Affinage

SFRP2

Secreted frizzled-related protein 2 · UniProt Q96HF1

Length
295 aa
Mass
33.5 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SFRP2 is a secreted cysteine-rich modulator of Wnt signaling that exerts opposite, strongly context-dependent effects on the pathway: it antagonizes Wnt by binding ligands such as Wnt-4, Wnt1, and Wnt6 through its cysteine-rich domain to block receptor engagement and β-catenin accumulation upstream of GSK-3 (PMID:9853965, PMID:10654605, PMID:10656762, PMID:16425220, PMID:26071893), yet it can also potentiate canonical Wnt/β-catenin signaling by augmenting LRP6 phosphorylation, β-catenin stabilization, and TCF-dependent transcription in a DKK1-sensitive manner (PMID:20723538, PMID:34857734). In non-canonical signaling it redirects Wnt output by stabilizing Wnt5a–Ror2 complexes at the membrane while inhibiting Fz7, with the cysteine-rich domain sufficient for Ror2 activation (PMID:27129770), and it engages Fzd5–calcineurin–NFATc3 signaling to drive cell-fate programs (PMID:38980870). Genetically, Sfrp1 and Sfrp2 act redundantly to control trunk and somite formation through both canonical Wnt and planar-cell-polarity pathways, with somite segmentation defects linked to disrupted Notch oscillations (PMID:16467359, PMID:18257070). Beyond Wnt, SFRP2 directly inhibits the BMP1/procollagen C-proteinase to limit collagen maturation and fibrosis (PMID:21078975), suppresses BMP/SMAD signaling to maintain mesenchymal stem cell self-renewal (PMID:20826809), and in disease contexts—including aged-stroma melanoma metastasis via a β-catenin→MITF→APE1 cascade (PMID:27042933), indolent breast-cancer survival through fibronectin/integrin signaling (PMID:32094692), and CAF-driven tumor microenvironment remodeling (PMID:40086438)—acts as a paracrine effector secreted by stromal and stem-cell populations. SFRP2 expression is itself controlled at multiple levels, including Pax2 transactivation, NF-κB induction, KDM2A-mediated histone demethylation, and lncRNA Safe/HuR-dependent mRNA stabilization (PMID:26751775, PMID:31695768, PMID:14561758, PMID:27074224).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1998 High

    Established the molecular basis for SFRP2's interaction with Wnt by showing its cysteine-rich domain directly binds a Wnt ligand, defining the structural module through which it modulates Wnt signaling.

    Evidence Co-immunoprecipitation and in vivo expression analysis in Wnt-4 knockout metanephric mesenchyme

    PMID:9853965

    Open questions at the time
    • Did not establish whether binding is antagonistic or agonistic
    • Binding affinity and specificity across Wnt family untested
  2. 2000 High

    Defined SFRP2 as a bona fide in vivo Wnt antagonist with ligand specificity, answering whether ligand binding translates into functional pathway inhibition.

    Evidence Xenopus embryo RNA injection and chick somitic mesoderm explant assays showing inhibition of Wnt1/Wnt4 but not Wnt3a

    PMID:10654605 PMID:10656762

    Open questions at the time
    • Mechanism of ligand selectivity unresolved
    • Did not address agonist contexts later observed
  3. 2006 High

    Placed SFRP2 antagonism upstream of GSK-3 and demonstrated genetic redundancy with SFRP1, clarifying where in the canonical cascade it acts and why single knockouts are silent.

    Evidence In vitro β-catenin accumulation with purified protein plus LiCl epistasis; double Sfrp1/Sfrp2 knockout mice with Notch oscillation readouts

    PMID:16425220 PMID:16467359

    Open questions at the time
    • Did not resolve how Sfrp2 links to Notch oscillations mechanistically
    • Receptor-level mechanism not defined
  4. 2008 High

    Revealed the agonist face of SFRP2—stabilizing β-catenin and activating Wnt targets via Frizzled—overturning a purely antagonistic model and tying it to thyroid hormone control and developmental phenotypes.

    Evidence Reporter and β-catenin stabilization assays, TR knockout and Sfrp2 knockout mice (brachydactyly), and PCP/canonical epistasis in triple knockouts

    PMID:18257070 PMID:18446812 PMID:19001373

    Open questions at the time
    • Molecular determinant switching antagonist vs agonist behavior unknown
    • Direct receptor-binding mode in agonist context not shown
  5. 2010 High

    Identified BMP1/procollagen C-proteinase as a direct, Wnt-independent enzymatic target of SFRP2, expanding its mechanism to direct protease inhibition controlling collagen maturation.

    Evidence In vitro fluorogenic procollagen C-proteinase assay with recombinant proteins, primary cardiac fibroblasts, and rat MI model

    PMID:21078975

    Open questions at the time
    • Structural basis of BMP1 inhibition undefined
    • Selectivity over related tolloid proteases not fully mapped
  6. 2010 Medium

    Showed SFRP2 augments canonical Wnt3a signaling at the receptor level and independently suppresses BMP/SMAD signaling, mechanistically separating its dual modulatory activities.

    Evidence Recombinant protein addition with LRP6 phosphorylation/β-catenin western blots, DKK1 epistasis, and pSMAD1/5/8 analysis in MSCs

    PMID:20723538 PMID:20826809

    Open questions at the time
    • Single-lab biochemistry
    • How a Wnt antagonist enhances LRP6 phosphorylation not reconciled
  7. 2011 Medium

    Connected SFRP2 to calcineurin/NFAT signaling in angiogenesis, establishing a non-Wnt transcriptional effector pathway.

    Evidence shRNA silencing of NFATc3 abolishing SFRP2-driven endothelial tube formation; in vivo MMTV-neu tumor model with tacrolimus

    PMID:21673995

    Open questions at the time
    • Receptor coupling SFRP2 to calcineurin not identified here
    • Single lab
  8. 2016 High

    Resolved how SFRP2 redirects rather than simply blocks non-canonical Wnt, defining a receptor-switching mechanism from Fz7 to Ror2 via Wnt5a-Ror2 complex stabilization.

    Evidence Xenopus gastrulation assays, dominant-negative constructs, membrane complex stabilization, and CRD truncation mapping

    PMID:27129770

    Open questions at the time
    • Structural detail of complex stabilization unresolved
    • Generality beyond gastrulation untested
  9. 2016 High

    Defined SFRP2's role in the aged tumor microenvironment, establishing a β-catenin→MITF→APE1 cascade driving melanoma metastasis and therapy resistance.

    Evidence Recombinant protein and shRNA with β-catenin/MITF/APE1 westerns and aged vs young in vivo metastasis models

    PMID:27042933

    Open questions at the time
    • Receptor mediating the aged-fibroblast SFRP2 signal not defined
    • Reconciliation with melanogenic β-catenin/MITF activation in melanocytes [#21] unresolved
  10. 2016 Medium

    Catalogued SFRP2's context-specific outputs in cardiac fibroblasts and cancer—Warburg metabolism with MMP-driven collagenolysis, WNT16B/FZD potentiation, and NF-κB-driven transcriptional induction.

    Evidence Recombinant protein treatment with metabolic, MMP, and signaling assays; Frizzled/LRP6 binding and NF-κB inhibitor studies

    PMID:26751775 PMID:26763443 PMID:27605451

    Open questions at the time
    • Single-lab mechanistic dissections
    • Cell-type specificity determinants unexplained
  11. 2015 Medium

    Showed SFRP2 upregulates TNAP and ectopic phosphate production specifically in cardiac fibroblasts in a protein-synthesis- and glycosylation-dependent manner, indicating a transcriptional/biosynthetic downstream program.

    Evidence Recombinant sFRP2 with TNAP activity assays, cycloheximide/tunicamycin controls, and hamster heart failure blockade

    PMID:25972450

    Open questions at the time
    • Signaling pathway linking SFRP2 to TNAP induction unidentified
    • Single lab
  12. 2018 Medium

    Demonstrated β-catenin-independent oncogenic SFRP2 signaling through FOXM1/CYR61 in osteosarcoma and through KLF4/PDGFR/AKT/SOX2 in glioblastoma, broadening its mechanistic repertoire beyond Wnt/β-catenin.

    Evidence iPSC-derived osteoblast and GBM overexpression/knockdown models with gene-expression and phospho-AKT analysis

    PMID:30385632 PMID:34021259

    Open questions at the time
    • Receptors mediating β-catenin-independent effects unknown
    • Single-lab models
  13. 2020 High

    Established SFRP2 as a pro-survival paracrine effector in disseminated cancer, promoting fibronectin fibril formation and integrin signaling that sustains indolent disease.

    Evidence In vivo RNA-seq, dropout CRISPR screen, metastasis models, and Sfrp2 blockade with fibronectin fibril assays

    PMID:32094692

    Open questions at the time
    • Molecular link between SFRP2 and fibronectin assembly undefined
    • Receptor not identified
  14. 2021 High

    Confirmed SFRP2 acts as a Wnt agonist in skeletal stem cells via LRP6 activation, with knockout impairing bone regeneration and recombinant protein rescuing it, reinforcing the agonist mechanism with genetic and rescue evidence.

    Evidence Sfrp2 knockout mice, ectopic and cortical bone defect assays, Lrp6/Wnt-target westerns, and recombinant rescue

    PMID:34857734

    Open questions at the time
    • Direct LRP6 binding not shown
    • Determinants of agonist vs antagonist outcome still unresolved
  15. 2024 High

    Defined a TGF-β1→fibroblast SFRP2→Fzd5/calcineurin/NFATc3 axis activating Krt5+ basal cell programs, linking SFRP2 to non-canonical NFAT signaling in lung remodeling.

    Evidence AEC2-fibroblast organoids, precision-cut lung slices, scRNA-seq, and Fzd5/calcineurin inhibition with NFATc3 imaging

    PMID:38980870

    Open questions at the time
    • Whether the same Fzd5/NFAT axis operates in other SFRP2 contexts untested
  16. 2019 Medium

    Identified upstream regulators of SFRP2 abundance, including lncRNA Safe/HuR-mediated mRNA stabilization and DRG-neuron-derived SFRP2 driving macrophage NF-κB/M1 polarization via β-catenin/p65 destabilization.

    Evidence EMSA/RIP/reporter assays for Safe-Sfrp2-HuR duplex; immunoprecipitation of β-catenin/p65 with in vivo lentiviral knockdown

    PMID:31281508 PMID:31695768

    Open questions at the time
    • Generalizability of Safe/HuR regulation across tissues unknown
    • β-catenin/p65 mechanism shown in single lab
  17. 2025 High

    Placed SFRP2 within tumor stroma plasticity, showing PAI-1/LRP1/p65-driven pericyte-to-CAF conversion generates SFRP2-high CAFs that suppress anti-tumor immunity, with knockout enhancing radioimmunotherapy.

    Evidence In vivo genome-wide CRISPR screen, conditional CAF Sfrp2 knockout, lineage tracing, and pharmacological SFRP2/PAI-1 blockade in PDX models

    PMID:40086438

    Open questions at the time
    • Direct SFRP2 effector on T cells/vasculature not fully resolved
    • Receptor mediating immunosuppression unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular determinant that switches SFRP2 between Wnt antagonist and agonist, and between canonical and non-canonical/β-catenin-independent outputs, remains undefined across cell contexts.
  • No structural model of context-dependent receptor selection
  • Concentration- and co-receptor-dependence not unified
  • No comprehensive receptor-interaction map

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0048018 receptor ligand activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-1643685 Disease 3
Partners
BMP1FZD5LRP6ROR2WNT4WNT5AWNT6

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 The cysteine-rich domain of sFRP-2 binds directly to Wnt-4, as demonstrated by co-immunoprecipitation, and sFRP-2 expression is induced downstream of Wnt-4 signaling in the developing metanephric kidney mesenchyme. Co-immunoprecipitation; in vivo expression analysis in Wnt-4 knockout mice; co-induction assay in isolated metanephric mesenchyme Developmental dynamics High 9853965
2000 Sfrp-2 functions as a Wnt antagonist in vivo; injection of Sfrp-2 RNA into Xenopus embryos phenocopies Wnt antagonism, and Sfrp-2-expressing cells reduce the dermomyotome-inducing activity of Wnt1 and Wnt4 (but not Wnt3a) in somitic mesoderm explants. Xenopus embryo injection assay; chick somitic mesoderm explant culture with Sfrp2-expressing cells Development (Cambridge, England) High 10654605 10656762
2006 Purified Sfrp-2 (and Sfrp-1) inhibits Wnt-3a-induced β-catenin accumulation in L cells, acting upstream of GSK-3 (as Sfrp-2 cannot inhibit LiCl-induced β-catenin accumulation), and Sfrp-2 inhibits ectopic Wnt-3a-stimulated proliferation in the chick neural tube. In vitro β-catenin accumulation assay with purified recombinant proteins; LiCl epistasis experiment; in ovo chick neural tube electroporation Developmental dynamics High 16425220
2006 Loss-of-function of both Sfrp1 and Sfrp2 in mice causes severe anteroposterior axis shortening and defective somite segmentation, with altered Notch signaling oscillations (abnormal Lfng and Hes7 expression); single knockouts show no phenotype, demonstrating functional redundancy. Double homozygous knockout mouse genetics; in situ hybridization for Notch pathway oscillation markers Development (Cambridge, England) High 16467359
2007 Sfrp2 is the key paracrine factor secreted by Akt-modified mesenchymal stem cells that mediates myocardial survival after ischemic injury; treatment of cardiomyocytes with Sfrp2 increases cellular β-catenin and upregulates antiapoptotic gene expression. Functional genomic screen; recombinant protein treatment of cardiomyocytes; β-catenin measurement; antiapoptotic gene expression analysis Proceedings of the National Academy of Sciences of the United States of America Medium 17251350
2007 SFRP2 inhibits cardiomyogenic differentiation by interrupting a positive transcriptional autofeedback loop of Wnt3a: SFRP2 inhibits Wnt3a transcription (which is normally driven by canonical Wnt/TCF4 signaling), thereby preventing mesoderm specification. Gain- and loss-of-function (recombinant protein addition; Sfrp2 siRNA knockdown) in mouse embryonal carcinoma stem cells; Wnt3a transcription assay; canonical Wnt signaling reporter assay Stem cells (Dayton, Ohio) Medium 17916803
2008 sFRP2 activates canonical Wnt/β-catenin signaling in intestinal epithelium via Frizzled receptors, stabilizing β-catenin, activating Wnt target genes, and enhancing cell proliferation; this activity is directly regulated by thyroid hormone receptor TRα1. In vitro and in vivo expression analysis; luciferase reporter assays; β-catenin stabilization assay; TR knockout mouse model; laser microdissection and transcriptional profiling The Journal of biological chemistry Medium 19001373
2008 sFRP2 enhances mesenchymal stem cell engraftment and regenerative capacity; specific shRNA knockdown of sFRP2 in MRL-MSCs decreases proliferation and engraftment, while retroviral overexpression of sFRP2 in WT-MSCs recapitulates the enhanced regenerative phenotype in vivo. shRNA knockdown; retroviral overexpression; in vivo engraftment and granulation tissue assays; murine myocardial infarct model Proceedings of the National Academy of Sciences of the United States of America Medium 19017790
2008 Inactivation of Sfrp2 in mice causes brachydactyly with decreased chondrocyte proliferation and delayed differentiation; Sfrp2 can repress canonical Wnt signaling by Wnt1, Wnt9a, and Wnt4 in vitro, and Sfrp2-/- mice show mild increases in β-catenin in phalangeal elements. Sfrp2 knockout mouse; in vitro Wnt signaling reporter assay; histological analysis; TOPGAL reporter mice Journal of cellular physiology Medium 18446812
2008 Sfrp1 and Sfrp2 regulate trunk formation through both canonical Wnt/β-catenin (somitogenesis) and planar cell polarity (convergent extension) pathways; genetic epistasis with Dkk1-deficient and Loop-tail (PCP mutant) mice placed Sfrps as modulators of both pathways. Triple knockout mouse genetics; genetic epistasis with Dkk1 KO and Loop-tail (Vangl2) mutants Genesis (New York, N.Y. : 2000) High 18257070
2008 Sfrp2 suppresses UV-induced apoptosis in canine mammary tumor cells through NF-κB activation and JNK suppression; sFRP2 co-localizes with extracellular matrix, enhances FAK tyrosine phosphorylation, and activates NF-κB (demonstrated by EMSA) while suppressing JNK after UV treatment. sFRP2 overexpression; TUNEL and DNA fragmentation assays; immunofluorescence co-localization; immunoprecipitation; immunoblotting; EMSA Breast cancer research and treatment Medium 16791480
2010 Sfrp2 specifically inhibits mammalian BMP1 (procollagen C-proteinase) activity in vitro, thereby inhibiting procollagen I processing and collagen maturation; this inhibition is specific to Sfrp2 (not Sfrp1 or Sfrp3), and exogenous Sfrp2 reduces collagen deposition and fibrosis after myocardial infarction. In vitro fluorogenic peptide procollagen C-proteinase activity assay with recombinant proteins; in vitro procollagen processing assay; primary cardiac fibroblast culture; rat MI model with direct injection Proceedings of the National Academy of Sciences of the United States of America High 21078975
2010 sFRP2 inhibits both Wnt and BMP signaling in mesenchymal stem cells to promote self-renewal; sFRP2-mediated inhibition of BMP signaling (assessed by pSMAD 1/5/8 levels) is independent of its effects on the Wnt pathway, and this suppresses MSC lineage commitment and reduces ectopic calcification. sFRP2 overexpression; western blot for pSMAD 1/5/8; osteogenic/chondrogenic differentiation assays; in vivo MSC transplantation The Journal of biological chemistry Medium 20826809
2010 sFRP2 augments canonical Wnt3a signaling in HEK293A cells, enhancing LRP6 phosphorylation, β-catenin cytosolic accumulation, nuclear translocation, and TCF-mediated transcription in a dose-dependent manner; this enhancement is abolished by DKK1. Recombinant sFRP2 addition to HEK293A cells; western blot for LRP6 phosphorylation and β-catenin; Top/Fop luciferase reporter assay; Wnt pathway qPCR arrays Biochemical and biophysical research communications Medium 20723538
2011 SFRP2-induced angiogenesis (endothelial tube formation) requires NFATc3; shRNA silencing of NFATc3 in endothelial cells abolishes SFRP2-stimulated tube formation, placing SFRP2 upstream of calcineurin/NFAT signaling in angiogenesis. shRNA knockdown of NFATc3; endothelial tube formation assay; in vivo MMTV-neu transgenic mouse tumor model with tacrolimus treatment PloS one Medium 21673995
2012 sFRP1 and sFRP2 activate the Wnt/planar-cell-polarity/Rac1 pathway in dopamine neurons; compound sFRP1-/-;sFRP2-/- mice display a Wnt/PCP phenotype (anteroposterior VM shortening, lateral expansion of Shh domain) similar to Wnt5a-/- mice, and low/medium concentrations of sFRP1/2 promote dopaminergic differentiation mimicking Wnt5a. Double knockout mouse genetics; primary ventral midbrain culture; embryonic stem cell differentiation assay; Rac1 pathway activation assay Stem cells (Dayton, Ohio) Medium 22290867
2015 Sfrp2 binds Wnt6 and inhibits Wnt6 canonical signaling in cardiac progenitor cells, which in turn activates the non-canonical Wnt/PCP pathway through JNK, inducing cardiac transcription factors and CPC differentiation. Sfrp2 treatment of cardiac progenitor cells; Wnt6 binding assay; canonical Wnt reporter assay; JNK activation assay; cardiac transcription factor expression; ischemia-reperfusion injury model Journal of molecular and cellular cardiology Medium 26071893
2015 sFRP2 upregulates tissue-nonspecific alkaline phosphatase (TNAP) expression and activity specifically in cardiac fibroblasts (not other cell types), promoting extracellular inorganic phosphate production; this induction requires protein synthesis (abolished by cycloheximide) and N-glycosylation (abolished by tunicamycin), and is not observed with sFRP4. Recombinant sFRP2 treatment of cardiac fibroblasts; TNAP activity biochemical assay; cycloheximide and tunicamycin treatment; in vivo sFRP2 blockade in hamster heart failure model American journal of physiology. Cell physiology Medium 25972450
2016 sFRP2 from aged fibroblasts activates a signaling cascade in melanoma cells: sFRP2 decreases β-catenin and MITF, leading to loss of APE1 (a redox effector), which attenuates DNA damage response and confers resistance to vemurafenib; aged fibroblast sFRP2 also augments angiogenesis and metastasis. Recombinant sFRP2 treatment; shRNA knockdown; western blot for β-catenin, MITF, APE1; in vitro and in vivo metastasis assays; aged vs. young mouse models Nature High 27042933
2016 SFRP2 augments WNT16B-initiated β-catenin signaling in cancer cells by enhancing WNT16B binding to Frizzled receptors FZD3/4/6 (coordinated by LRP6 co-receptor); SFRP2 transcription in fibroblasts after genotoxic treatment is primarily driven by the NF-κB complex. Co-treatment assays; Frizzled receptor binding experiments; LRP6 co-receptor assay; DKK1 inhibition; NF-κB inhibitor studies; neutralizing antibody co-treatment Oncogene Medium 26751775
2016 sFRP2 activates Wnt/β-catenin signaling in cardiac fibroblasts (increased Axin2, Wnt3a, nuclear β-catenin), promotes fibroblast proliferation coupled with anaerobic glycolysis (Warburg effect), and upregulates MMP1, MMP13, MMP2, and MMP9 activity leading to collagenolysis; these effects are specific to cardiac fibroblasts. Recombinant sFRP2 treatment; western blot for β-catenin; Axin2/Wnt3a expression; glucose/lactate measurement; MMP activity assays; collagen quantification; Wnt perturbation experiments American journal of physiology. Cell physiology Medium 27605451
2016 sFRP2 functions as a melanogenic stimulator through β-catenin signaling, upregulating MITF and tyrosinase in melanocytes; this was demonstrated in primary human melanocytes using sFRP2 lentiviral overexpression and shRNA knockdown. Lentiviral sFRP2 overexpression; shRNA knockdown; melanogenesis assays; MITF and tyrosinase expression analysis; melanocyte-fibroblast co-culture; ex vivo skin culture The Journal of investigative dermatology Medium 26763443
2016 sFRP2 redirects non-canonical Wnt signaling from Frizzled 7 (Fz7) to Ror2 during Xenopus gastrulation; sFRP2 stabilizes Wnt5a-Ror2 complexes at the membrane promoting Ror2 signal transduction, while simultaneously inhibiting Fz7 signaling (likely by blocking Fz7 endocytosis); the cysteine-rich domain of sFRP2 is sufficient for Ror2 activation. Xenopus gastrulation assay; dominant-negative and overexpression constructs; membrane complex stabilization assay; CRD domain truncation experiments The Journal of biological chemistry High 27129770
2018 SFRP2 promotes osteosarcoma phenotypes (suppressed osteoblast differentiation, induction of FOXM1 and CYR61) through a β-catenin-independent mechanism; ectopic SFRP2 overexpression in normal osteoblast precursors is sufficient to induce OS phenotypes, and inhibition of SFRP2, FOXM1, or CYR61 represses tumorigenic potential. iPSC-derived osteoblast differentiation model; ectopic overexpression; shRNA knockdown; gene expression analysis; in vitro tumor phenotype assays Proceedings of the National Academy of Sciences of the United States of America Medium 30385632
2019 LncRNA Safe stabilizes Sfrp2 mRNA through complementary binding at the 3'-end forming a Safe-Sfrp2 RNA duplex; the RNA-binding protein HuR binds this duplex and maintains stability of both RNAs; knockdown of HuR dramatically reduces Safe and Sfrp2 mRNA levels and inhibits TGF-β-induced cardiac fibrosis. Dual-luciferase assay; RNA electrophoretic mobility shift assay (EMSA); RNA immunoprecipitation (RIP); shRNA knockdown; cardiac fibroblast culture; MI mouse model Theranostics High 31695768
2019 DRG neuron-derived sFRP2 activates NF-κB pathway in macrophages by destabilizing the β-catenin/p65 complex, promoting M1 polarization and macrophage migration; lentiviral knockdown of sFRP2 in L4/L5 DRG suppresses inflammatory cell infiltration in gouty arthritis. Lentiviral shRNA in vivo; immunoprecipitation (β-catenin/p65 complex); western blot; immunofluorescence; macrophage polarization assays; MSU-induced GA mouse model Theranostics Medium 31281508
2020 Sfrp2 mediates interactions between indolent breast cancer cells and alveolar epithelial cells: signals from alveolar type 1 epithelial cells induce Sfrp2 in breast cancer cells, which promotes fibronectin fibril formation and integrin-dependent pro-survival signaling; Sfrp2 blockade reduces the burden of indolent disease. Combined in vivo RNA sequencing; drop-out CRISPR screen; in vivo metastasis model; Sfrp2 blocking experiments; fibronectin fibril formation assay Nature cell biology High 32094692
2021 Sfrp2 deficiency reduces BMSC/SSC colony-forming efficiency, impairs trabecular bone formation in ectopic assay, and dramatically impairs cortical bone defect regeneration; Sfrp2-deficient BMSCs show reduced Lrp6 activation and reduced Wnt target gene expression (Axin2, c-myc, Cyclin D1); addition of recombinant Sfrp2 restores these activities, demonstrating Sfrp2 acts as a Wnt agonist in skeletal stem cells. Sfrp2 knockout mouse; ectopic bone formation assay; cortical bone defect model; colony-forming efficiency assay; western blot for Lrp6/Wnt targets; recombinant Sfrp2 rescue experiment; osteogenic differentiation assays Bone research High 34857734
2021 SFRP2 induces a mesenchymal glioblastoma subtype transition by suppressing SOX2 through a non-canonical Wnt/KLF4/PDGFR/phospho-AKT/SOX2 signaling axis; SFRP2 decreases tumor sphere formation and proliferation but increases cell motility, and conditioned media from SFRP2-overexpressing cells increases CD206 on macrophages. In vitro overexpression/knockdown; sphere formation assay; limiting dilution assay; phospho-AKT western blot; spatial gene expression analysis of human tumor tissue Oncogene Medium 34021259
2024 TGF-β1 signaling in alveolar fibroblasts induces sFRP2 expression near AEC2s; sFRP2 then activates a Krt5+ basal cell program via Frizzled 5 (Fzd5) receptor, requiring downstream calcineurin signaling and nuclear NFATc3 accumulation for KRT5 expression (non-canonical Wnt pathway). AEC2-fibroblast coculture organoids; precision-cut lung slices; single-cell RNA-seq; EGCG TGF-β1 inhibitor treatment; Fzd5 and calcineurin pathway inhibition experiments; NFATc3 nuclear localization imaging The Journal of clinical investigation High 38980870
2025 SFRP2 in CAFs regulates the abscopal effect of radioimmunotherapy; conditional Sfrp2 knockout in CAFs boosts the abscopal effect by rewiring the vascular-immune microenvironment to promote CD8+ T cell recruitment; PAI-1 secreted from irradiated tumors triggers pericyte-to-CAF transition into SFRP2high CAFs via the LRP1/p65 axis. In vivo genome-wide CRISPR screen; conditional CAF-specific Sfrp2 KO; in vivo lineage tracing; serum proteomics; LRP1/p65 signaling assays; humanized PDX models with SFRP2/PAI-1 pharmacological blockade Cancer cell High 40086438
2003 The SFRP2 gene is a transcriptional target of the Pax2 transcription factor; Pax2 expression in embryonic kidney cells strongly activates Sfrp2 expression correlated with changes in chromatin structure at the Sfrp2 locus including regions of Pax2 binding. Pax2-expressing retroviral transformation of embryonic kidney cells; gene expression screen; chromatin structure analysis at Sfrp2 locus; transient transactivation assays The Journal of biological chemistry Medium 14561758
2005 Multiple myeloma cells constitutively secrete sFRP-2 (but not sFRP-1, sFRP-3, or DKK-1) and thereby suppress osteoblast differentiation induced by BMP-2; immunodepletion of sFRP-2 from conditioned medium significantly restores mineralized nodule formation, establishing sFRP-2 as the predominant mediator of impaired bone formation. ELISA/western blot protein detection in conditioned medium; alkaline phosphatase activity assay; in vitro mineralization assay; immunodepletion of sFRP-2 Blood High 16030194
2016 KDM2A, a histone demethylase, represses SFRP2 transcription by decreasing H3K4 and H3K36 methylation at the SFRP2 promoter; silencing KDM2A de-represses SFRP2 expression and promotes osteogenic/dentinogenic differentiation of dental stem cells via Osterix. ChIP assay for H3K4/H3K36 methylation at SFRP2 promoter; KDM2A siRNA knockdown; osteogenic differentiation assays; in vivo transplantation Cell proliferation Medium 27074224

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proceedings of the National Academy of Sciences of the United States of America 416 17251350
2016 sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 329 27042933
2017 SFRP2/DPP4 and FMO1/LSP1 Define Major Fibroblast Populations in Human Skin. The Journal of investigative dermatology 278 29080679
2005 Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. Blood 262 16030194
2021 Myofibroblast transcriptome indicates SFRP2hi fibroblast progenitors in systemic sclerosis skin. Nature communications 218 34282151
2010 Exogenously administered secreted frizzled related protein 2 (Sfrp2) reduces fibrosis and improves cardiac function in a rat model of myocardial infarction. Proceedings of the National Academy of Sciences of the United States of America 183 21078975
2000 Cloning and expression of the Wnt antagonists Sfrp-2 and Frzb during chick development. Developmental biology 138 10656762
2008 The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair. Proceedings of the National Academy of Sciences of the United States of America 136 19017790
2008 SFRP1 and SFRP2 suppress the transformation and invasion abilities of cervical cancer cells through Wnt signal pathway. Gynecologic oncology 122 19095296
2006 Sfrp1 and Sfrp2 regulate anteroposterior axis elongation and somite segmentation during mouse embryogenesis. Development (Cambridge, England) 122 16467359
2018 Chemoprevention of colorectal cancer by black raspberry anthocyanins involved the modulation of gut microbiota and SFRP2 demethylation. Carcinogenesis 113 29361151
2007 Frequent epigenetic inactivation of secreted frizzled-related protein 2 (SFRP2) by promoter methylation in human gastric cancer. British journal of cancer 111 17848950
2021 SFRP2 Improves Mitochondrial Dynamics and Mitochondrial Biogenesis, Oxidative Stress, and Apoptosis in Diabetic Cardiomyopathy. Oxidative medicine and cellular longevity 110 34790288
2008 Sfrp1, Sfrp2, and Sfrp5 regulate the Wnt/beta-catenin and the planar cell polarity pathways during early trunk formation in mouse. Genesis (New York, N.Y. : 2000) 108 18257070
1998 sFRP-2 is a target of the Wnt-4 signaling pathway in the developing metanephric kidney. Developmental dynamics : an official publication of the American Association of Anatomists 108 9853965
2006 Differential inhibition of Wnt-3a by Sfrp-1, Sfrp-2, and Sfrp-3. Developmental dynamics : an official publication of the American Association of Anatomists 107 16425220
2001 Pax-6 regulates expression of SFRP-2 and Wnt-7b in the developing CNS. The Journal of neuroscience : the official journal of the Society for Neuroscience 106 11222670
2008 The frizzled-related sFRP2 gene is a target of thyroid hormone receptor alpha1 and activates beta-catenin signaling in mouse intestine. The Journal of biological chemistry 105 19001373
2010 sFRP2 suppression of bone morphogenic protein (BMP) and Wnt signaling mediates mesenchymal stem cell (MSC) self-renewal promoting engraftment and myocardial repair. The Journal of biological chemistry 102 20826809
2016 SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment. Oncogene 100 26751775
2017 Colorectal adenoma and cancer detection based on altered methylation pattern of SFRP1, SFRP2, SDC2, and PRIMA1 in plasma samples. Epigenetics 96 28753106
2008 Hypermethylated SFRP2 gene in fecal DNA is a high potential biomarker for colorectal cancer noninvasive screening. World journal of gastroenterology 95 18203283
2000 SHH-N upregulates Sfrp2 to mediate its competitive interaction with WNT1 and WNT4 in the somitic mesoderm. Development (Cambridge, England) 93 10654605
2020 Crosstalk with lung epithelial cells regulates Sfrp2-mediated latency in breast cancer dissemination. Nature cell biology 92 32094692
2019 Exosomes Derived from TIMP2-Modified Human Umbilical Cord Mesenchymal Stem Cells Enhance the Repair Effect in Rat Model with Myocardial Infarction Possibly by the Akt/Sfrp2 Pathway. Oxidative medicine and cellular longevity 92 31182988
2016 sFRP2 activates Wnt/β-catenin signaling in cardiac fibroblasts: differential roles in cell growth, energy metabolism, and extracellular matrix remodeling. American journal of physiology. Cell physiology 85 27605451
2019 LncRNA-Safe contributes to cardiac fibrosis through Safe-Sfrp2-HuR complex in mouse myocardial infarction. Theranostics 81 31695768
2017 TET1 inhibits EMT of ovarian cancer cells through activating Wnt/β-catenin signaling inhibitors DKK1 and SFRP2. Gynecologic oncology 80 28851501
2011 The role of calcineurin/NFAT in SFRP2 induced angiogenesis--a rationale for breast cancer treatment with the calcineurin inhibitor tacrolimus. PloS one 77 21673995
2014 Exendin-4 protects adipose-derived mesenchymal stem cells from apoptosis induced by hydrogen peroxide through the PI3K/Akt-Sfrp2 pathways. Free radical biology & medicine 75 25452142
2008 Promoter hypermethylation of the SFRP2 gene is a high-frequent alteration and tumor-specific epigenetic marker in human breast cancer. Molecular cancer 74 18990230
2008 Sfrp1 and Sfrp2 are required for normal male sexual development in mice. Developmental biology 74 19100252
2024 A fibroblast-dependent TGF-β1/sFRP2 noncanonical Wnt signaling axis promotes epithelial metaplasia in idiopathic pulmonary fibrosis. The Journal of clinical investigation 69 38980870
2007 VDR-mediated inhibition of DKK1 and SFRP2 suppresses adipogenic differentiation of murine bone marrow stromal cells. Journal of cellular biochemistry 69 17212358
2007 Hypermethylation of SFRP2 as a potential marker for stool-based detection of colorectal cancer and precancerous lesions. Digestive diseases and sciences 69 17410438
2011 Genistein attenuates WNT signaling by up-regulating sFRP2 in a human colon cancer cell line. Experimental biology and medicine (Maywood, N.J.) 66 21571909
2010 Secreted Frizzled-related protein-2 (sFRP2) augments canonical Wnt3a-induced signaling. Biochemical and biophysical research communications 63 20723538
2008 Brachy-syndactyly caused by loss of Sfrp2 function. Journal of cellular physiology 58 18446812
2007 SFRP2 methylation in fecal DNA--a marker for colorectal polyps. International journal of colorectal disease 58 17639423
2015 Combined detection of plasma GATA5 and SFRP2 methylation is a valid noninvasive biomarker for colorectal cancer and adenomas. World journal of gastroenterology 56 25759530
2007 SFRP2 regulates cardiomyogenic differentiation by inhibiting a positive transcriptional autofeedback loop of Wnt3a. Stem cells (Dayton, Ohio) 56 17916803
2016 Secreted Frizzled-Related Protein 2 (sFRP2) Functions as a Melanogenic Stimulator; the Role of sFRP2 in UV-Induced Hyperpigmentary Disorders. The Journal of investigative dermatology 55 26763443
2010 Detection of colorectal neoplasm using promoter methylation of ITGA4, SFRP2, and p16 in stool samples: a preliminary report in Korean patients. Hepato-gastroenterology 55 21033217
2014 DNA methylation analysis of SFRP2, GATA4/5, NDRG4 and VIM for the detection of colorectal cancer in fecal DNA. Oncology letters 53 25202404
2012 SFRP1 and SFRP2 dose-dependently regulate midbrain dopamine neuron development in vivo and in embryonic stem cells. Stem cells (Dayton, Ohio) 53 22290867
2015 Wnt pathway antagonists, SFRP1, SFRP2, SOX17, and PPP2R2B, are methylated in gliomas and SFRP1 methylation predicts shorter survival. Journal of applied genetics 50 26337424
2000 Sfrp-1 and sfrp-2 are expressed in overlapping and distinct domains during chick development. Mechanisms of development 50 11025221
2020 Multiple Roles of sFRP2 in Cardiac Development and Cardiovascular Disease. International journal of biological sciences 49 32071544
2018 Oncogenic role of SFRP2 in p53-mutant osteosarcoma development via autocrine and paracrine mechanism. Proceedings of the National Academy of Sciences of the United States of America 48 30385632
2019 miR-218-5p regulates skin and hair follicle development through Wnt/β-catenin signaling pathway by targeting SFRP2. Journal of cellular physiology 47 30953362
2016 Demethylation of SFRP2 by histone demethylase KDM2A regulated osteo-/dentinogenic differentiation of stem cells of the apical papilla. Cell proliferation 47 27074224
2004 Secreted frizzled-related protein 2 (SFRP2) is highly expressed in canine mammary gland tumors but not in normal mammary glands. Breast cancer research and treatment 47 14999144
2006 Secreted frizzled related protein 2 (sFRP2) decreases susceptibility to UV-induced apoptosis in primary culture of canine mammary gland tumors by NF-kappaB activation or JNK suppression. Breast cancer research and treatment 45 16791480
2010 The advantages and disadvantages of sfrp1 and sfrp2 expression in pathological events. The Tohoku journal of experimental medicine 43 20448436
2008 Inhibition of myoblast differentiation by Sfrp1 and Sfrp2. Cell and tissue research 43 18322704
2001 Characterization of Spiroplasma citri adhesion related protein SARP1, which contains a domain of a novel family designated sarpin. Gene 42 11574152
2017 SFRP2 enhances the osteogenic differentiation of apical papilla stem cells by antagonizing the canonical WNT pathway. Cellular & molecular biology letters 40 28794794
2016 Secreted Frizzled-Related Protein 2 (sFRP2) promotes osteosarcoma invasion and metastatic potential. BMC cancer 40 27821163
2016 Methylation of SFRP2 gene as a promising noninvasive biomarker using feces in colorectal cancer diagnosis: a systematic meta-analysis. Scientific reports 39 27659069
2014 Downregulation of sFRP-2 by epigenetic silencing activates the β-catenin/Wnt signaling pathway in esophageal basaloid squamous cell carcinoma. Virchows Archiv : an international journal of pathology 35 24464051
2012 Label-free LC-MSMS analysis of vitreous from autoimmune uveitis reveals a significant decrease in secreted Wnt signalling inhibitors DKK3 and SFRP2. Journal of proteomics 35 22634081
2022 HNRNPA2B1 inhibited SFRP2 and activated Wnt-β/catenin via m6A-mediated miR-106b-5p processing to aggravate stemness in lung adenocarcinoma. Pathology, research and practice 33 35364458
2017 Is methylation analysis of SFRP2, TFPI2, NDRG4, and BMP3 promoters suitable for colorectal cancer screening in the Korean population? Intestinal research 33 29142517
2016 Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt Signaling from Fz7 to Ror2 during Vertebrate Gastrulation. The Journal of biological chemistry 33 27129770
2008 The anti-apoptotic effect of IGF-1 on tissue resident stem cells is mediated via PI3-kinase dependent secreted frizzled related protein 2 (Sfrp2) release. Biochemical and biophysical research communications 33 18466761
2016 KRAS, BRAF oncogene mutations and tissue specific promoter hypermethylation of tumor suppressor SFRP2, DAPK1, MGMT, HIC1 and p16 genes in colorectal cancer patients. Cancer biomarkers : section A of Disease markers 32 27540971
2015 Inhibition of Wnt6 by Sfrp2 regulates adult cardiac progenitor cell differentiation by differential modulation of Wnt pathways. Journal of molecular and cellular cardiology 32 26071893
2009 Secreted frizzled related protein (sFRP)-2 inhibits bone formation and promotes cell proliferation in ameloblastoma. Oral oncology 32 19362047
2006 WNT pathways in the neonatal ovine uterus: potential specification of endometrial gland morphogenesis by SFRP2. Biology of reproduction 32 16407498
2020 sFRP2 Supersedes VEGF as an Age-related Driver of Angiogenesis in Melanoma, Affecting Response to Anti-VEGF Therapy in Older Patients. Clinical cancer research : an official journal of the American Association for Cancer Research 31 33097493
2018 TET1 exerts its anti-tumor functions via demethylating DACT2 and SFRP2 to antagonize Wnt/β-catenin signaling pathway in nasopharyngeal carcinoma cells. Clinical epigenetics 31 30075814
2003 The secreted frizzled related protein 2 (SFRP2) gene is a target of the Pax2 transcription factor. The Journal of biological chemistry 30 14561758
2019 Performance of a MethyLight assay for methylated SFRP2 DNA detection in colorectal cancer tissue and serum. The International journal of biological markers 29 30852954
2019 Nerve modulation therapy in gouty arthritis: targeting increased sFRP2 expression in dorsal root ganglion regulates macrophage polarization and alleviates endothelial damage. Theranostics 29 31281508
2018 Decreased expression of SFRP2 promotes development of the pituitary corticotroph adenoma by upregulating Wnt signaling. International journal of oncology 29 29620167
2014 Detection of aberrant promoter methylation of RNF180, DAPK1 and SFRP2 in plasma DNA of patients with gastric cancer. Oncology letters 29 25202403
2022 m6A Methyltransferase METTL3 Reduces Hippocampal Neuron Apoptosis in a Mouse Model of Autism Through the MALAT1/SFRP2/Wnt/β-catenin Axis. Psychiatry investigation 28 36327957
2016 miR-522 contributes to cell proliferation of hepatocellular carcinoma by targeting DKK1 and SFRP2. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 28 26960688
2016 SFRP2 Is Associated with Increased Adiposity and VEGF Expression. PloS one 28 27685706
2017 SFRP2 enhanced the adipogenic and neuronal differentiation potentials of stem cells from apical papilla. Cell biology international 26 28244619
2015 Tissue-nonspecific alkaline phosphatase as a target of sFRP2 in cardiac fibroblasts. American journal of physiology. Cell physiology 26 25972450
2011 Expansion of CpG methylation in the SFRP2 promoter region during colorectal tumorigenesis. Acta medica Okayama 26 21709714
2009 Wnt modulators, SFRP-1, and SFRP-2 are expressed in osteoblasts and differentially regulate hematopoietic stem cells. Biochemical and biophysical research communications 25 19778523
2022 Identification of novel early pancreatic cancer biomarkers KIF5B and SFRP2 from "first contact" interactions in the tumor microenvironment. Journal of experimental & clinical cancer research : CR 24 36002889
2021 Downregulation of SFRP2 facilitates cancer stemness and radioresistance of glioma cells via activating Wnt/β-catenin signaling. PloS one 24 34852024
2019 sFRP2 promotes airway inflammation and Th17/Treg imbalance in COPD via Wnt/β-catenin pathway. Respiratory physiology & neurobiology 24 31430541
2018 DNA hypermethylation of SFRP2 influences the pathology of rheumatoid arthritis through the canonical Wnt signaling in model rats. Autoimmunity 24 30345838
2025 PAI-1-driven SFRP2high cancer-associated fibroblasts hijack the abscopal effect of radioimmunotherapy. Cancer cell 23 40086438
2019 SFRP2 promotes stem cells from apical papilla-mediated periodontal tissue regeneration in miniature pig. Journal of oral rehabilitation 23 31469431
2018 Secreted frizzled-related protein 2 (SFRP2) expression promotes lesion proliferation via canonical WNT signaling and indicates lesion borders in extraovarian endometriosis. Human reproduction (Oxford, England) 23 29462326
2014 Expression of sfrp2 is increased in catagen of hair follicles and inhibits keratinocyte proliferation. Annals of dermatology 23 24648690
2021 SFRP2 induces a mesenchymal subtype transition by suppression of SOX2 in glioblastoma. Oncogene 22 34021259
2021 Secreted frizzled related-protein 2 (Sfrp2) deficiency decreases adult skeletal stem cell function in mice. Bone research 22 34857734
2018 Methylation status of SFRP1, SFRP2, RASSF1A, RARβ and DAPK1 genes in patients with oral squamous cell carcinoma. Archives of oral biology 21 30576962
2011 Alterations in promoter methylation status of tumor suppressor HIC1, SFRP2, and DAPK1 genes in prostate carcinomas. DNA and cell biology 21 22136354
2023 METTL3 promotes the malignancy of non-small cell lung cancer by N6-methyladenosine modifying SFRP2. Cancer gene therapy 20 37106069
2021 Methylated SFRP2 and SDC2 in stool specimens for Colorectal Cancer early detection: A cost-effective strategy for Chinese population. Journal of Cancer 20 33854626
2022 Langerhans cells and SFRP2/Wnt/beta-catenin signalling control adaptation of skin epidermis to mechanical stretching. Journal of cellular and molecular medicine 19 35019227
2015 Study of SFRP1 and SFRP2 methylation status in patients with de novo Acute Myeloblastic Leukemia. International journal of hematology-oncology and stem cell research 19 25802696
2013 Sfrp1 and Sfrp2 are not involved in Wnt/β-catenin signal silencing during lens induction but are required for maintenance of Wnt/β-catenin signaling in lens epithelial cells. Developmental biology 19 24140542

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