Affinage

SFRP2

Secreted frizzled-related protein 2 · UniProt Q96HF1

Length
295 aa
Mass
33.5 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SFRP2 is a secreted cysteine-rich domain (CRD)-containing protein that functions as a context-dependent modulator of Wnt signaling, capable of acting as either a Wnt antagonist or agonist depending on cell type and ligand availability. SFRP2 directly binds multiple Wnt ligands (Wnt1, Wnt3a, Wnt4, Wnt6, Wnt9a) via its CRD to inhibit canonical Wnt/β-catenin signaling in many contexts, including somitogenesis, limb patterning, and stem cell differentiation (PMID:9853965, PMID:16425220, PMID:17916803, PMID:18446812), but in other settings it enhances canonical Wnt signaling by promoting LRP6 phosphorylation and β-catenin stabilization, as observed in skeletal stem cells, lens epithelium, and cardiac fibroblasts (PMID:20723538, PMID:34857734, PMID:24140542, PMID:27605451). Beyond Wnt ligand sequestration, SFRP2 redirects non-canonical Wnt signaling by stabilizing Wnt5a–Ror2 complexes while inhibiting Frizzled endocytosis, activates calcineurin/NFATc3 signaling in endothelial cells and alveolar epithelium, inhibits BMP1/Tolloid-mediated procollagen processing to reduce fibrosis, and engages the AMPK/PGC1-α axis for cardioprotection (PMID:27129770, PMID:38980870, PMID:21078975, PMID:34790288). Through these pleiotropic mechanisms, SFRP2 regulates somitogenesis, skeletal development, cardiac repair and fibrosis, mesenchymal stem cell self-renewal, melanogenesis, and tumor microenvironment signaling including therapy resistance and metastatic dormancy (PMID:16467359, PMID:19017790, PMID:27042933, PMID:32094692).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 High

    Establishing that SFRP2 directly engages Wnt ligands resolved how secreted CRD-containing proteins intercept Wnt signals extracellularly.

    Evidence Co-immunoprecipitation of sFRP-2 with Wnt-4 in kidney cells, corroborated by loss of Sfrp2 expression in Wnt-4 knockout mice

    PMID:9853965

    Open questions at the time
    • Binding affinities and stoichiometry of sFRP2–Wnt complexes not determined
    • Whether sFRP2 binds Frizzled receptors directly was untested
  2. 2000 High

    In vivo demonstration that SFRP2 antagonizes canonical Wnt signaling during embryonic patterning established its functional role as a Wnt inhibitor in developmental contexts.

    Evidence Xenopus embryo overexpression and chick somite explant assays showing SFRP2 blocks WNT1/WNT4-dependent dermomyotome induction

    PMID:10654605 PMID:10656762

    Open questions at the time
    • Mechanism of Wnt ligand selectivity (blocks Wnt1/Wnt4 but not Wnt3a in somites) unexplained
    • No structural basis for CRD–Wnt specificity
  3. 2006 High

    Genetic loss-of-function in mice revealed that SFRP2 (redundantly with SFRP1) is required for proper somitogenesis and anteroposterior axis elongation, linking Wnt modulation to Notch signaling oscillations.

    Evidence Sfrp1/Sfrp2 double knockout mice with shortened thoracic region, abnormal Lfng and Hes7 oscillations

    PMID:16425220 PMID:16467359

    Open questions at the time
    • Whether SFRP2 directly modulates Notch pathway components or acts indirectly through Wnt remains unresolved
    • Individual contribution of Sfrp2 vs. Sfrp1 unclear due to redundancy
  4. 2007 High

    Identification of SFRP2 as a key paracrine survival factor from MSCs and an inhibitor of cardiomyogenic differentiation revealed its dual role in maintaining stemness while promoting cardiac cell survival after injury.

    Evidence Functional genomic screen of Akt-MSC secretome identifying SFRP2, recombinant SFRP2 activating β-catenin and anti-apoptotic genes in cardiomyocytes; separately, SFRP2 blocks Wnt3a autoregulatory loop in embryonal carcinoma cells

    PMID:17251350 PMID:17916803

    Open questions at the time
    • Paradox of SFRP2 as Wnt antagonist yet β-catenin activator in cardiomyocytes not mechanistically resolved
    • Receptor requirements for SFRP2 pro-survival signaling not identified
  5. 2008 High

    Expanded genetic studies demonstrated SFRP2 regulates both canonical and non-canonical (PCP) Wnt pathways in vivo and controls limb skeletal patterning, gonadal development, and MSC engraftment.

    Evidence Sfrp1/2/5 triple KO epistasis with Vangl2 (Loop-tail) mutants demonstrating PCP involvement; Sfrp2 KO brachydactyly phenotype; Sfrp2 shRNA/overexpression in MSC engraftment models

    PMID:18257070 PMID:18446812 PMID:19017790 PMID:19100252

    Open questions at the time
    • PCP pathway activation mechanism by a secreted factor not biochemically defined
    • How SFRP2 differentially engages canonical vs. non-canonical branches unknown
  6. 2010 High

    Discovery that SFRP2 directly inhibits BMP1/Tolloid metalloproteinase activity independently of Wnt signaling revealed a second, Wnt-independent mechanism for anti-fibrotic action through blockade of procollagen processing.

    Evidence In vitro fluorogenic peptide and procollagen C-proteinase assays with recombinant proteins, confirmed by reduced fibrosis in rat MI model

    PMID:21078975

    Open questions at the time
    • Structural basis of sFRP2–BMP1 interaction unknown
    • Whether sFRP2 inhibits other metalloproteinases beyond BMP1/Tolloid not tested
  7. 2010 High

    Demonstration that SFRP2 can enhance rather than inhibit canonical Wnt3a signaling through LRP6 phosphorylation resolved the long-standing paradox of its context-dependent agonist activity.

    Evidence TOPFlash reporter, LRP6 phosphorylation and β-catenin nuclear translocation assays in HEK293A cells with recombinant SFRP2, abolished by DKK1

    PMID:20723538

    Open questions at the time
    • Concentration dependence and cell-type determinants of agonist vs. antagonist function not systematically defined
    • Whether SFRP2 directly binds LRP6 or acts indirectly unclear
  8. 2011 Medium

    Identification of calcineurin/NFATc3 as a downstream effector of SFRP2 in endothelial cells established a non-canonical signaling cascade mediating SFRP2-driven angiogenesis.

    Evidence NFATc3 shRNA and tacrolimus abolish SFRP2-induced endothelial tube formation in vitro and tumor angiogenesis in vivo

    PMID:21673995

    Open questions at the time
    • Receptor through which SFRP2 activates calcineurin in endothelial cells not identified at this stage
    • Relationship between NFATc3 signaling and canonical Wnt modulation by SFRP2 not clarified
  9. 2016 High

    A cluster of studies in 2016 established that SFRP2 functions as a molecular switch redirecting Wnt signaling between receptors (Fz7→Ror2), drives age-dependent melanoma therapy resistance via β-catenin/MITF/APE1 suppression, and cooperates with WNT16B to promote cancer cell survival through FZD3/4/6 and LRP6.

    Evidence Xenopus Ror2/Fz7 endocytosis and Co-IP assays for receptor switching; aged fibroblast co-culture melanoma models with siRNA; WNT16B-SFRP2 cooperation via DKK1 epistasis and luciferase reporters

    PMID:26751775 PMID:27042933 PMID:27129770

    Open questions at the time
    • Whether CRD-mediated receptor switching occurs in mammalian systems not shown
    • How SFRP2 simultaneously suppresses β-catenin in melanoma but cooperates with WNT16B to activate it in other cancers not reconciled
  10. 2019 High

    Post-transcriptional regulation of Sfrp2 mRNA by the lncRNA Safe and RNA-binding protein HuR established that SFRP2 expression itself is tightly controlled at the mRNA stability level during fibrosis.

    Evidence REMSA and RIP demonstrating Safe–Sfrp2 RNA duplex bound by HuR; mutual stabilization confirmed by knockdown/rescue in TGF-β fibrosis model

    PMID:31695768

    Open questions at the time
    • Whether Safe-mediated regulation operates in tissues beyond cardiac fibroblasts unknown
    • Other post-transcriptional regulators of Sfrp2 not surveyed
  11. 2021 High

    Demonstration that Sfrp2 knockout reduces skeletal stem cell self-renewal and Lrp6 activation, rescued by recombinant Sfrp2, confirmed its Wnt agonist function in bone biology and established that cardioprotection involves the AMPK/PGC1-α axis.

    Evidence Sfrp2 KO mice with impaired bone repair and reduced Wnt target gene expression, rescued by recombinant Sfrp2; SFRP2 overexpression in diabetic cardiomyopathy model activates AMPK, reversed by AMPK inhibitor

    PMID:34790288 PMID:34857734

    Open questions at the time
    • How SFRP2 activates AMPK mechanistically is undefined
    • Whether Wnt agonist function in bone and AMPK activation in heart share a common upstream receptor is unknown
  12. 2024 High

    In IPF, SFRP2 secreted by fibroblasts drives alveolar epithelial metaplasia through a defined Fzd5→calcineurin→NFATc3 non-canonical Wnt cascade, unifying prior calcineurin/NFATc3 observations with a specific receptor.

    Evidence AEC2-fibroblast coculture organoids, precision-cut lung slices, scRNA-Seq, calcineurin inhibitor experiments identifying Fzd5 as the receptor

    PMID:38980870

    Open questions at the time
    • Whether Fzd5 is the receptor for SFRP2-calcineurin signaling in other tissues (endothelial, cardiac) not tested
    • Direct SFRP2–Fzd5 binding not biochemically demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular determinants that switch SFRP2 between Wnt agonist and antagonist modes — including concentration thresholds, receptor availability, and co-factor requirements — remain poorly defined, and no structural model of SFRP2 in complex with any Wnt ligand, Frizzled, or BMP1 exists.
  • No crystal or cryo-EM structure of SFRP2 with any binding partner
  • Systematic dose-response studies across cell types needed to resolve agonist/antagonist duality
  • Whether SFRP2 directly binds Frizzled CRDs in trans has not been biochemically confirmed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0008289 lipid binding 3 GO:0048018 receptor ligand activity 3
Localization
GO:0005576 extracellular region 6 GO:0031012 extracellular matrix 1
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 3 R-HSA-1474244 Extracellular matrix organization 2
Partners
BMP1FZD5LRP6ROR2WNT3AWNT4WNT5AWNT6

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 The cysteine-rich domain of sFRP-2 directly binds to Wnt-4, as demonstrated by co-immunoprecipitation, and sFRP-2 expression is regulated downstream of Wnt-4 signaling in the developing metanephric kidney. Co-immunoprecipitation, in situ hybridization, genetic loss-of-function (Wnt-4 knockout mice) Developmental dynamics High 9853965
2000 Sfrp-2 functions as a Wnt antagonist in vivo, as demonstrated by overexpression in Xenopus embryos; SFRP2-expressing cells reduce dermomyotome-inducing activity of WNT1 and WNT4 (but not WNT3a) in somitic explants, and SHH-N upregulates Sfrp2 to compete with WNT signaling in somitic mesoderm. Xenopus overexpression in vivo assay, chick somite explant cultures, recombinant protein treatment Development (Cambridge, England) / Developmental biology High 10654605 10656762
2006 Purified Sfrp-1 and Sfrp-2 inhibit Wnt-3a-induced β-catenin accumulation in L cells via a GSK-3-dependent mechanism (upstream of GSK-3), and Sfrp-2 inhibits Wnt-3a-stimulated proliferation in the chick neural tube. Cell-based β-catenin accumulation assay with purified proteins, LiCl epistasis experiment, chick neural tube overexpression Developmental dynamics High 16425220
2007 SFRP2 is the key paracrine factor released by Akt-modified mesenchymal stem cells that mediates myocardial survival after ischemic injury; treatment of cardiomyocytes with SFRP2 increases β-catenin and upregulates anti-apoptotic genes. Functional genomic screen, recombinant protein treatment, cardiomyocyte survival assay, rat MI model Proceedings of the National Academy of Sciences of the United States of America High 17251350
2007 SFRP2 inhibits cardiomyogenic differentiation by blocking a positive transcriptional autofeedback loop of Wnt3a; SFRP2 inhibits Wnt3a-induced Wnt3a transcription via suppression of canonical Wnt/TCF4 signaling, maintaining stem cells in an undifferentiated state. Gain- and loss-of-function (recombinant SFRP2, Sfrp2 siRNA), luciferase reporter assay, embryonal carcinoma stem cell differentiation assay Stem cells (Dayton, Ohio) High 17916803
2005 Myeloma cell-derived sFRP-2 suppresses osteoblast differentiation induced by BMP-2 and inhibits in vitro mineralization; immunodepletion of sFRP-2 from conditioned medium significantly restores mineralized nodule formation, establishing sFRP-2 as an inhibitor of canonical Wnt signaling-dependent bone formation. Conditioned medium experiments, alkaline phosphatase activity assay, in vitro mineralization assay, immunodepletion of sFRP-2 Blood High 16030194
2008 sFRP2 modulates MSC self-renewal and engraftment by downregulating canonical Wnt signaling; shRNA knockdown of sFRP2 in MRL-MSCs decreased their proliferation and engraftment, while overexpression of sFRP2 in WT-MSCs recapitulated the enhanced regenerative MRL phenotype in vivo. shRNA knockdown, retroviral overexpression, in vivo engraftment and MI models, genomic analysis Proceedings of the National Academy of Sciences of the United States of America High 19017790
2006 Sfrp1 and Sfrp2 double knockout mice show shortened thoracic region, incomplete somite segmentation, and altered Notch signaling oscillations (Lfng and Hes7), demonstrating functional redundancy and requirement for Wnt regulation by Sfrp1/Sfrp2 in anteroposterior axis elongation and somitogenesis. Double knockout mouse genetics, in situ hybridization for Notch targets Development (Cambridge, England) High 16467359
2008 Sfrp1, Sfrp2, and Sfrp5 regulate both canonical Wnt/β-catenin and the planar cell polarity (PCP) non-canonical Wnt pathway during early trunk formation; genetic analysis combining Sfrp triple mutants with Loop-tail mice revealed Sfrp involvement in convergent extension via PCP regulation. Triple knockout mouse genetics, genetic epistasis with Loop-tail (Vangl2) mutants and Dkk1-deficient mice Genesis (New York, N.Y. : 2000) High 18257070
2010 Sfrp2 specifically inhibits BMP1/Tolloid metalloproteinase activity (but not sFRP1 or sFRP3), thereby inhibiting type I procollagen processing; exogenous Sfrp2 inhibits mature collagen deposition in cardiac fibroblasts and in rat infarcted myocardium, reducing fibrosis and improving cardiac function. Fluorogenic peptide-based procollagen C-proteinase assay, in vitro procollagen processing assay with recombinant proteins, primary cardiac fibroblast culture, rat MI injection model, echocardiography, trichrome staining Proceedings of the National Academy of Sciences of the United States of America High 21078975
2010 sFRP2 inhibits both Wnt and BMP signaling pathways in MSCs, with BMP inhibition (measured by pSMAD 1/5/8) occurring independently of its effects on the Wnt pathway; this dual inhibition suppresses osteogenic and chondrogenic differentiation and promotes MSC self-renewal. Western blot for pSMAD 1/5/8, osteogenic/chondrogenic differentiation assays, apoptosis assays, in vivo engraftment The Journal of biological chemistry High 20826809
2010 sFRP2 enhances canonical Wnt3a signaling rather than inhibiting it, promoting LRP6 phosphorylation and β-catenin nuclear translocation in HEK293A cells; this enhancement is abolished by DKK1. TOPFlash/FOPFlash luciferase reporter assay, Western blot for LRP6 phosphorylation and β-catenin, Wnt pathway qPCR array, recombinant protein treatment of HEK293A cells Biochemical and biophysical research communications High 20723538
2008 sFRP2 (TRα1 target gene) activates Wnt/β-catenin signaling via Frizzled receptors in the intestinal epithelium, stabilizing β-catenin, activating its target genes, and enhancing cell proliferation; TRα1 directly regulates sFRP2 transcription. Laser microdissected crypt transcriptomics, in vitro and in vivo TRα1 regulation analysis, β-catenin reporter assays The Journal of biological chemistry Medium 19001373
2016 Aged fibroblast-secreted sFRP2 activates a signaling cascade in melanoma cells that decreases β-catenin and MITF, leading to loss of the redox effector APE1, rendering cells resistant to ROS-induced DNA damage and vemurafenib; sFRP2 also augments angiogenesis and metastasis. Co-culture systems, western blot, siRNA knockdown, in vivo mouse models of metastasis, aged vs. young fibroblast comparisons Nature High 27042933
2016 SFRP2 is produced by genotoxically-treated fibroblasts via NF-κB transcriptional control and augments WNT16B-initiated β-catenin signaling in cancer cells by enhancing WNT16B binding to FZD3/4/6 receptors, cooperating with co-receptor LRP6; this promotes cancer cell survival and acquired therapy resistance. Conditioned medium experiments, co-culture, siRNA knockdown, neutralizing antibody experiments, luciferase reporter assays Oncogene Medium 26751775
2011 SFRP2 stimulates angiogenesis via calcineurin/NFATc3 signaling in endothelial cells; NFATc3 shRNA knockdown abrogates SFRP2-induced endothelial tube formation, and tacrolimus (calcineurin inhibitor) blocks SFRP2-induced angiogenesis. Endothelial tube formation assay, NFATc3 shRNA knockdown, tacrolimus treatment, in vivo MMTV-neu tumor model PloS one Medium 21673995
2016 sFRP2 activates canonical Wnt/β-catenin signaling in adult mouse cardiac fibroblasts (evidenced by Axin2 and Wnt3a upregulation and nuclear β-catenin accumulation), induces cell proliferation coupled to aerobic glycolysis (Warburg effect), and upregulates MMP1, MMP13, MMP2, and MMP9 activities, reducing steady-state collagen. Recombinant sFRP2 treatment of primary cardiac fibroblasts, qPCR for Wnt targets, nuclear β-catenin Western blot, MMP activity assays, glucose/lactate measurements American journal of physiology. Cell physiology Medium 27605451
2016 sFRP2 redirects non-canonical Wnt signaling from Frizzled 7 (Fz7) to the Ror2 receptor during Xenopus gastrulation; sFRP2 stabilizes Wnt5a-Ror2 complexes at the membrane while inhibiting Fz7 receptor endocytosis, functioning as a molecular switch between non-canonical Wnt pathways. The cysteine-rich domain of sFRP2 is sufficient for Ror2 activation. Xenopus gastrulation assays, co-immunoprecipitation, receptor endocytosis assays, domain deletion experiments, epistasis with Fz7 and Ror2 The Journal of biological chemistry High 27129770
2012 sFRP1 and sFRP2 activate the Wnt/planar cell polarity (PCP)/Rac1 pathway in dopamine neurons; compound sFRP1-/-;sFRP2-/- mice display a Wnt/PCP phenotype (anteroposterior VM shortening, lateral Shh domain expansion) similar to Wnt5a-/- mice, and low/medium concentrations of sFRP1 or sFRP2 promote dopamine differentiation mimicking Wnt5a. Double knockout mouse genetics, in vitro primary VM cultures, mouse ESC differentiation assays, Rac1 pathway activation assays Stem cells (Dayton, Ohio) High 22290867
2015 Sfrp2 binds Wnt6 and inhibits canonical Wnt6 signaling, which is required for inhibition of cardiac progenitor cell (CPC) proliferation; this inhibition activates the non-canonical Wnt/PCP pathway through JNK, inducing cardiac transcription factors and CPC differentiation. Co-immunoprecipitation (Sfrp2-Wnt6 binding), luciferase reporter assays for canonical Wnt, JNK activity assays, CPC differentiation assays, ischemia-reperfusion model Journal of molecular and cellular cardiology Medium 26071893
2015 sFRP2 induces tissue-nonspecific alkaline phosphatase (TNAP) expression and activity specifically in cardiac fibroblasts via a protein synthesis-dependent mechanism, suggesting sFRP2 promotes cardiac fibrocalcification through coordinate activation of tolloid-like metalloproteinases and TNAP. Biochemical TNAP activity assay, recombinant sFRP2 treatment of primary cardiac fibroblasts, cycloheximide/tunicamycin inhibition, in vivo hamster heart failure model with sFRP2 blockade American journal of physiology. Cell physiology Medium 25972450
2019 LncRNA Safe stabilizes Sfrp2 mRNA by forming a Safe-Sfrp2 RNA duplex that is bound by the RNA-binding protein HuR; HuR knockdown reduces both Safe and Sfrp2 mRNA stability, while Safe and Sfrp2 mutually stabilize each other, driving cardiac fibrosis. RNA electrophoretic mobility shift assay (REMSA), RNA immunoprecipitation (RIP), dual-luciferase assay, shRNA knockdown, TGF-β fibrosis model Theranostics High 31695768
2020 SFRP2 mediates the interaction between indolent breast cancer cells and alveolar type 1 epithelial cells in the lung; Sfrp2 is induced in breast cancer cells by lung epithelial signals, promotes fibronectin fibril formation and integrin-dependent pro-survival signaling, and blockade of Sfrp2 reduces indolent disease burden. In vivo RNA sequencing combined with drop-out screening, co-culture experiments, in vivo mouse models of indolent metastasis, fibronectin fibril imaging Nature cell biology High 32094692
2024 In IPF, fibroblast TGF-β1 signaling induces sFRP2 expression near AEC2s; sFRP2 then activates a non-canonical Wnt pathway through Frizzled 5 (Fzd5) and downstream calcineurin/NFATc3 signaling, driving nuclear NFATc3 accumulation and KRT5 basal cell program activation (epithelial metaplasia). AEC2-fibroblast coculture organoids, precision-cut lung slices, single-cell RNA-Seq, calcineurin inhibitor experiments, Fzd5 expression analysis, recombinant sFRP2 treatment The Journal of clinical investigation High 38980870
2008 Sfrp2 inactivation in mice causes brachydactyly due to decreased chondrocyte proliferation and delayed differentiation in distal limb elements; Sfrp2 can repress canonical Wnt signaling by Wnt1, Wnt9a, and Wnt4 in vitro, and Sfrp2-/- mice show mild increases in β-catenin and TOPGAL reporter activity in phalangeal elements. Sfrp2 knockout mouse, histological analysis, TOPGAL reporter mouse cross, in vitro Wnt reporter assays Journal of cellular physiology High 18446812
2008 Sfrp1 and Sfrp2 double knockout mice exhibit defects in gonad morphology, reproductive tract maturation, and gonad positioning in males (failed gubernaculum development); similarities with Looptail and Wnt5a mutants suggest disrupted non-canonical Wnt signaling causes these defects. Double knockout mouse genetics, morphological and histological analysis, Insl3/Lgr8 expression analysis Developmental biology Medium 19100252
2008 Sfrp1 and Sfrp2 inhibit myoblast terminal differentiation; recombinant Sfrp1 or Sfrp2 added during proliferation phase inhibit myotube formation without affecting cell cycle or apoptosis, and removal restores differentiation. Recombinant protein treatment of C2C12 and primary satellite cell cultures, myotube formation assay, cell cycle analysis, apoptosis assay Cell and tissue research Medium 18322704
2016 sFRP2 stimulates melanogenesis through MITF and/or tyrosinase upregulation via β-catenin signaling in normal human melanocytes; this was confirmed in fibroblast-melanocyte co-culture and ex vivo skin. Lentiviral SFRP2 overexpression and shSFRP2 knockdown in primary melanocytes, melanogenesis assays, co-culture, ex vivo skin experiments The Journal of investigative dermatology Medium 26763443
2021 SFRP2 exerts cardioprotective effects in diabetic cardiomyopathy by improving mitochondrial dynamics and biogenesis through an AMPK/PGC1-α-dependent pathway; SFRP2 overexpression activates p-AMPK and reverses glucolipotoxicity-induced mitochondrial dysfunction and apoptosis. SFRP2 overexpression/knockdown in H9C2 cells, AAV-mediated overexpression in rat T2DM model, AMPK inhibitor experiments, MitoTracker, TUNEL assay Oxidative medicine and cellular longevity Medium 34790288
2021 Sfrp2 deficiency in mice reduces skeletal stem cell self-renewal, osteogenic differentiation, and cortical bone defect repair; Sfrp2-deficient BMSCs show reduced activation of Lrp6 and Wnt target genes (Axin2, C-myc, Cyclin D1), and recombinant Sfrp2 restores these activities, indicating Sfrp2 acts as a Wnt agonist in skeletal stem cells. Sfrp2 knockout mice, colony-forming efficiency assays, ectopic bone formation assay, cortical drill-hole repair model, recombinant Sfrp2 rescue, Western blot for Lrp6 activation and Wnt targets Bone research High 34857734
2019 DRG neuron-derived sFRP2 promotes M1 macrophage polarization and migration via NF-κB pathway activation; mechanistically, sFRP2 destabilizes the β-catenin/p65 complex, activating NF-κB, as shown by immunoprecipitation. Lentiviral shRNA knockdown in DRG, in vivo MSU-induced arthritis model, primary macrophage co-culture, immunoprecipitation for β-catenin/p65 complex, Western blot Theranostics Medium 31281508
2003 Sfrp2 is a transcriptional target of the Pax2 transcription factor; Pax2 expression activates Sfrp2 in embryonic kidney cells, associated with changes in chromatin structure at the Sfrp2 locus at regions of Pax2 binding. Pax2-expressing retroviral transformation of embryonic kidney cells, chromatin structure analysis, transcriptional activation assays The Journal of biological chemistry Medium 14561758
2016 SFRP2 promotes an oncogenic program in p53-mutant osteosarcoma in a β-catenin-independent manner, inducing FOXM1 and CYR61 expression; ectopic SFRP2 overexpression in normal osteoblast precursors suppresses osteoblast differentiation and promotes OS phenotypes. iPSC-derived osteoblast model from LFS patients, SFRP2 overexpression and knockdown, gene expression analysis, in vivo tumor assays Proceedings of the National Academy of Sciences of the United States of America Medium 30385632
2016 SFRP2 inhibits canonical Wnt signaling in cervical cancer cells by decreasing nuclear β-catenin accumulation, and suppresses EMT by inhibiting SLUG, TWIST, and SNAIL transcription factors while enhancing E-cadherin expression. Overexpression and shRNA approaches in cervical cancer cell lines, β-catenin localization assays, EMT marker analysis, xenograft model Gynecologic oncology Medium 19095296
2013 Sfrp1 and Sfrp2 double knockout mice show reduced Wnt/β-catenin signaling in lens epithelial cells (not increased), indicating Sfrp1/Sfrp2 positively regulate Wnt/β-catenin in lens epithelium; DKO lenses are smaller with deficient epithelium. Sfrp1/Sfrp2 double knockout mice, TCF/Lef reporter (TOPGAL) analysis, lens morphology assessment Developmental biology Medium 24140542

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 328 27042933
2017 SFRP2/DPP4 and FMO1/LSP1 Define Major Fibroblast Populations in Human Skin. The Journal of investigative dermatology 273 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 207 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 181 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 108 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
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 90 31182988
2020 Crosstalk with lung epithelial cells regulates Sfrp2-mediated latency in breast cancer dissemination. Nature cell biology 86 32094692
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 84 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 75 21673995
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
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 73 25452142
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
2024 A fibroblast-dependent TGF-β1/sFRP2 noncanonical Wnt signaling axis promotes epithelial metaplasia in idiopathic pulmonary fibrosis. The Journal of clinical investigation 65 38980870
2011 Genistein attenuates WNT signaling by up-regulating sFRP2 in a human colon cancer cell line. Experimental biology and medicine (Maywood, N.J.) 65 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
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
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 54 26763443
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
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
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 47 30385632
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 42 18322704
2001 Characterization of Spiroplasma citri adhesion related protein SARP1, which contains a domain of a novel family designated sarpin. Gene 42 11574152
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
2017 SFRP2 enhances the osteogenic differentiation of apical papilla stem cells by antagonizing the canonical WNT pathway. Cellular & molecular biology letters 38 28794794
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
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 34 24464051
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 30 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
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
2019 Nerve modulation therapy in gouty arthritis: targeting increased sFRP2 expression in dorsal root ganglion regulates macrophage polarization and alleviates endothelial damage. Theranostics 28 31281508
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
2022 m6A Methyltransferase METTL3 Reduces Hippocampal Neuron Apoptosis in a Mouse Model of Autism Through the MALAT1/SFRP2/Wnt/β-catenin Axis. Psychiatry investigation 27 36327957
2017 SFRP2 enhanced the adipogenic and neuronal differentiation potentials of stem cells from apical papilla. Cell biology international 26 28244619
2011 Expansion of CpG methylation in the SFRP2 promoter region during colorectal tumorigenesis. Acta medica Okayama 26 21709714
2015 Tissue-nonspecific alkaline phosphatase as a target of sFRP2 in cardiac fibroblasts. American journal of physiology. Cell physiology 25 25972450
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
2021 Downregulation of SFRP2 facilitates cancer stemness and radioresistance of glioma cells via activating Wnt/β-catenin signaling. PloS one 24 34852024
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 23 36002889
2019 sFRP2 promotes airway inflammation and Th17/Treg imbalance in COPD via Wnt/β-catenin pathway. Respiratory physiology & neurobiology 23 31430541
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
2018 DNA hypermethylation of SFRP2 influences the pathology of rheumatoid arthritis through the canonical Wnt signaling in model rats. Autoimmunity 23 30345838
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 21 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
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
2023 METTL3 promotes the malignancy of non-small cell lung cancer by N6-methyladenosine modifying SFRP2. Cancer gene therapy 19 37106069
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
2022 Langerhans cells and SFRP2/Wnt/beta-catenin signalling control adaptation of skin epidermis to mechanical stretching. Journal of cellular and molecular medicine 18 35019227
2008 Syndactyly and preaxial synpolydactyly in the single Sfrp2 deleted mutant mice. Developmental dynamics : an official publication of the American Association of Anatomists 17 18729207