Affinage

WNT3A

Protein Wnt-3a · UniProt P56704

Length
352 aa
Mass
39.4 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WNT3A is a palmitoyleoylated, N-glycosylated secreted ligand that activates both canonical β-catenin and multiple β-catenin-independent signaling cascades to regulate paraxial mesoderm formation, left-right axis determination, somite segmentation, osteoblast differentiation, neural progenitor proliferation, and innate immune modulation (PMID:10090727, PMID:16291790, PMID:19482078, PMID:31884387). The lipid moiety at Ser209, added by PORCN, threads through a hydrophobic tunnel in the WLS transmembrane domain (resolved at 2.2 Å by cryo-EM) to mediate ER-to-plasma-membrane trafficking via clathrin/AP-1-dependent basolateral secretion; extracellularly, WNT3A assembles into diffusion-restricted homo-trimeric complexes that are dissociated by Frizzled-CRD or sFRP binding (PMID:20826466, PMID:34315898, PMID:23613470, PMID:30320232). Upon receptor engagement, WNT3A functions as a GPCR ligand coupling Frizzled to Go/Gi proteins and signals through LRP6-dependent β-catenin stabilization (requiring LEF-1/TCF nuclear effectors and facilitated by ILK, RhoA/ROCK-mediated GSK-3β phosphorylation, and Pyk2-mediated Ca²⁺ cross-talk), as well as β-catenin-independent Raf-MEK-ERK, PI3K-Akt, Src-PDGFR transactivation, and PI4KIIα/PIP5KI phosphoinositide pathways (PMID:21128903, PMID:15615777, PMID:16799642, PMID:27575935, PMID:28694190, PMID:19561074, PMID:22927028, PMID:29176883). WNT3A-driven β-catenin transcriptional activity, modulated by H3K27me3 epigenetic marks, also directs asymmetric stem cell division and cooperates with mechanical strain to trigger mitosis (PMID:34642323, PMID:27782880).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 High

    Establishing that WNT3A functions as a diffusible paracrine signal: conditioned medium transfer showed that secreted WNT3A stabilizes β-catenin and remodels the actin cytoskeleton in recipient cells, providing the first demonstration that WNT3A has both canonical and cytoskeletal outputs.

    Evidence Conditioned medium from WNT3A-transfected L cells applied to C57MG cells; β-catenin Western blot and actin/adhesion protein immunostaining

    PMID:9893023

    Open questions at the time
    • Receptor identity for WNT3A not yet determined
    • Mechanism of cytoskeletal reorganization downstream of WNT3A undefined
    • Whether WNT3A acts at long range in vivo unknown
  2. 1999 High

    Identifying the nuclear effectors: genetic epistasis showed that LEF-1 and TCF-1 double knockout phenocopies Wnt3a deficiency in mice, establishing them as essential downstream transcription factors for WNT3A in paraxial mesoderm and neural tube patterning.

    Evidence Lef1−/−;Tcf1−/− double-knockout mouse phenotypic comparison with Wnt3a−/− mice

    PMID:10090727

    Open questions at the time
    • Whether additional TCF family members contribute in other tissues unknown
    • Signal transduction steps between WNT3A and LEF-1/TCF nuclear activation undefined
  3. 2004 High

    Resolving pathway bifurcation: WNT3A was shown to activate cell proliferation through two parallel arms — canonical β-catenin/TCF-4 and a β-catenin-independent Raf-1–MEK–ERK cascade — demonstrating that WNT3A is not solely a canonical Wnt ligand.

    Evidence β-catenin siRNA, MEK inhibitor U0126, dominant-negative TCF-4 in NIH3T3 cells with proliferation readouts

    PMID:15615777

    Open questions at the time
    • Proximal receptor-level mechanism activating ERK independently of β-catenin not identified
    • Whether the two arms converge on shared gene targets unclear
  4. 2005 High

    Linking WNT3A to developmental patterning beyond mesoderm: Wnt3a knockout mice revealed that WNT3A from the primitive streak/dorsal node activates Delta/Notch to regulate perinodal Nodal expression for left-right axis determination while simultaneously controlling the segmentation clock.

    Evidence Wnt3a knockout mouse with in situ hybridization and genetic epistasis with Notch/Delta components

    PMID:16291790

    Open questions at the time
    • Direct versus indirect activation of Delta/Notch by WNT3A not resolved
    • Whether WNT3A protein acts at long range to reach perinodal cells or requires relay unknown
  5. 2006 High

    Expanding the non-canonical signaling repertoire: WNT3A was found to activate PI3K–Akt independently of β-catenin and to require ILK for GSK-3β Ser9 phosphorylation and β-catenin stabilization, adding two new signaling branches to the WNT3A network.

    Evidence PI3K inhibitors and Akt siRNA in NIH3T3 cells; ILK pharmacological inhibition plus co-IP of ILK with APC/GSK-3β

    PMID:16799642 PMID:17011750

    Open questions at the time
    • How ILK is activated by WNT3A receptor complex unknown
    • Whether PI3K–Akt and ILK pathways cross-talk in WNT3A context untested
  6. 2009 High

    Defining phosphoinositide and RhoA co-requirement: WNT3A was shown to activate PI4KIIα through Dvl to produce PtdIns(4,5)P₂ via a ternary Dvl–PI4KIIα–PIP5KI complex, and separately RhoA GTPase activity was found to be required for a subset of β-catenin-dependent WNT3A target genes and osteoblast differentiation.

    Evidence In vitro kinase reconstitution with purified PI4KIIα and Dvl; RhoA inhibition (C3 toxin) with microarray in C3H10T1/2 cells

    PMID:19482078 PMID:19561074

    Open questions at the time
    • How Dvl is selectively directed to PI4KIIα versus other effectors unknown
    • Whether RhoA-dependent gene subset is tissue-specific untested
  7. 2010 High

    Elucidating the secretory mechanism: PORCN-dependent palmitoyleoylation at Ser209 was shown to be required for WNT3A–WLS binding, and vacuolar acidification was found necessary to release WNT3A from WLS into secretory vesicles, establishing the ER-to-vesicle transit mechanism.

    Evidence Ser209 mutagenesis, V-ATPase inhibitor treatment, WNT3A–WLS co-immunoprecipitation, cell fractionation

    PMID:20826466

    Open questions at the time
    • Structural basis of pH-dependent WNT3A–WLS dissociation unknown at this stage
    • Post-WLS carriers of WNT3A not identified
  8. 2011 High

    Establishing Frizzled as a bona fide GPCR for WNT3A: direct GTPγS-binding assays demonstrated that WNT3A triggers Frizzled-mediated guanine-nucleotide exchange on Go/Gi proteins, blocked by pertussis toxin, proving GPCR-like signaling.

    Evidence GTPγS-binding assay on rat brain membranes and cultured cells with pertussis toxin and Wnt antagonist

    PMID:21128903

    Open questions at the time
    • Which specific Frizzled family member(s) couple to Go/Gi upon WNT3A not resolved
    • Downstream effectors of Go/Gi in this context not identified
  9. 2013 High

    Defining polarized secretion and receptor transactivation: WNT3A was shown to undergo basolateral secretion via clathrin/AP-1 with two high-mannose N-glycans, and separately WNT3A was found to stimulate osteoblast proliferation through Src/Dishevelled-mediated PDGFR transactivation independent of β-catenin.

    Evidence Mass spectrometry glycan analysis with AP-1/AP-2 knockdown in MDCK cells; PDGFR siRNA and Src inhibitors in MC3T3-E1 osteoblasts

    PMID:22927028 PMID:23613470

    Open questions at the time
    • Whether basolateral polarity of WNT3A secretion is universal across epithelia unknown
    • PDGFR transactivation mechanism (direct phosphorylation vs. adaptor) not molecularly defined
  10. 2016 High

    Reconstituting the RhoA/ROCK–GSK-3β axis and mechanical synergy: in vitro kinase assays showed ROCK directly phosphorylates GSK-3β Ser9, establishing a RhoA/ROCK branch that feeds into canonical β-catenin stabilization; concurrently, mechanical strain was shown to synergize with WNT3A to drive mitosis via a β-catenin transcriptional threshold mechanism.

    Evidence Purified ROCK kinase assay on recombinant GSK-3β with shRNA validation; mechanical strain device on MDCK cells with WNT3A addition and cell cycle analysis

    PMID:27575935 PMID:27782880

    Open questions at the time
    • Whether ROCK-mediated GSK-3β phosphorylation operates in all WNT3A-responsive tissues untested
    • How mechanical strain integrates with WNT3A at the receptor level unknown
  11. 2017 Medium

    Clarifying co-receptor specificity and Ca²⁺ cross-talk: genome-wide RNA-seq in Lrp5/Lrp6-knockout osteoblasts revealed LRP6 as the primary canonical co-receptor for WNT3A, and in neural progenitors WNT3A was found to trigger Ca²⁺ influx activating Pyk2, which phosphorylates GSK-3β to stabilize β-catenin, bridging non-canonical Ca²⁺ and canonical pathways.

    Evidence RNA-seq in Lrp5-KO and Lrp6-KO primary osteoblasts; Ca²⁺ imaging and Pyk2 phosphorylation analysis in human neural progenitor cells

    PMID:28694190 PMID:29176883

    Open questions at the time
    • Whether LRP6 preference over LRP5 extends beyond osteoblasts unknown
    • Ca²⁺ channel identity activated by WNT3A not identified
    • Whether Pyk2-mediated cross-talk operates in non-neural cell types untested
  12. 2018 High

    Revealing oligomeric state and ROS-dependent nuclear RhoA–β-catenin complex: biophysical analyses demonstrated WNT3A forms homo-trimeric complexes that restrict diffusion and are dissociated by Frizzled-CRD or sFRP binding; separately, WNT3A-induced superoxide was shown to drive Src-mediated Tyr42 phosphorylation of RhoA, enabling RhoA–β-catenin nuclear translocation to the Vimentin promoter.

    Evidence Analytical ultracentrifugation, fluorescence correlation spectroscopy in Xenopus embryos; co-IP of p-Tyr42 RhoA with β-catenin and ChIP on Vim promoter

    PMID:30320232 PMID:33388549

    Open questions at the time
    • Stoichiometry and lipid requirements for WNT3A trimerization not fully defined
    • Whether ROS-dependent RhoA–β-catenin complex is a general WNT3A mechanism or context-specific unknown
  13. 2019 Medium

    Defining WNT3A's anti-inflammatory role: WNT3A/Dvl3/β-catenin signaling was found to restrain TLR4-induced NF-κB activation in monocytes, with JAK3-mediated stabilization of Wnt3 protein (via Nedd4-2 inactivation) amplifying this pathway; in vivo Wnt3a inhibition exacerbated endotoxemia and periodontal disease.

    Evidence siRNA/ectopic expression of Wnt3a, Dvl3, β-catenin in primary monocytes; JAK3–Nedd4-2 ubiquitination assays; murine endotoxemia and periodontal disease models

    PMID:31884387 PMID:32433819

    Open questions at the time
    • Whether WNT3A anti-inflammatory function is Frizzled subtype-specific untested
    • Direct binding of Nedd4-2 to WNT3A protein not demonstrated
  14. 2021 High

    Atomic resolution of the WNT3A–WLS complex and epigenetic outputs: cryo-EM at 2.2 Å revealed the palmitoyleoyl lipid threading through a GPCR-like WLS transmembrane tunnel, establishing the structural basis of WNT secretion; concurrently, single-cell multi-omic profiling showed WNT3A-driven asymmetric stem cell division correlates with H3K27me3 redistribution.

    Evidence Cryo-EM structure with mutagenesis validation; same-cell epigenome+transcriptome sequencing in mouse ESCs

    PMID:34315898 PMID:34642323

    Open questions at the time
    • Structural basis of pH-dependent WNT3A release from WLS not captured in current structure
    • Whether H3K27me3 changes are directly instructed by β-catenin/TCF or secondary unknown
    • Structure of WNT3A bound to Frizzled CRD together with LRP6 not available

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the structural basis of WNT3A engagement with the Frizzled–LRP6 holoreceptor complex, the mechanism by which Frizzled–Go/Gi coupling is selected over β-catenin-dependent versus -independent outputs, how WNT3A homo-trimers are formed and regulated in vivo, and whether the multiple β-catenin-independent branches (ERK, PI3K-Akt, RhoA, PDGFR transactivation, Ca²⁺/Pyk2) operate simultaneously or are context-selectively activated.
  • No ternary WNT3A–Frizzled–LRP6 structure exists
  • Selectivity mechanism for canonical versus non-canonical pathway activation undefined
  • In vivo regulation of WNT3A oligomeric state not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 1
Localization
GO:0005576 extracellular region 4 GO:0005783 endoplasmic reticulum 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1266738 Developmental Biology 4 R-HSA-9609507 Protein localization 3 R-HSA-168256 Immune System 2
Partners
DVL3FZD1FZD8ILKLRP6SFRP2WLS
Complex memberships
WNT3A homo-trimerWNT3A–WLS secretory complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Genetic epistasis shows that LEF-1 and TCF-1 transcription factors act downstream of WNT3A; double knockout of Lef1 and Tcf1 phenocopies Wnt3a-deficient mice (paraxial mesoderm defects, extra neural tubes, limb bud failure), demonstrating that LEF-1/TCF-1 are the primary nuclear effectors of WNT3A signaling in early mouse embryogenesis. Genetic double-knockout mouse (Lef1−/−Tcf1−/−) phenotypic analysis and epistasis Genes & Development High 10090727
1998 Soluble WNT3A secreted from transfected L cells stabilizes β-catenin in recipient cells and reorganizes the actin cytoskeleton (directional alignment of stress fibers, redistribution of villin to leading edges) in C57MG mammary epithelial cells, establishing that WNT3A acts as a diffusible paracrine signal that both activates β-catenin and remodels cytoskeletal architecture. Conditioned medium transfer assay, immunostaining for actin/adhesion proteins, β-catenin Western blot Genes to Cells High 9893023
2004 WNT3A activates cell proliferation via two parallel pathways: (1) the canonical β-catenin/TCF-4 pathway and (2) a β-catenin-independent Raf-1–MEK–ERK cascade; ERK activation by WNT3A persists even when β-catenin is depleted by siRNA, and β-catenin can secondarily activate ERK through a TCF-4-dependent transcriptional event. siRNA knockdown of β-catenin and ERK, MEK inhibitor (U0126), dominant-negative TCF-4 transfection, proliferation and cell cycle assays in NIH3T3 cells Journal of Cell Science High 15615777
2010 WNT3A secretion requires PORCN-dependent lipid (palmitoyleoyl) modification at Ser209 of WNT3A, and the WNT3A–WLS complex accumulates when vacuolar acidification is inhibited; WLS is ER-resident in human cells and binds WNT3A through its lipid-binding domain, with vacuolar acidification needed to release palmitoylated WNT3A from WLS into secretory vesicles. V-ATPase inhibitor treatment, mutagenesis of Ser209, co-immunoprecipitation of WNT3A–WLS, cell fractionation, Xenopus convergent extension assay, structural modeling Journal of Cell Science High 20826466
2005 WNT3A acts as a long-range signaling molecule from the primitive streak/dorsal posterior node that activates the Delta/Notch pathway to regulate perinodal Nodal expression (left-right determination) while simultaneously controlling the segmentation clock oscillations of both Wnt/β-catenin and Notch pathways, genetically linking the segmentation clock to left-right axis specification. Wnt3a knockout mouse analysis, in situ hybridization, genetic epistasis with Notch/Delta pathway components Development High 16291790
2006 Integrin-linked kinase (ILK) activity is required for WNT3A-induced β-catenin stabilization and nuclear translocation; ILK inhibition suppresses GSK-3β Ser9 phosphorylation triggered by WNT3A conditioned medium and reverses β-catenin/LEF-mediated transcription; ILK co-immunoprecipitates with APC and GSK-3β as part of a Wnt pathway complex. Pharmacological ILK inhibition (QLT-0267), molecular inhibition constructs, purified WNT3A protein treatment, co-IP of ILK with APC/GSK-3β, β-catenin stabilization and nuclear translocation assays Oncogene High 16799642
2009 WNT3A stimulation, via Frizzled and Dishevelled, activates PI4-kinase type IIα to produce PtdIns(4)P; Dvl directly interacts with and activates PI4KIIα (increasing its Vmax for ATP and PtdIns), and Dvl, PI4KIIα, and PIP5KI form a ternary complex upon WNT3A stimulation to efficiently produce PtdIns(4,5)P2 from PtdIns. Co-immunoprecipitation, in vitro kinase assay with purified components, lipid measurement in HEK293T cells, dominant-negative Fz and Dvl constructs Journal of Biological Chemistry High 19561074
2009 WNT3A-stimulated RhoA GTPase activity is required for full induction of a subset of canonical WNT3A target genes in a β-catenin-dependent transcriptional program, but RhoA does not affect β-catenin stabilization or nuclear translocation itself; Rho activation is an independent co-requirement for WNT3A-driven osteoblastic differentiation. RhoA inhibition (C3 toxin, dominant-negative RhoA), microarray mRNA expression, real-time RT-PCR, C3H10T1/2 osteoblastic differentiation assay Cellular Signalling Medium 19482078
2011 WNT3A stimulation of mammalian Frizzled receptors triggers guanine-nucleotide exchange on heterotrimeric Go/Gi proteins; this response is blocked by pertussis toxin (which ADP-ribosylates Go/Gi) and by a Wnt antagonist, demonstrating that mammalian Frizzled receptors function as bona fide GPCRs coupling to Go/i upon WNT3A binding. GTPγS-binding assay on rat brain membranes and cultured cells, pertussis toxin treatment, Wnt antagonist blockade Biochemical Journal High 21128903
2013 WNT3A undergoes basolateral secretion in polarized epithelial cells via a clathrin/adaptor protein-1 (AP-1)-dependent route, and this requires WLS recycling by AP-2; WNT3A carries two high-mannose-type N-glycans (at Asn87 and Asn298), and glycosylation processing at these sites does not redirect WNT3A to apical secretion (unlike WNT11, which uses complex-type glycan at Asn40 for apical targeting). Mass spectrometric glycan analysis, clathrin/AP-1 knockdown, AP-2 disruption, polarized MDCK cell secretion assay, WLS localization by immunostaining Journal of Cell Science High 23613470
2006 WNT3A activates the PI3K–Akt pathway independently of β-catenin in NIH3T3 fibroblasts; Wnt3a-induced Akt activation is abrogated by PI3K inhibitors (LY294002, wortmannin) but not by MEK inhibitor U0126, and activated Akt transiently accumulates in the nucleus; PI3K–Akt activation contributes to WNT3A-induced cell proliferation. PI3K inhibitors, Akt siRNA, β-catenin siRNA, subcellular fractionation/nuclear Akt detection, proliferation assay in NIH3T3 cells Cellular Signalling Medium 17011750
2016 WNT3A induces GSK-3β Ser9 phosphorylation and β-catenin accumulation through activation of the RhoA/ROCK axis; shRNA knockdown of RhoA or ROCK inhibition (Y27632) abolishes both GSK-3β phosphorylation and β-catenin accumulation induced by WNT3A; purified active ROCK directly phosphorylates recombinant GSK-3β in vitro. shRNA against RhoA, ROCK inhibitor Y27632, Tat-C3 (RhoA inhibitor), in vitro kinase assay with purified ROCK and recombinant GSK-3β, Western blot in RAW264.7 and HEK293 cells Journal of Cellular Physiology High 27575935
2018 WNT3A promotes superoxide generation leading to Src-mediated Tyr42 phosphorylation of RhoA; phospho-Tyr42-RhoA binds to β-catenin via β-catenin's N-terminal domain and the complex translocates to the nucleus, where it associates with the Vimentin (Vim) gene promoter to drive vimentin transcription. Co-immunoprecipitation of p-Tyr42 RhoA with β-catenin, ChIP on Vim promoter, domain mapping (N-terminal β-catenin deletion), ROS detection, NADPH oxidase inhibition, ROCK2 inhibition Redox Biology Medium 33388549
2021 Cryo-EM structure of human WLS in complex with WNT3A at 2.2 Å reveals that the WLS transmembrane domain adopts a GPCR-like fold with a conserved core cavity and lateral opening; the palmitoyleoyl lipid moiety on WNT3A (at its conserved palmitoleoylation site on a β-hairpin) threads through a hydrophobic tunnel of the WLS transmembrane domain and inserts into the membrane; this WNT3A β-hairpin–WLS interaction is essential for WLS-mediated Wnt secretion. Cryo-EM structure determination (2.2 Å resolution), functional validation of lipid-binding contacts, mutagenesis of WNT3A palmitoleoylation site Nature Communications High 34315898
2018 WNT3A assembles into high-molecular-weight homo-trimeric and larger complexes in serum-containing media; binding to the extracellular CRD of Frizzled8 or to sFRP2 dissociates these complexes; assembly restricts WNT3A diffusion range in Xenopus embryos as shown by fluorescence correlation spectroscopy and immunohistochemistry. Analytical ultracentrifugation with fluorescence detection (AUC-FDS), gel filtration + cross-linking + single-particle analysis, fluorescence correlation spectroscopy (FCS), immunohistochemistry in Xenopus embryos Communications Biology High 30320232
2016 Mechanical strain and WNT3A/β-catenin signaling synergize to drive cells through mitosis: strain alone induces Src-dependent Y654 phosphorylation of β-catenin and S/G2 accumulation without division; addition of WNT3A (or CKI inhibition) raises β-catenin-mediated transcription to a threshold required to trigger mitosis in strained cells. Mechanical strain device on MDCK cells, Casein Kinase I inhibitor, WNT3A addition, β-catenin Y654 phospho-specific antibody, cell cycle analysis, β-catenin reporter assay eLife Medium 27782880
2013 PDGF receptor transactivation is the predominant β-catenin-independent mechanism by which WNT3A stimulates osteoblastic cell proliferation: WNT3A activates Src family kinases (SFKs) via Dishevelled, which transactivate PDGF receptors; soluble decoy PDGF-R excludes autocrine PDGF as the source; siRNA knockdown of PDGF-R confirms its predominant role. Selective kinase inhibitors (SFK, PDGF-R, PKC), DKK1 to exclude β-catenin contribution, PDGF-R siRNA, soluble decoy PDGF-R, time-course phosphorylation analysis in MC3T3-E1 cells Journal of Bone and Mineral Research Medium 22927028
2007 WNT3A transcriptionally induces Lef-1 gene expression in airway submucosal gland progenitor cells in vivo through TCF4/β-catenin binding to a Wnt-responsive region in the Lef-1 promoter; ChIP confirmed TCF4 occupancy, and Wnt3a-deficient mice show loss of Lef-1 induction in forming gland buds. ChIP for TCF4 on Lef-1 promoter in primary airway epithelial cells, Lef-1 promoter–GFP reporter mice crossed to Wnt3a-deficient mice, dominant-active β-catenin + TCF4 transfection luciferase assay Developmental Biology High 17335794
2010 Sox17 directly represses WNT3A/β-catenin-mediated transcriptional activation of the Lef-1 promoter; EMSA and ChIP identified four Sox17-binding sites in the Lef-1 promoter that collaborate with TCF4 sites; Sox17–TCF complexes form through protein–protein interaction via Sox17's DNA- or β-catenin-binding domains. EMSA, ChIP, site-directed mutagenesis of Sox17 and TCF binding sites, luciferase reporter assay in primary airway epithelial cells and cell lines American Journal of Physiology – Lung Cellular and Molecular Physiology Medium 20802155
2017 WNT3A induces AChE expression in osteoblasts through a β-catenin–Runx2 axis; Wnt3a treatment increases Runx2 protein which binds a defined Runx2-binding site in the ACHE promoter (confirmed by ChIP), and deletion of this site reduces promoter activity; DKK-1 blocks the WNT3A-induced AChE expression. ChIP for Runx2 on ACHE promoter, ACHE promoter luciferase reporter with deletion mutants, Runx2 overexpression, DKK-1 inhibition, primary rat osteoblast culture Journal of Biological Chemistry Medium 28607150
2017 LRP6, not LRP5, is the primary co-receptor mediating WNT3A canonical signaling in osteoblasts; genome-wide RNA-seq in Lrp5- and Lrp6-deficient primary calvarial osteoblasts treated with WNT3A identified 782 WNT3A-regulated genes, with LRP6 loss abolishing the majority of WNT3A transcriptional responses while LRP5 loss had minor effects. RNA-seq in Lrp5-KO and Lrp6-KO primary osteoblasts treated with WNT3A, receptor-specific genetic deletion PLOS ONE Medium 29176883
2017 WNT3A non-canonically triggers Ca2+ influx and CaMKII activation in differentiating human neural progenitor cells; elevated intracellular Ca2+ activates Pyk2, which in turn phosphorylates GSK-3β and stabilizes β-catenin, revealing a Wnt/Ca2+→Pyk2→GSK-3β→β-catenin cross-talk pathway. Intracellular Ca2+ imaging, CaMKII activity assay, Pyk2 phosphorylation Western blot, GSK-3β and β-catenin phosphorylation analysis in differentiating hNPCs Biochemical and Biophysical Research Communications Medium 28694190
2019 TLR4 activation increases Wnt3a and Dvl3 expression in monocytes; Wnt3a–Dvl3 signaling restrains TLR4-induced inflammatory responses by stabilizing β-catenin and suppressing NF-κB activity; siRNA or ectopic expression of Dvl3, GSK3β, and β-catenin confirmed the pathway; in vivo, Wnt3a inhibition during endotoxemia enhances systemic cytokines and neutrophil infiltration. siRNA knockdown and ectopic expression of Wnt3a, Dvl3, GSK3β, β-catenin in primary monocytes; ELISA, Western blot, NF-κB DNA binding assay; murine endotoxemia model with Wnt3a inhibition Molecular Immunology Medium 31884387
2020 JAK3 phospho-inactivates the E3 ubiquitin ligase Nedd4-2, reducing ubiquitination of Wnt3 protein and thereby increasing Wnt3a protein levels; elevated Wnt3a then signals through Dvl3 and β-catenin to suppress NF-κB and pro-inflammatory cytokines in innate immune cells; JAK3 or Wnt3a inhibition in vivo worsens P. gingivalis-induced periodontal disease. Gain- and loss-of-function of JAK3, Nedd4-2 ubiquitination assay, Wnt3 co-immunoprecipitation with Nedd4-2, Dvl3 and β-catenin downstream analysis, in vivo periodontal disease mouse model FASEB Journal Medium 32433819
2015 WNT3A activates MyoD expression by directly targeting cis-regulatory elements: WNT3A highly activates a composite proximal promoter + distal enhancer reporter and targets an upstream −8 to −9 kb Wnt-response element (L fragment) through Pax3/Pax7-binding sites; β-catenin and Pax7 binding to their respective sites in the distal enhancer and L fragment was confirmed by ChIP. Luciferase reporter deletion analysis of MyoD cis-elements, ChIP for β-catenin and Pax7, dominant-negative pathway constructs in HEK293T cells Bioscience Reports Medium 25651906
2014 Intranasal WNT3A activates the Frizzled-1/PIWIL1a/FOXM1 pathway to reduce neuronal apoptosis after ischemic stroke; Frizzled-1 siRNA and PIWI1a siRNA reverse WNT3A neuroprotection, while PIWI1a CRISPR restoration after Frizzled-1 knockdown rescues FOXM1 and reduces cleaved caspase-3, placing Frizzled-1 upstream of PIWIL1a and FOXM1. Intranasal WNT3A administration in MCAO rats, Frizzled-1 siRNA, PIWI1a siRNA, PIWI1a CRISPR restoration, Western blot, immunohistochemistry, neurobehavioral testing, infarct volume measurement Journal of Neuroscience Medium 29954850
2014 Rmb WNT3A normalizes altered hepatic lipogenesis and cholesterol biosynthesis in LRP6(R611C) mutant mice by reversing the Sp1-dependent IGF1/AKT/mTORC1/mTORC2 signaling activation that causes combined hyperlipidemia; in vitro rmWNT3A treatment of LRP6-mutant hepatocytes also restores pathway signaling to normal. In vivo rmWNT3A administration to LRP6(R611C) mice, in vitro primary hepatocyte treatment, IGF1R antagonist and rapamycin comparisons, plasma lipid and gene expression analysis Cell Metabolism Medium 24506864
2021 Localized WNT3A signaling induces asymmetric division of mouse embryonic stem cells; H3K27me3 (but not H3K4me3) modifications are correlated with gene expression changes that determine daughter cell fate after WNT3A-induced asymmetric division, as revealed by joint single-cell epigenome+transcriptome profiling. Same-cell epigenome and transcriptome sequencing (H3K27me3/H3K4me3 + gene expression), localized WNT3A stimulation of mouse ESCs Nature Communications Medium 34642323
2020 WNT3A-loaded exosomes activate canonical WNT signaling in intact cartilage in vivo (where soluble recombinant WNT3A fails), and a single injection improves osteochondral defect repair in mice over 8 weeks, demonstrating that exosomal delivery overcomes the hydrophobic barrier to WNT3A tissue penetration. TOPFlash reporter assay for in vitro WNT activity, TCF/Lef:H2B-GFP reporter mice for in vivo signaling, osteochondral defect mouse model, histological scoring Journal of Extracellular Vesicles Medium 34025953
2014 WNT3A protein requires association with a lipid vesicle for in vivo stability and activity; liposome-reconstituted WNT3A (L-WNT3A) associates with the external lipid membrane surface, prolonging pathway activation in primary cells, and activates mesenchymal/skeletal stem cell populations in bone marrow engraftment assays in vivo. Liposome reconstitution of WNT3A, primary cell Wnt reporter assays, bone marrow engraftment in vivo assay, stem cell population analysis PLOS ONE Medium 24400074
2020 Nintedanib inhibits WNT3A-induced myofibroblast activation by blocking Src kinase activation and Src-dependent Y654 phosphorylation of β-catenin, thereby preventing β-catenin nuclear translocation; Src knockdown phenocopies nintedanib treatment, placing Src downstream of WNT3A and upstream of β-catenin nuclear entry in pulmonary fibroblasts. Nintedanib treatment, Src-specific siRNA knockdown, Src inhibitor KX2-391, β-catenin Y654 phosphorylation Western blot, nuclear fractionation, downstream Wnt target gene expression in lung fibroblasts Frontiers in Pharmacology Medium 32231574
2011 Heparanase modulates WNT3A signaling in medulloblastoma cells by altering syndecan co-receptor function and GEF-H1 (a Rho-GEF) distribution; HPSE pretreatment differentially regulates Rac1/RhoA activities after WNT3A exposure, and the HPSE/HSPG axis modulates WNT3A-dependent β-catenin and N-Myc distribution as well as Gli transcription factor gene expression. Exogenous active heparanase treatment, Rac1/RhoA activity assays, immunofluorescence for GEF-H1/β-catenin, RT-PCR for Wnt target and HSPG genes, MB cell proliferation and invasion assays Experimental and Therapeutic Medicine Low 21442027

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Wnt3a-/--like phenotype and limb deficiency in Lef1(-/-)Tcf1(-/-) mice. Genes & development 403 10090727
1998 Cytoskeletal reorganization by soluble Wnt-3a protein signalling. Genes to cells : devoted to molecular & cellular mechanisms 233 9893023
2004 Both ERK and Wnt/beta-catenin pathways are involved in Wnt3a-induced proliferation. Journal of cell science 171 15615777
2010 WLS-dependent secretion of WNT3A requires Ser209 acylation and vacuolar acidification. Journal of cell science 162 20826466
2005 Wnt3a links left-right determination with segmentation and anteroposterior axis elongation. Development (Cambridge, England) 137 16291790
2014 Wnt3a expression is associated with epithelial-mesenchymal transition and promotes colon cancer progression. Journal of experimental & clinical cancer research : CR 108 25499541
2018 Nrf2 attenuates inflammatory response in COPD/emphysema: Crosstalk with Wnt3a/β-catenin and AMPK pathways. Journal of cellular and molecular medicine 106 29659176
2014 The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue. Cell metabolism 95 24506864
2013 Secreted Frizzled-related protein potentiation versus inhibition of Wnt3a/β-catenin signaling. Cellular signalling 83 24080158
2006 Modulation of Wnt3a-mediated nuclear beta-catenin accumulation and activation by integrin-linked kinase in mammalian cells. Oncogene 83 16799642
2016 TLR4 Activation Promotes Bone Marrow MSC Proliferation and Osteogenic Differentiation via Wnt3a and Wnt5a Signaling. PloS one 80 26930594
2019 Captopril attenuates TAC-induced heart failure via inhibiting Wnt3a/β-catenin and Jak2/Stat3 pathways. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 79 30889487
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