 28087636
2013 RSPO1 injection into the third brain ventricle of male rats inhibits food intake and decreases neuropeptide Y while increasing proopiomelanocortin expression in the arcuate nucleus; LGR4 (RSPO1 receptor) is expressed in arcuate, ventromedial, and median eminence hypothalamic nuclei colocalizing with NPY, POMC and BDNF neurons; Rspo1 is expressed by neurons and is down-regulated by fasting. In situ hybridization, intracerebroventricular injection, food intake measurement, gene expression analysis Endocrinology Medium 24280058
2023 Bispecific ROTACs (signaling-disabled RSPO chimeras) leverage RSPO specificity for ZNRF3/RNF43 E3 ubiquitin ligases to target degradation of transmembrane proteins; a bispecific RSPO2 chimera (R2PD1) targeting PD-L1 induces lysosomal degradation of PD-L1 strictly dependent on ZNRF3/RNF43, confirming RSPO's mechanistic role in directing ZNRF3/RNF43-mediated lysosomal degradation. Bispecific protein engineering, PD-L1 degradation assay, ZNRF3/RNF43 dependency assay, T cell reactivation assay Cell chemical biology Medium 37321224
2004 R-spondin (RSPO1) encodes a secreted protein with a thrombospondin type 1 motif expressed in the dorsal neural tube; transfection of epitope-tagged R-spondin into COS7 and 293 cells shows both nuclear and secreted localization, suggesting processing-dependent localization; its expression is reduced in Wnt-1/3a double-knockout mice, placing it downstream of Wnt-1/3a signaling. Northern blot, in situ hybridization, epitope-tag transfection/fractionation, Wnt-1/3a double knockout expression analysis Biochimica et biophysica acta Low 14732490
2011 RSPO1 augments β-catenin signaling in a dose-dependent manner; co-transfection of RSPO1 with CTNNB1 (β-catenin) results in ~10-fold synergistic activation of a TOPFLASH reporter; wild-type RSPO1 shows strong nuclear localization in several cell lines; an individual with a RSPO1 splice mutation shows reduced β-catenin protein and WNT4 mRNA in ovotestis tissue. TOPFLASH reporter transfection assay, subcellular localization (nuclear staining), patient tissue analysis PloS one Low 21297984
2020 RSPO1 overexpression in ApcMin/+ mice increases apoptosis and reduces Wnt signaling and proliferation in adenomas; this effect is mediated in part through activation of TGFβ/SMAD2 signaling, as TGFBR inhibition restores organoid formation and Wnt target gene expression suppressed by RSPO1; RSPO1 thus activates a cross-talk between Wnt and TGFβ pathways in adenoma cells. AAV-RSPO1-Fc delivery to ApcMin/+ mice, organoid culture with RSPO1 and TGFBR inhibitor, scRNA-seq, immunohistochemistry, phospho-SMAD2 analysis Gastroenterology Medium 32941878
2020 Rspo1/Rspo3-LGR4 signaling in hepatocytes inhibits cholesterol synthesis via the AMPKα-SREBP2 pathway; Rspo1 increases phosphorylation of AMPKα Thr172, reducing SREBP2 nuclear translocation; hepatic LGR4 knockdown increases cholesterol synthesis and decreases AMPKα phosphorylation; AMPKα knockdown abrogates Rspo1-induced inhibition of cholesterol synthesis. LGR4/Rspo1/Rspo3 knockdown mice, AMPKα agonist/antagonist/shRNA epistasis, SREBP2 nuclear translocation assay, phospho-AMPKα analysis FASEB journal Medium 32926477
2023 LGR4 and LGR5 form distinct homodimers; only LGR4 (not LGR5) complexes with RNF43/ZNRF3 to provide high-affinity bivalent binding of RSPO ligands; co-expression of ZNRF3 with LGR4 greatly increases binding affinity for monovalent RSPO2 furin domain, whereas co-expression with LGR5 has no effect, establishing distinct receptor complex architectures that explain differential RSPO signaling through LGR4 vs LGR5. Binding affinity assays with monovalent and bivalent RSPO in whole cells, co-expression experiments, structural modeling Scientific reports Medium 37402772

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 1062 21727895
2012 Recurrent R-spondin fusions in colon cancer. Nature 800 22895193
2011 LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling. EMBO reports 477 21909076
2008 Activation of beta-catenin signaling by Rspo1 controls differentiation of the mammalian ovary. Human molecular genetics 358 18250098
2017 Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal. Nature 354 28467820
2008 R-Spondin family members regulate the Wnt pathway by a common mechanism. Molecular biology of the cell 286 18400942
2018 Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis. Cell 267 30096312
2012 The R-spondin protein family. Genome biology 236 22439850
2006 R-Spondin proteins: a novel link to beta-catenin activation. Cell cycle (Georgetown, Tex.) 216 16357527
2017 Stromal R-spondin orchestrates gastric epithelial stem cells and gland homeostasis. Nature 172 28813421
2008 R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis. Development (Cambridge, England) 167 18256198
2013 Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin. Nature communications 166 24225776
2006 The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, is mutated in inherited anonychia. Nature genetics 149 17041604
2012 R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. PloS one 146 22815884
2008 The Wnt signaling regulator R-spondin 3 promotes angioblast and vascular development. Development (Cambridge, England) 141 18842812
2014 Stem cells marked by the R-spondin receptor LGR5. Gastroenterology 137 24859206
2013 Induction of intestinal stem cells by R-spondin 1 and Slit2 augments chemoradioprotection. Nature 128 23903657
2004 R-spondin, a novel gene with thrombospondin type 1 domain, was expressed in the dorsal neural tube and affected in Wnts mutants. Biochimica et biophysica acta 127 14732490
2013 The structural basis of R-spondin recognition by LGR5 and RNF43. Genes & development 126 23756651
2022 Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 in osteoarthritis. Annals of the rheumatic diseases 112 36175067
2019 R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon. Nature communications 112 31554819
2012 The R-spondin family of proteins: emerging regulators of WNT signaling. The international journal of biochemistry & cell biology 108 22982762
2006 Dynamic expression of R-spondin family genes in mouse development. Gene expression patterns : GEP 106 17035101
2009 Wnt11 promotes osteoblast maturation and mineralization through R-spondin 2. The Journal of biological chemistry 103 19213727
2011 RSPO1/β-catenin signaling pathway regulates oogonia differentiation and entry into meiosis in the mouse fetal ovary. PloS one 102 21991325
2008 Syndromic true hermaphroditism due to an R-spondin1 (RSPO1) homozygous mutation. Human mutation 101 18085567
2013 Structural basis for R-spondin recognition by LGR4/5/6 receptors. Genes & development 100 23756652
2015 Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types. Cancer research 98 26719531
2017 R-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine. Nature communications 96 28695896
2011 Rspo1/Wnt signaling promotes angiogenesis via Vegfc/Vegfr3. Development (Cambridge, England) 92 22007135
2013 Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin. EMBO reports 89 24165923
2011 A WNT/beta-catenin signaling activator, R-spondin, plays positive regulatory roles during skeletal myogenesis. The Journal of biological chemistry 89 21252233
2012 WNT4 and RSPO1 together are required for cell proliferation in the early mouse gonad. Development (Cambridge, England) 86 23095882
2006 Mutations in the gene encoding the Wnt-signaling component R-spondin 4 (RSPO4) cause autosomal recessive anonychia. American journal of human genetics 81 17186469
2013 Structure of stem cell growth factor R-spondin 1 in complex with the ectodomain of its receptor LGR5. Cell reports 75 23809763
2021 The role of R-spondin proteins in cancer biology. Oncogene 72 34663878
2025 Hepatic stellate cells control liver zonation, size and functions via R-spondin 3. Nature 70 40074890
2013 R-spondin 2 signalling mediates susceptibility to fatal infectious diarrhoea. Nature communications 68 23695692
2013 Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling. PloS one 67 24349440
2011 Human RSPO1/R-spondin1 is expressed during early ovary development and augments β-catenin signaling. PloS one 65 21297984
2016 R-spondin 1 and noggin facilitate expansion of resident stem cells from non-damaged gallbladders. EMBO reports 62 26993089
2008 Genetics of ovarian differentiation: Rspo1, a major player. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 62 18987496
2013 Wnt/Rspondin/β-catenin signals control axonal sorting and lineage progression in Schwann cell development. Proceedings of the National Academy of Sciences of the United States of America 58 24151333
2012 WNT4, RSPO1, and FOXL2 in sex development. Seminars in reproductive medicine 55 23044875
2016 Involvement of FOXL2 and RSPO1 in Ovarian Determination, Development, and Maintenance in Mammals. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 51 27649556
2010 R-spondin 1 protects against inflammatory bone damage during murine arthritis by modulating the Wnt pathway. Arthritis and rheumatism 51 20506554
2016 LGR4 acts as a key receptor for R-spondin 2 to promote osteogenesis through Wnt signaling pathway. Cellular signalling 50 27140682
2015 Crystal structure of R-spondin 2 in complex with the ectodomains of its receptors LGR5 and ZNRF3. Journal of structural biology 44 26123262
2020 Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs. PloS one 43 32160239
2016 Rspo1-activated signalling molecules are sufficient to induce ovarian differentiation in XY medaka (Oryzias latipes). Scientific reports 41 26782368
2016 Dmy initiates masculinity by altering Gsdf/Sox9a2/Rspo1 expression in medaka (Oryzias latipes). Scientific reports 41 26806354
2007 RSPO4 is the major gene in autosomal-recessive anonychia and mutations cluster in the furin-like cysteine-rich domains of the Wnt signaling ligand R-spondin 4. The Journal of investigative dermatology 41 17914448
2013 Sequence and gene content of a large fragment of a lizard sex chromosome and evaluation of candidate sex differentiating gene R-spondin 1. BMC genomics 39 24344927
2020 Transcriptional Profiling of the Adult Hair Follicle Mesenchyme Reveals R-spondin as a Novel Regulator of Dermal Progenitor Function. iScience 38 32289736
2007 Mutations in R-spondin 4 (RSPO4) underlie inherited anonychia. The Journal of investigative dermatology 37 17805348
2021 Role of R-spondin 2 in arterial lymphangiogenesis and atherosclerosis. Cardiovascular research 36 32750106
2020 Expression of R-Spondin 1 in ApcMin/+ Mice Suppresses Growth of Intestinal Adenomas by Altering Wnt and Transforming Growth Factor Beta Signaling. Gastroenterology 36 32941878
2019 R-spondin 2-LGR4 system regulates growth, migration and invasion, epithelial-mesenchymal transition and stem-like properties of tongue squamous cell carcinoma via Wnt/β-catenin signaling. EBioMedicine 35 31097406
2017 Evidence of the Role of R-Spondin 1 and Its Receptor Lgr4 in the Transmission of Mechanical Stimuli to Biological Signals for Bone Formation. International journal of molecular sciences 35 28272338
2019 R-spondin signaling as a pivotal regulator of tissue development and homeostasis. The Japanese dental science review 34 31049116
2013 Lmx1a encodes a rostral set of mesodiencephalic dopaminergic neurons marked by the Wnt/B-catenin signaling activator R-spondin 2. PloS one 34 24066094
2016 R-spondin 2 facilitates differentiation of proliferating chondrocytes into hypertrophic chondrocytes by enhancing Wnt/β-catenin signaling in endochondral ossification. Biochemical and biophysical research communications 32 27012200
2023 ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation. Cell chemical biology 31 37321224
2020 Tissue-targeted R-spondin mimetics for liver regeneration. Scientific reports 31 32811902
2020 R-Spondin 2 Induces Odontogenic Differentiation of Dental Pulp Stem/Progenitor Cells via Regulation of Wnt/β-Catenin Signaling. Frontiers in physiology 30 32848860
2020 R-spondin substitutes for neuronal input for taste cell regeneration in adult mice. Proceedings of the National Academy of Sciences of the United States of America 29 33443181
2022 Comprehensive Analysis of R-Spondin Fusions and RNF43 Mutations Implicate Novel Therapeutic Options in Colorectal Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 28 35254413
2016 MYC and PVT1 synergize to regulate RSPO1 levels in breast cancer. Cell cycle (Georgetown, Tex.) 28 26889781
2014 Crystal structure of LGR4-Rspo1 complex: insights into the divergent mechanisms of ligand recognition by leucine-rich repeat G-protein-coupled receptors (LGRs). The Journal of biological chemistry 27 25480784
2019 The Role of Wnt and R-spondin in the Stomach During Health and Disease. Biomedicines 26 31248166
2018 R-spondin 2 promotes osteoblastic differentiation of immature human periodontal ligament cells through the Wnt/β-catenin signaling pathway. Journal of periodontal research 26 30284717
2013 Reconstitution of R-spondin:LGR4:ZNRF3 adult stem cell growth factor signaling complexes with recombinant proteins produced in Escherichia coli. Biochemistry 26 24050775
2013 Syndecan-4 inhibits Wnt/β-catenin signaling through regulation of low-density-lipoprotein receptor-related protein (LRP6) and R-spondin 3. The international journal of biochemistry & cell biology 26 24275095
2013 LGR4 and its ligands, R-spondin 1 and R-spondin 3, regulate food intake in the hypothalamus of male rats. Endocrinology 26 24280058
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
2017 An Eye Organoid Approach Identifies Six3 Suppression of R-spondin 2 as a Critical Step in Mouse Neuroretina Differentiation. Cell reports 25 29117559
2016 Novel Bispecific Domain Antibody to LRP6 Inhibits Wnt and R-spondin Ligand-Induced Wnt Signaling and Tumor Growth. Molecular cancer research : MCR 25 27401612
2013 Secreted factor R-Spondin 2 is involved in refinement of patterning of the mammalian cochlea. Developmental dynamics : an official publication of the American Association of Anatomists 25 23192966
2013 R-Spondin 1 promotes vibration-induced bone formation in mouse models of osteoporosis. Journal of molecular medicine (Berlin, Germany) 25 23974989
2019 R-spondin 2 Drives Liver Tumor Development in a Yes-Associated Protein-Dependent Manner. Hepatology communications 24 31701073
2014 R-spondin 3 regulates dorsoventral and anteroposterior patterning by antagonizing Wnt/β-catenin signaling in zebrafish embryos. PloS one 24 24918770
2013 Sexual dimorphism of AMH, DMRT1 and RSPO1 localization in the developing gonads of six anuran species. The International journal of developmental biology 24 24623081
2016 R-spondin 2 promotes acetylcholine receptor clustering at the neuromuscular junction via Lgr5. Scientific reports 23 27328992
2020 R-spondin signalling is essential for the maintenance and differentiation of mouse nephron progenitors. eLife 22 32324134
2019 Mianserin suppresses R-spondin 2-induced activation of Wnt/β-catenin signaling in chondrocytes and prevents cartilage degradation in a rat model of osteoarthritis. Scientific reports 22 30808932
2023 R-spondin family biology and emerging linkages to cancer. Annals of medicine 21 36645115
2018 The Matricellular Protein R-Spondin 2 Promotes Midbrain Dopaminergic Neurogenesis and Differentiation. Stem cell reports 21 30146491
2018 The role of R-spondin 1 through activating Wnt/β-catenin in the growth, survival and migration of ovarian cancer cells. Gene 21 30572097
2008 Mutations in the RSPO1 coding region are not the main cause of canine SRY-negative XX sex reversal in several breeds. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 21 18577875
2014 TALEN-mediated mutagenesis in zebrafish reveals a role for r-spondin 2 in fin ray and vertebral development. FEBS letters 20 25448983
2014 Engineering high-potency R-spondin adult stem cell growth factors. Molecular pharmacology 20 25504990
2023 Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet-Induced Adiposity. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 19 36755192
2017 R-spondin 1 is required for specification of hematopoietic stem cells through Wnt16 and Vegfa signaling pathways. Development (Cambridge, England) 19 28087636
2017 R-spondin 2 promotes proliferation and migration via the Wnt/β-catenin pathway in human hepatocellular carcinoma. Oncology letters 19 28789406
2023 LGR4 and LGR5 form distinct homodimers that only LGR4 complexes with RNF43/ZNRF3 to provide high affinity binding of R-spondin ligands. Scientific reports 18 37402772
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 Novel RSPO1 mutation causing 46,XX testicular disorder of sex development with palmoplantar keratoderma: A review of literature and expansion of clinical phenotype. American journal of medical genetics. Part A 17 29575617
2007 Search for the sex-determining switch in monotremes: mapping WT1, SF1, LHX1, LHX2, FGF9, WNT4, RSPO1 and GATA4 in platypus. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 17 17717721
2021 Drug Conjugates of Antagonistic R-Spondin 4 Mutant for Simultaneous Targeting of Leucine-Rich Repeat-Containing G Protein-Coupled Receptors 4/5/6 for Cancer Treatment. Journal of medicinal chemistry 16 34406767
2019 Amphiregulin mediates the hormonal regulation on Rspondin-1 expression in the mammary gland. Developmental biology 15 31610144

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