Affinage

WNT3A

Protein Wnt-3a · UniProt P56704

Length
352 aa
Mass
39.4 kDa
Annotated
2026-06-11
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WNT3A is a secreted, lipid-modified morphogen that orchestrates cell fate, proliferation, and tissue patterning by activating canonical β-catenin signaling and an array of non-canonical branches in a context-dependent manner (PMID:16291790, PMID:15615777). Its production and export depend on PORCN-mediated lipid modification: palmitoylation at Ser209, and palmitoylation at the conserved Cys77 driven by available palmitic acid, are required for membrane localization and for binding to the ER-resident carrier WLS (PMID:20826466, PMID:39193618). A high-resolution structure of the WLS–WNT3A complex shows that the WNT3A lipid moiety traverses a hydrophobic tunnel in the GPCR-fold transmembrane domain of WLS while a palmitoleoylation-bearing β-hairpin docks onto WLS, an interface essential for secretion; vacuolar acidification then releases the complex to a soluble carrier (PMID:34315898, PMID:20826466). Once secreted, WNT3A self-assembles into homo-trimeric and higher-order complexes that restrict its diffusion and signaling range, complexes that are dissociated upon binding the Frizzled8 ectodomain or sFRP2 (PMID:30320232). Canonically, WNT3A signals through Frizzled and LRP5/6 to inhibit the β-catenin destruction complex, stabilizing β-catenin and driving TCF/LEF-dependent transcription of targets including Lef-1, MyoD, AChE (via Runx2), and Nodal pathway components, thereby controlling left-right asymmetry, the segmentation clock, osteoblastic and myogenic differentiation (PMID:16291790, PMID:20802155, PMID:25651906, PMID:28607150). In parallel, WNT3A activates multiple β-catenin-independent routes — Raf-1/MEK/ERK, PI3K/Akt, and a Dishevelled-directed PI4KIIα/PIP5KI lipid kinase module producing PtdIns(4)P and PtdIns(4,5)P2 — that together drive G1-to-S progression and proliferation (PMID:15615777, PMID:17011750, PMID:19561074). Convergent non-canonical inputs feed back onto GSK-3β: RhoA/ROCK directly phosphorylates GSK-3β, and a Wnt/Ca2+/CaMKII/Pyk2 axis stabilizes β-catenin through GSK-3β inhibition, while GSK-3β inactivation can also activate AMPK to promote autophagy (PMID:27575935, PMID:28694190, PMID:29642895). Pathway output is further tuned by interacting proteins and matrix components — ILK, heparan sulfate, basic calcium phosphate crystals that concentrate WNT3A, and antagonistic Wnt5a — and by the receptor/co-receptor context such as LRP6 in hepatic lipid metabolism (PMID:16799642, PMID:20547765, PMID:32371389, PMID:26112214, PMID:24506864).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2005 High

    Established WNT3A as a long-range developmental morphogen, placing it upstream of Notch/Nodal in left-right axis specification and of the segmentation clock, defining its role in body-plan patterning.

    Evidence Wnt3a genetic mutant analysis with pathway epistasis in mouse embryos

    PMID:16291790

    Open questions at the time
    • Does not resolve the receptor/co-receptor configuration mediating long-range signaling
    • Mechanism of graded diffusion not addressed at biophysical level
  2. 2004 High

    Showed that WNT3A signaling bifurcates into β-catenin-dependent and β-catenin-independent (Raf-1/MEK/ERK) arms that both feed cell cycle progression, establishing that WNT3A is not a purely canonical ligand.

    Evidence Reciprocal siRNA knockdown of β-catenin and ERK, dominant-negative Tcf-4, cell cycle analysis in NIH3T3

    PMID:15615777

    Open questions at the time
    • Receptor route distinguishing ERK from β-catenin activation not defined
    • Single cell type
  3. 2006 High

    Identified ILK and PI3K/Akt as required modulators of WNT3A-induced β-catenin stabilization and proliferation, distinguishing acute purified ligand (GSK-3β Ser9-independent) from conditioned medium (PI3K-dependent Ser9 phosphorylation).

    Evidence ILK and PI3K pharmacological/genetic inhibition, ILK/APC/GSK-3β Co-IP, β-catenin/Lef reporter in fibroblasts

    PMID:16799642 PMID:17011750

    Open questions at the time
    • Direct biochemical link between ILK and the destruction complex not fully defined
    • How acute vs chronic stimulation diverge mechanistically remains unclear
  4. 2009 High

    Defined a Dishevelled-directed lipid-kinase module in which Dvl directly activates PI4KIIα and assembles a PI4KIIα/PIP5KI complex, connecting WNT3A receptor engagement to phosphoinositide production.

    Evidence In vitro kinase assays, reciprocal Co-IP, Dvl domain mapping, lipid analysis

    PMID:19561074

    Open questions at the time
    • Downstream functional consequence of the phosphoinositides in vivo not established
    • Single lab
  5. 2009 Medium

    Placed RhoA downstream of or parallel to β-catenin accumulation, controlling a transcriptional subset of Wnt targets during osteoblastic differentiation independently of β-catenin stabilization.

    Evidence Microarray, RT-PCR, RhoA manipulation in C3H10T1/2 cells

    PMID:19482078

    Open questions at the time
    • Identity of the transcriptional effector linking RhoA to specific genes not resolved
    • Single lab
  6. 2010 High

    Mechanistically linked WNT3A secretion to PORCN-dependent Ser209 lipid modification and a WLS hand-off cycle gated by vacuolar acidification, resolving how the lipidated ligand is exported.

    Evidence Chemical-genetic screen, V-ATPase inhibition, Ser209 mutagenesis, Xenopus functional assay

    PMID:20826466

    Open questions at the time
    • Identity of the proposed soluble carrier protein not established
    • Structural basis of WLS release left open
  7. 2010 High

    Established context-specific transcriptional control of WNT3A signaling: heparan sulfate co-stimulates osteogenic PI3K/Akt-RUNX2 output, while Sox17 directly represses β-catenin-driven Lef-1 transcription.

    Evidence Biochemical binding, RUNX2/ALP assays (heparin); EMSA, ChIP, promoter mutagenesis (Sox17)

    PMID:20547765 PMID:20802155

    Open questions at the time
    • Generality of Sox17 repression beyond Lef-1 promoter unknown
    • How heparin sulfation patterns are sensed mechanistically unresolved
  8. 2016 High

    Demonstrated direct biochemical reconstitution that ROCK phosphorylates GSK-3β, defining a RhoA/ROCK→GSK-3β→β-catenin axis as a non-canonical route to β-catenin stabilization.

    Evidence In vitro kinase assay with purified ROCK and GSK-3β plus RhoA/ROCK inhibition

    PMID:27575935

    Open questions at the time
    • How WNT3A engages RhoA upstream of ROCK not defined
    • Relative contribution vs canonical destruction-complex inhibition unquantified
  9. 2018 High

    Showed that secreted WNT3A self-assembles into trimeric and higher-order complexes that limit its diffusion range and are disassembled by Frizzled8 ectodomain or sFRP2, providing a biophysical basis for morphogen gradient control.

    Evidence Analytical ultracentrifugation, single-particle EM, FCS, Xenopus imaging

    PMID:30320232

    Open questions at the time
    • Molecular determinants of inter-WNT3A contacts not mapped
    • Whether assembly modulates receptor avidity in vivo unresolved
  10. 2017 High

    Defined transcriptional targets and a Wnt/Ca2+/CaMKII/Pyk2 non-canonical route, showing WNT3A drives Runx2-dependent AChE and Wnt/Ca2+-mediated β-catenin stabilization in differentiation contexts.

    Evidence ChIP and reporter assays (AChE/Runx2); calcium imaging, Pyk2 knockdown, GSK-3β phospho-blots in neural progenitors

    PMID:28607150 PMID:28694190

    Open questions at the time
    • Receptor identity coupling WNT3A to calcium flux not pinned down
    • Crosstalk between Ca2+ and canonical arms incompletely defined
  11. 2019 Medium

    Extended WNT3A regulation to physiological systems and post-translational control: Nedd4-2-mediated ubiquitination limits Wnt3a abundance, exosomal delivery selectively activates canonical signaling, and WNT3A controls neuronal autophagy via GSK-3β→AMPK.

    Evidence Ubiquitination assays and JAK3 gain/loss (Nedd4-2); exosome isolation and TCF/LEF reporters; AMPK/autophagy readouts and EM in neurons

    PMID:29642895 PMID:30901906 PMID:32433819

    Open questions at the time
    • Whether exosomal vs free WNT3A differ mechanistically at the receptor remains open
    • In vivo relevance of Nedd4-2 regulation across tissues not established
  12. 2021 High

    Provided atomic-resolution insight into WNT3A export, showing the WLS GPCR-fold transmembrane domain captures the WNT3A lipid in a hydrophobic tunnel and that a palmitoleoylation-bearing β-hairpin is the key secretion interface.

    Evidence 2.2 Å cryo-EM of the WLS–WNT3A complex with functional validation

    PMID:34315898

    Open questions at the time
    • How the lipid is subsequently transferred to extracellular carriers not captured
    • Conformational steps of release not visualized
  13. 2024 Medium

    Linked WNT3A palmitoylation to environmental and metabolic inputs, showing bacterial adhesin–driven palmitic acid accumulation enhances Cys77 palmitoylation and that DKK1/CKAP4/PI3K-AKT signaling can rebalance WNT3A-driven β-catenin and migration.

    Evidence Acyl-biotin exchange and Co-IP/MS (FadAL-FLOT1); CKAP4 mutant analysis with AKT, LRP6 and migration readouts in MSCs

    PMID:38469899 PMID:39193618

    Open questions at the time
    • Generality of palmitic-acid-driven palmitoylation beyond infection contexts unknown
    • Quantitative thresholds setting CKAP4 vs LRP6 dominance not generalized

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the array of canonical and non-canonical WNT3A branches are selected and integrated within a single cell, and what determines the choice of Frizzled/co-receptor and downstream kinase module in a given tissue.
  • No unified model of receptor-context-dependent branch selection
  • Quantitative contribution of each non-canonical arm to physiological β-catenin output is undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 2 GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 2 GO:0031012 extracellular matrix 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
DVLFZD1FZD8ILKLRP6PORCNSFRP2WLS
Complex memberships
Dvl–PI4KIIα–PIP5KI ternary complexWLS–WNT3A secretion complexWNT3A homo-trimer / higher-order complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 Cryo-EM structure of human WLS (Wntless) in complex with WNT3A at 2.2 Å resolution revealed that the transmembrane domain of WLS bears a GPCR fold with a conserved core cavity and lateral opening; the lipid moiety on WNT3A traverses a hydrophobic tunnel of the WLS transmembrane domain and inserts into the membrane; a β-hairpin of WNT3A containing the conserved palmitoleoylation site interacts extensively with WLS and is crucial for WLS-mediated Wnt secretion. Cryo-EM structure determination at 2.2 Å resolution with functional validation Nature Communications High 34315898
2010 WNT3A secretion requires PORCN-dependent lipid modification (palmitoylation) at serine 209; WLS is ER-resident in human cells and WNT3A binding to WLS requires this lipid modification; inhibition of vacuolar acidification causes accumulation of the WNT3A-WLS complex at the plasma membrane, suggesting vacuolar acidification is required to release palmitoylated WNT3A from WLS, possibly to facilitate transfer to a soluble carrier protein. Small-molecule inhibitor screen, cell biology assays, V-ATPase inhibition, site-specific mutation (Ser209), Xenopus functional assay Journal of Cell Science High 20826466
2021 Localized WNT3A signaling induces asymmetric division of mouse embryonic stem cells where proximal daughter cells maintain self-renewal and distal daughter cells acquire differentiation hallmarks; H3K27me3 (but not H3K4me3) correlates with gene expression changes during this asymmetric cell division. Localized Wnt3a delivery, single-cell joint epigenome and transcriptome sequencing (same-cell H3K27me3/H3K4me3 and RNA profiling) Nature Communications High 34642323
2004 WNT3A activates both the Wnt/β-catenin pathway (leading to β-catenin accumulation and nuclear translocation) and the Raf-1-MEK-ERK cascade in NIH3T3 fibroblasts; WNT3A-induced ERK activation is independent of β-catenin (maintained after β-catenin siRNA), whereas ERK pathway can also be activated downstream of β-catenin/Tcf-4; both pathways contribute to G1-to-S cell cycle progression. siRNA knockdown of β-catenin and ERK, dominant-negative Tcf-4 co-transfection, Western blot, cell proliferation assays, cell cycle analysis Journal of Cell Science High 15615777
2006 Integrin-linked kinase (ILK) activity is required for Wnt3a-induced β-catenin stabilization, nuclear translocation, and β-catenin/Lef-mediated transcription; ILK inhibition reverses Wnt3a-induced suppression of β-catenin phosphorylation; ILK can be identified in a complex with APC and GSK-3β; Wnt3a-CM (but not acute purified Wnt3a) induces GSK-3β Ser9 phosphorylation in a PI3K-dependent manner, whereas acute WNT3A stabilizes β-catenin independently of GSK-3β Ser9 phosphorylation. Pharmacological ILK inhibition, molecular inhibition, Co-immunoprecipitation (ILK/APC/GSK-3β complex), siRNA, Western blot, β-catenin/Lef reporter assay Oncogene High 16799642
2009 WNT3A stimulates production of phosphatidylinositol 4-phosphate (PtdIns(4)P) via PI4K type II alpha in a Frizzled- and Dishevelled-dependent manner; Dvl directly interacts with and activates PI4KIIα by increasing its Vmax for ATP and PtdIns; Dvl, PI4KIIα, and PIP5KI form a ternary complex upon Wnt3a stimulation, enabling efficient PtdIns(4,5)P2 production. Co-immunoprecipitation, in vitro kinase assay, lipid analysis, domain mapping of Dvl Journal of Biological Chemistry High 19561074
2006 WNT3A activates the PI3K-Akt pathway independently of β-catenin in NIH3T3 cells; Akt is transiently activated within 30 min and accumulates in the nucleus, while β-catenin accumulates in a prolonged manner; PI3K inhibitors (LY294002, Wortmannin) block Wnt3a-induced Akt activation and proliferation, whereas MEK inhibitor does not; Akt siRNA blocks Wnt3a-induced proliferation. siRNA knockdown (β-catenin, Akt), pharmacological inhibition, nuclear fractionation, Western blot, proliferation assays Cellular Signalling Medium 17011750
2016 WNT3A induces RhoA GTPase activation, which is required for GSK-3β Ser9 phosphorylation and β-catenin accumulation; pharmacological ROCK inhibition (Y27632) or RhoA inhibition (Tat-C3, sh-RhoA) abolishes both GSK-3β phosphorylation and β-catenin accumulation; active ROCK domain directly phosphorylates purified recombinant GSK-3β in vitro, establishing a RhoA/ROCK→GSK-3β→β-catenin axis. RhoA inhibition (Tat-C3, sh-RhoA), ROCK inhibitor (Y27632), in vitro kinase assay with purified ROCK and GSK-3β, Western blot Journal of Cellular Physiology High 27575935
2009 Activated RhoA GTPase is required for WNT3A-stimulated transcription of a subset of β-catenin target genes in C3H10T1/2 mesenchymal stem cells during osteoblastic differentiation; RhoA inhibition does not affect β-catenin stabilization or nuclear translocation, indicating that Rho acts downstream of or parallel to β-catenin accumulation to regulate transcription of specific Wnt target genes. Expression microarrays, real-time RT-PCR, RhoA expression manipulation, osteoblast differentiation assay Cellular Signalling Medium 19482078
2010 WNT3A-heparin signaling synergistically activates the PI3K/Akt pathway and requires the RUNX2 transcription factor to stimulate alkaline phosphatase activity in osteoblasts; N-sulfation and O-sulfation of heparin contribute to physical binding of heparin to WNT3A and optimal co-stimulation of osteogenesis. Biochemical binding assays, PI3K/Akt pathway analysis, RUNX2 reporter assay, alkaline phosphatase activity assay, osteoblast differentiation Journal of Biological Chemistry Medium 20547765
2013 WNT3A-induced proliferation of osteoblastic cells is mediated primarily by a Dishevelled-dependent, β-catenin-independent pathway involving transactivation of PDGF receptors via Src family kinases; DKK1 (blocking Wnt/β-catenin via Lrp5/6) did not block Wnt3a-induced proliferation; soluble decoy PDGF-Rs and siRNA against PDGF-R confirmed its dominant role; SFK inhibitor abrogated PDGF-R phosphorylation and proliferation. siRNA (PDGF-R), decoy PDGF-R, SFK inhibitors, DKK1, Western blot, proliferation assays Journal of Bone and Mineral Research Medium 22927028
2018 WNT3A assembles into high-molecular-weight complexes (smallest form: homo-trimer) in serum-containing medium; these complexes are dissociated by interaction with the extracellular domain of Frizzled8 receptor or sFRP2; fluorescence correlation spectroscopy and immunohistochemistry in Xenopus embryos showed that assembly of WNT3A complexes restricts their diffusion and signaling range. Analytical ultracentrifugation with fluorescence detection, gel filtration chromatography, cross-linking and single-particle analysis, fluorescence correlation spectroscopy, immunohistochemistry in Xenopus embryos Communications Biology High 30320232
2018 WNT3A signals through Frizzled-1 receptor to increase PIWIL1a expression, which in turn increases FOXM1 (a pro-survival protein), reducing neuronal apoptosis after ischemic stroke in rats; Frizzled-1 siRNA and PIWIL1a siRNA each reversed the neuroprotective effects of WNT3A; restoration of PIWIL1a after Frizzled-1 knockdown rescued FOXM1 and reduced cleaved caspase-3, placing the pathway as Frizzled-1→PIWIL1a→FOXM1. Intranasal WNT3A administration, siRNA knockdown (Frizzled-1, PIWIL1a), CRISPR-mediated PIWIL1a restoration, Western blot, immunohistochemistry, neurobehavioral tests, infarct volume measurement (MCAO rat model) Journal of Neuroscience Medium 29954850
2014 WNT3A signals through the Wnt/Ca2+ pathway and the Wnt/β-catenin pathway in hippocampal neurons; intrahippocampal WNT3A antibody impaired contextual fear memory acquisition and consolidation; the Wnt/Ca2+ pathway (blocked by sFRP1) is involved in acquisition, while Wnt/β-catenin (blocked by Dkk1) is involved in consolidation; constitutively active β-catenin rescued the consolidation deficit caused by WNT3A antibody injection. Intrahippocampal infusion of WNT3A antibody, Dkk1, sFRP1, constitutively active β-catenin; contextual fear conditioning behavioral assay; genetic rescue Cerebral Cortex Medium 24904070
2013 WNT3A overexpression in mesenchymal stem cells (MSCs) activates both canonical (β-catenin) and non-canonical (CaMKII) Wnt pathways; canonical pathway promotes MSC proliferation, while non-canonical CaMKII pathway inhibits chondrogenesis; blocking canonical pathway (DKK1) enhanced inhibition of chondrogenesis synergistically, and blocking non-canonical pathway (KN93) enhanced proliferation, demonstrating these two pathways counteract each other. WNT3A overexpression, DKK1 treatment, CaMKII inhibitor (KN93), chondrogenesis assay, proliferation assay Frontiers in Bioscience Medium 23276938
2017 WNT3A induces expression of AChE in osteoblasts via the Wnt/β-catenin signaling pathway; Runx2 (a downstream transcription factor of Wnt/β-catenin) binds to the ACHE gene promoter as shown by ChIP; deletion of the Runx2-binding site in the ACHE promoter reduced activity during osteoblastic differentiation; DKK1 blocked Wnt3a-induced AChE expression. Recombinant WNT3A treatment, Runx2 overexpression, ChIP, luciferase reporter assay with deletion mutants, DKK1 inhibition, Western blot Journal of Biological Chemistry High 28607150
2015 WNT3A directly activates MyoD expression by targeting cis-regulatory elements including the distal enhancer (DE) and a Wnt-response element (L fragment at -8 to -9k region); activation occurs through both canonical and non-canonical pathways; Pax3/Pax7 binding sites in the L fragment are partially required for Wnt3a response; ChIP confirmed β-catenin binding to DE and Pax7 binding to L fragment. Luciferase reporter assays with promoter deletion constructs, ChIP for β-catenin and Pax7, Wnt3a-conditioned medium treatment Bioscience Reports Medium 25651906
2020 WNT3A stimulation promotes primary ciliogenesis through a pathway in which CK1δ phosphorylates β-catenin at S47, leading to reorganization of centriolar satellites and ciliogenesis; this pathway was confirmed in MCF-7/ADR multidrug-resistant cells. Cell biology assays, phospho-specific antibodies, centriolar satellite imaging, WNT3A treatment, MCF-7/ADR validation Cell Reports Medium 32023461
2005 Wnt3a is required for left-right (LR) asymmetry in mice; Wnt3a activates the Delta/Notch pathway to regulate perinodal expression of the left determinant Nodal; simultaneously, Wnt3a controls the segmentation clock and molecular oscillations of both the Wnt/β-catenin and Notch pathways; Wnt3a acts as a long-range signaling molecule from the primitive streak/dorsal posterior node to regulate target gene expression throughout the node and presomitic mesoderm. Wnt3a genetic mutant analysis, gene expression analysis, epistasis via Wnt3a/Notch/Nodal pathway, in vivo mouse embryology Development High 16291790
2012 In Xenopus laevis, Wnt3a activates Meis3 transcription factor; upon strong Wnt3a/Meis3 feedback loop activity, Tsh1 is induced and forms a Meis3-Tsh1 transcription repressor complex that represses the Meis3 promoter, allowing cell cycle exit and neuron differentiation in hindbrain development; functional and biochemical analyses confirmed Tsh1 induction by Wnt3a/Meis3 and the repressive complex. Functional assays in Xenopus embryos, biochemical (co-immunoprecipitation of Meis3-Tsh1 complex), promoter assays, loss-of-function Development Medium 22399680
2019 WNT3A exosomal delivery inhibits GSK3β activity, induces nuclear translocation of β-catenin, and activates TCF/LEF transcriptional program in cardiac fibroblasts; WNT3A-rich exosomes did not activate ERK, JNK, or AP-1 pathways. Exosome isolation by ultracentrifugation, Western blot for GSK3β phosphorylation, nuclear fractionation, TCF/LEF reporter assay International Journal of Molecular Sciences Medium 30901906
2020 WNT3A-loaded exosomes (but not recombinant WNT3A alone) activated canonical WNT signaling in cartilage in vivo, as demonstrated by TCF/Lef:H2B-GFP reporter mice, and improved repair of osteochondral defects; in vitro, WNT3A on exosomes activated WNT signaling via SUPER8TOPFlash reporter. Exosome loading, TCF/Lef:H2B-GFP reporter mice (in vivo pathway activation), SUPER8TOPFlash reporter (in vitro), osteochondral defect histological scoring Journal of Extracellular Vesicles Medium 34025953
2018 JAK3 phospho-inactivates Nedd4-2 (an ubiquitin E3 ligase) in innate immune cells infected with P. gingivalis; reduced Nedd4-2 activity decreases Wnt3a ubiquitination, increasing Wnt3a protein levels; downstream, Dvl3 and β-catenin mediate the anti-inflammatory role of Wnt3a. JAK3 gain/loss-of-function, Nedd4-2 ubiquitination assay, Western blot, in vivo periodontal disease model FASEB Journal Medium 32433819
2010 Sox17 suppresses WNT3A/β-catenin-dependent transcriptional activation of the Lef-1 promoter; Sox17 binds to four sites in the Lef-1 promoter (directly or indirectly through TCF complexes) as shown by EMSA and ChIP; the DNA- and β-catenin-binding domains of Sox17 control context-specific binding; combinatorial mutagenesis of Sox17- and TCF-binding sites controls Wnt/β-catenin-mediated induction and repression. Reporter assays, EMSA, ChIP, site-directed mutagenesis of promoter binding sites American Journal of Physiology - Lung Cellular and Molecular Physiology High 20802155
2016 Mechanical strain induces Src-dependent phosphorylation of β-catenin at Y654 and increases β-catenin-mediated transcription; WNT3A addition (or Casein Kinase I inhibition) increases β-catenin transcription and causes cell accumulation in S/G2, but only the combination of mechanical strain plus WNT3A/β-catenin activation triggers mitosis, indicating synergism between Src-mediated Y654 phosphorylation and Wnt-dependent β-catenin stabilization. Mechanical strain device, WNT3A addition, CKI inhibition, phospho-specific Y654 antibody, live-cell imaging, cell cycle analysis in MDCK cells eLife Medium 27782880
2017 WNT3A signals through Frizzled receptors to activate the Wnt/Ca2+ pathway (increasing cytosolic free calcium and CaMKII activity) in differentiating human neural progenitor cells; Wnt3a-mediated Ca2+ increase activates Pyk2 kinase, which phosphorylates GSK-3β and stabilizes β-catenin, representing a non-canonical route to β-catenin stabilization via the Wnt/Ca2+/CaMKII/Pyk2/GSK-3β axis. Calcium imaging, CaMKII activation assay, Pyk2 knockdown/inhibition, Western blot for GSK-3β phosphorylation and β-catenin, human neural progenitor cell differentiation model Biochemical and Biophysical Research Communications Medium 28694190
2019 Wnt3a ligand promotes autophagy in hippocampal neurons by inactivating GSK-3β, which in turn activates AMPK (a major GSK-3β target regulating cellular metabolism); this mechanism is independent of β-catenin, defining a non-canonical Wnt3a→Frizzled→GSK-3β inhibition→AMPK activation→autophagy pathway. Primary hippocampal neuron culture, hippocampal slice CA1 region, GSK-3β inhibition, AMPK activation assay, Western blot, CYTO-ID fluorescent probe, transmission electron microscopy Cell Communication and Signaling Medium 29642895
2020 Basic calcium phosphate (BCP) crystals physically bind to WNT3A in vitro and co-localize with WNT3A and heparan sulfate proteoglycans in the pericellular matrix of OA chondrocytes; BCP crystal-bound WNT3A is sufficient to induce canonical Wnt signaling (LRP6 phosphorylation, β-catenin stabilization) and hypertrophic shift in chondrocyte phenotype, identifying BCP crystals as a concentrating factor for WNT3A. Immunohistochemistry (WNT3A/BCP co-localization), in vitro BCP-WNT3A binding (western blot), LRP6 phosphorylation assay, β-catenin western blot, qRT-PCR for chondrocyte marker genes Annals of the Rheumatic Diseases Medium 32371389
2015 Wnt5a inhibits Wnt3a-induced alkaline phosphatase (ALP) expression in dental follicle cells without affecting β-catenin nuclear translocation or Tcf-mediated transcription, indicating that Wnt5a inhibits a point downstream of the β-catenin-Tcf complex; Wnt5a gene silencing enhanced Wnt3a-mediated ALP expression, confirming a cross-inhibitory mechanism between canonical and non-canonical Wnt pathways in dental follicle cells. Wnt5a siRNA knockdown, recombinant Wnt5a treatment, ALP expression assay, β-catenin nuclear translocation assay, Tcf transcriptional reporter assay Experimental Cell Research Medium 26112214
2014 WNT3A activates β1-integrin and regulates migration and adhesion of vascular smooth muscle cells; WNT3A treatment triggers phosphorylation of β-catenin at Ser675 and GSK-3β at Ser9, increases ILK protein expression, and activates β1-integrin without changing total cell surface expression. Wnt3a recombinant protein treatment, Western blot for phospho-β-catenin and phospho-GSK-3β, ILK expression analysis, β1-integrin activation assay, migration and adhesion assays Molecular Medicine Reports Low 24535659
2024 DKK1 activates the PI3K/AKT pathway via its receptor CKAP4 (cytoskeleton-associated protein 4) in MSCs, which can balance DKK1's inhibitory effect on Wnt/β-catenin signaling and regulate Wnt3a-induced MSC migration; at lower DKK1 concentrations the CKAP4/PI3K/AKT arm promotes active β-catenin accumulation and migration, while at higher concentrations inhibition of LRP6 phosphorylation dominates. CKAP4 overexpression including CRD2-deletion mutant and intracellular domain mutant (P/A), AKT phosphorylation assay, active β-catenin accumulation, LRP6 phosphorylation, MSC migration assays Stem Cells Medium 38469899
2024 FadAL adhesin of Fusobacterium periodonticum interacts with FLOT1, activating PI3K-AKT/FASN signaling to increase palmitic acid accumulation; this palmitic acid enhances WNT3A palmitoylation at conserved Cys-77, promoting WNT3A membrane localization and nuclear translocation of β-catenin; demonstrated by acyl-biotin exchange and co-immunoprecipitation coupled to mass spectrometry. Acyl-biotin exchange assay (palmitoylation), Co-IP coupled to mass spectrometry (FadAL-FLOT1 interaction), PI3K-AKT-FASN pathway analysis, β-catenin nuclear translocation Gut Microbes Medium 39193618
2019 PITX2 transcription factor directly activates WNT3A transcription in lung adenocarcinoma; PITX2 knockdown reduced WNT3A expression and Wnt/β-catenin pathway activity; the oncogenic role of PITX2 was dependent on WNT3A-mediated canonical Wnt signaling. siRNA knockdown of PITX2, qRT-PCR and Western blot for WNT3A, Wnt/β-catenin pathway reporter assay, xenograft mouse model Cancer Cell International Low 31043858
2019 LINC00665 lncRNA binds to the transcription factor YBX1 (RNA pulldown, RIP, RIP-seq); YBX1 regulates WNT3A transcriptional activity as shown by luciferase reporter and ChIP; LINC00665/YBX1 forms a positive feed-forward loop that activates Wnt3a/β-catenin signaling to promote gastric cancer EMT and progression. RNA pulldown, RIP, RIP-seq, luciferase reporter assay, ChIP for YBX1 on WNT3A promoter Cancer Gene Therapy Medium 37563362
2014 In vivo administration of recombinant mouse Wnt3a (rmWnt3a) to LRP6(R611C) mutant mice normalized altered expression of enzymes of de novo lipogenesis and cholesterol biosynthesis, and restored plasma TG and LDL levels; in vitro, rmWnt3a treatment of primary LRP6(R611C) hepatocytes normalized IGF1, AKT, mTORC1, and mTORC2 pathway hyperactivation, placing WNT3A upstream of LRP6-mediated hepatic lipid regulation. In vivo rmWnt3a injection in LRP6(R611C) mice, primary hepatocyte culture treatment, pathway analysis (IGF1/AKT/mTOR), lipid and cholesterol enzyme expression assays Cell Metabolism Medium 24506864

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2004 Wnt3a growth factor induces androgen receptor-mediated transcription and enhances cell growth in human prostate cancer cells. Cancer research 117 15604245
2014 Wnt3a expression is associated with epithelial-mesenchymal transition and promotes colon cancer progression. Journal of experimental & clinical cancer research : CR 110 25499541
2001 Molecular cloning and characterization of WNT3A and WNT14 clustered in human chromosome 1q42 region. Biochemical and biophysical research communications 110 11414706
2014 The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue. Cell metabolism 95 24506864
2015 Wnt3a: functions and implications in cancer. Chinese journal of cancer 93 26369691
2002 Regulation of WNT3 and WNT3A mRNAs in human cancer cell lines NT2, MCF-7, and MKN45. International journal of oncology 88 11788904
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
2019 Captopril attenuates TAC-induced heart failure via inhibiting Wnt3a/β-catenin and Jak2/Stat3 pathways. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 80 30889487
2016 TLR4 Activation Promotes Bone Marrow MSC Proliferation and Osteogenic Differentiation via Wnt3a and Wnt5a Signaling. PloS one 80 26930594
2010 Synergism between Wnt3a and heparin enhances osteogenesis via a phosphoinositide 3-kinase/Akt/RUNX2 pathway. The Journal of biological chemistry 80 20547765
2019 WNT3a and WNT5a Transported by Exosomes Activate WNT Signaling Pathways in Human Cardiac Fibroblasts. International journal of molecular sciences 69 30901906
2017 miR-15a-5p suppresses endometrial cancer cell growth via Wnt/β-catenin signaling pathway by inhibiting WNT3A. European review for medical and pharmacological sciences 67 29164582
2015 Transcriptome analysis of Wnt3a-treated triple-negative breast cancer cells. PloS one 66 25848952
2006 The PI3 kinase-Akt pathway mediates Wnt3a-induced proliferation. Cellular signalling 62 17011750
2015 Wnt3a Promotes the Vasculogenic Mimicry Formation of Colon Cancer via Wnt/β-Catenin Signaling. International journal of molecular sciences 59 26266404
2009 Wnt3a regulates proliferation and migration of HUVEC via canonical and non-canonical Wnt signaling pathways. Biochemical and biophysical research communications 59 19523451
2009 Regulation of phosphatidylinositol kinases and metabolism by Wnt3a and Dvl. The Journal of biological chemistry 59 19561074
2018 MiR-195 suppresses colon cancer proliferation and metastasis by targeting WNT3A. Molecular genetics and genomics : MGG 52 29948330
2018 Intranasal wnt3a Attenuates Neuronal Apoptosis through Frz1/PIWIL1a/FOXM1 Pathway in MCAO Rats. The Journal of neuroscience : the official journal of the Society for Neuroscience 52 29954850
2014 Drugging a stem cell compartment using Wnt3a protein as a therapeutic. PloS one 50 24400074
2016 Wnt3A Induces GSK-3β Phosphorylation and β-Catenin Accumulation Through RhoA/ROCK. Journal of cellular physiology 49 27575935
2021 WNT3A-loaded exosomes enable cartilage repair. Journal of extracellular vesicles 47 34025953
2011 Effects of Wnt3A and mechanical load on cartilage chondrocyte homeostasis. Arthritis research & therapy 47 22151902
2018 GBM-Derived Wnt3a Induces M2-Like Phenotype in Microglial Cells Through Wnt/β-Catenin Signaling. Molecular neurobiology 46 29948952
2009 Rho GTPase activity modulates Wnt3a/beta-catenin signaling. Cellular signalling 45 19482078
2009 Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies. Disease models & mechanisms 45 19638421
2023 Quercetin induces MGMT+ glioblastoma cells apoptosis via dual inhibition of Wnt3a/β-Catenin and Akt/NF-κB signaling pathways. Phytomedicine : international journal of phytotherapy and phytopharmacology 44 37451151
2018 Wnt3a ligand facilitates autophagy in hippocampal neurons by modulating a novel GSK-3β-AMPK axis. Cell communication and signaling : CCS 42 29642895
2002 WNT3-WNT14B and WNT3A-WNT14 gene clusters (Review). International journal of molecular medicine 42 12011973
2020 BCP crystals promote chondrocyte hypertrophic differentiation in OA cartilage by sequestering Wnt3a. Annals of the rheumatic diseases 41 32371389
2021 GOLPH3/CKAP4 promotes metastasis and tumorigenicity by enhancing the secretion of exosomal WNT3A in non-small-cell lung cancer. Cell death & disease 40 34671013
2014 Hippocampal Wnt3a is Necessary and Sufficient for Contextual Fear Memory Acquisition and Consolidation. Cerebral cortex (New York, N.Y. : 1991) 40 24904070
2018 Wnt3a/β-Catenin Signaling Conditions Differentiation of Partially Exhausted T-effector Cells in Human Cancers. Cancer immunology research 39 30018041
2016 Increasing β-catenin/Wnt3A activity levels drive mechanical strain-induced cell cycle progression through mitosis. eLife 39 27782880
2019 PITX2 enhances progression of lung adenocarcinoma by transcriptionally regulating WNT3A and activating Wnt/β-catenin signaling pathway. Cancer cell international 38 31043858
2020 Wnt3a Stimulation Promotes Primary Ciliogenesis through β-Catenin Phosphorylation-Induced Reorganization of Centriolar Satellites. Cell reports 36 32023461
2019 Wnt3a promotes radioresistance via autophagy in squamous cell carcinoma of the head and neck. Journal of cellular and molecular medicine 35 31111621
2021 Cryo-EM structure of human Wntless in complex with Wnt3a. Nature communications 33 34315898
2021 Joint single-cell multiomic analysis in Wnt3a induced asymmetric stem cell division. Nature communications 33 34642323
2017 Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts. PloS one 32 29176883
2015 Wnt8a and Wnt3a cooperate in the axial stem cell niche to promote mammalian body axis extension. Developmental dynamics : an official publication of the American Association of Anatomists 32 25809880
2013 WNT3A modulates chondrogenesis via canonical and non-canonical Wnt pathways in MSCs. Frontiers in bioscience (Landmark edition) 32 23276938
2014 R-spondin1 regulates cell proliferation of corneal endothelial cells via the Wnt3a/β-catenin pathway. Investigative ophthalmology & visual science 30 25277232
2017 Wnt3a induces the expression of acetylcholinesterase during osteoblast differentiation via the Runx2 transcription factor. The Journal of biological chemistry 29 28607150
2023 Achyranthoside D attenuates chondrocyte loss and inflammation in osteoarthritis via targeted regulation of Wnt3a. Phytomedicine : international journal of phytotherapy and phytopharmacology 28 36657317
2020 Wnt-3a Induces Epigenetic Remodeling in Human Dental Pulp Stem Cells. Cells 28 32156036
2015 Wnt5a attenuates Wnt3a-induced alkaline phosphatase expression in dental follicle cells. Experimental cell research 28 26112214
2014 Wnt3a activates β1-integrin and regulates migration and adhesion of vascular smooth muscle cells. Molecular medicine reports 28 24535659
2023 Wnt3a-Loaded Extracellular Vesicles Promote Alveolar Epithelial Regeneration after Lung Injury. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 27 37072558
2019 Therapeutic Potential of Wnt-3a in Neurological Recovery after Spinal Cord Injury. European neurology 27 31336380
2018 Wnt3a Neutralization Enhances T-cell Responses through Indirect Mechanisms and Restrains Tumor Growth. Cancer immunology research 27 30018042
2014 Wnt3a mitigates acute lung injury by reducing P2X7 receptor-mediated alveolar epithelial type I cell death. Cell death & disease 26 24922070
2010 Sox17 modulates Wnt3A/beta-catenin-mediated transcriptional activation of the Lef-1 promoter. American journal of physiology. Lung cellular and molecular physiology 26 20802155
2018 Assembly of protein complexes restricts diffusion of Wnt3a proteins. Communications biology 25 30320232
2021 Piezoelectric Microvibration Mitigates Estrogen Loss-Induced Osteoporosis and Promotes Piezo1, MicroRNA-29a, and Wnt3a Signaling in Osteoblasts. International journal of molecular sciences 23 34502380
2019 Wnt3a Activates the WNT-YAP/TAZ Pathway to Sustain CDX2 Expression in Bovine Trophoblast Stem Cells. DNA and cell biology 23 30896984
2016 Wnt3a suppresses Pseudomonas aeruginosa-induced inflammation and promotes bacterial killing in macrophages. Molecular medicine reports 23 26846714
2015 Expression of Wnt3a, Wnt10b, β-catenin and DKK1 in periodontium during orthodontic tooth movement in rats. Acta odontologica Scandinavica 23 26414930
2012 Wnt3a/β-catenin increases proliferation in heart valve interstitial cells. Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology 23 22889676
2023 LINC00665 activating Wnt3a/β-catenin signaling by bond with YBX1 promotes gastric cancer proliferation and metastasis. Cancer gene therapy 22 37563362
2021 LGR5/R-Spo1/Wnt3a axis promotes stemness and aggressive phenotype in hepatoblast-like hepatocellular carcinoma cell lines. Cellular signalling 22 33684507
2020 Blockers of Wnt3a, Wnt10a, or β-Catenin Prevent Chemotherapy-Induced Neuropathic Pain In Vivo. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 22 33128175
2019 Apigenin inhibits fibroblast proliferation and reduces epidural fibrosis by regulating Wnt3a/β-catenin signaling pathway. Journal of orthopaedic surgery and research 22 31412883
2019 MiR-27a regulates WNT3A and KITLG expression in Cashmere goats with different coat colors. Animal biotechnology 22 31613171
2019 Oncogenic Wnt3a: A Candidate Specific Marker and Novel Molecular Target for Hepatocellular Carcinoma. Journal of Cancer 22 31737122
2017 Effects of WNT3A and WNT16 on the Osteogenic and Adipogenic Differentiation of Perivascular Stem/Stromal Cells. Tissue engineering. Part A 22 28463594
2023 S1PR2/Wnt3a/RhoA/ROCK1/β-catenin signaling pathway promotes diabetic nephropathy by inducting endothelial mesenchymal transition and impairing endothelial barrier function. Life sciences 21 37307963
2020 Nintedanib Inhibits Wnt3a-Induced Myofibroblast Activation by Suppressing the Src/β-Catenin Pathway. Frontiers in pharmacology 21 32231574
2013 Predominant role of PDGF receptor transactivation in Wnt3a-induced osteoblastic cell proliferation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 21 22927028
2012 A hindbrain-repressive Wnt3a/Meis3/Tsh1 circuit promotes neuronal differentiation and coordinates tissue maturation. Development (Cambridge, England) 21 22399680
2020 YAP and Wnt3a independently promote AECIIs proliferation and differentiation by increasing nuclear β‑catenin expression in experimental bronchopulmonary dysplasia. International journal of molecular medicine 20 33236141
2023 Wnt3a promotes odonto/osteogenic differentiation in vitro and tertiary dentin formation in a rat model. International endodontic journal 19 36633501
2020 JAK3 restrains inflammatory responses and protects against periodontal disease through Wnt3a signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 32433819
2017 Expression of Wnt3a in hepatocellular carcinoma and its effects on cell cycle and metastasis. International journal of oncology 19 28902357
2023 Wnt3a-Modified Nanofiber Scaffolds Facilitate Tendon Healing by Driving Macrophage Polarization during Repair. ACS applied materials & interfaces 18 36758166
2019 Role of Wnt3a in the pathogenesis of cancer, current status and prospective. Molecular biology reports 18 31236761
2014 Predicting and validating the pathway of Wnt3a-driven suppression of osteoclastogenesis. Cellular signalling 18 25038457
2015 Wnt3a signal pathways activate MyoD expression by targeting cis-elements inside and outside its distal enhancer. Bioscience reports 17 25651906
2020 Wnt3a and wnt5a as Potential Chondrogenic Stimulators for Nucleus Pulposus Cell Induction: A Comprehensive Review. Neurospine 16 32252152
2017 MicroRNA‑214 targets Wnt3a to suppress liver cancer cell proliferation. Molecular medicine reports 16 28901526
2024 DKK1 Activates the PI3K/AKT Pathway via CKAP4 to Balance the Inhibitory Effect on Wnt/β-Catenin Signaling and Regulates Wnt3a-Induced MSC Migration. Stem cells (Dayton, Ohio) 15 38469899
2023 Protective effects of oridonin against osteoporosis by regulating immunity and activating the Wnt3a/β-catenin/VEGF pathway in ovariectomized mice. International immunopharmacology 15 36924567
2020 CBP-mediated Wnt3a/β-catenin signaling promotes cervical oncogenesis initiated by Piwil2. Neoplasia (New York, N.Y.) 15 33190089
2018 miR-497/Wnt3a/c-jun feedback loop regulates growth and epithelial-to-mesenchymal transition phenotype in glioma cells. International journal of biological macromolecules 15 30171955
2017 PEGylated liposomes associate with Wnt3A protein and expand putative stem cells in human bone marrow populations. Nanomedicine (London, England) 15 28351228
2017 Dickkopf-1 inhibits Wnt3a-induced migration and epithelial-mesenchymal transition of human lens epithelial cells. Experimental eye research 15 28587752
2017 Non-canonical pathway induced by Wnt3a regulates β-catenin via Pyk2 in differentiating human neural progenitor cells. Biochemical and biophysical research communications 15 28694190
2021 SNHG9 promotes Hepatoblastoma Tumorigenesis via miR-23a-5p/Wnt3a Axis. Journal of Cancer 14 34539877
2020 (-)-Epigallocatechin Gallate Promotes MicroRNA 145 Expression against Myocardial Hypoxic Injury through Dab2/Wnt3a/-catenin. The American journal of Chinese medicine 14 32138537
2019 Wnt3a disrupts GR-TEAD4-PPARγ2 positive circuits and cytoskeletal rearrangement in a β-catenin-dependent manner during early adipogenesis. Cell death & disease 14 30622240
2015 Distinct Patterns of Wnt3a and Wnt5a Signaling Pathway in the Lung from Rats with Endotoxic Shock. PloS one 14 26218875
2024 Synergism of Fusobacterium periodonticum and N-nitrosamines promote the formation of EMT subtypes in ESCC by modulating Wnt3a palmitoylation. Gut microbes 13 39193618
2021 lncRNA DQ786243 promotes hepatocellular carcinoma cell invasion and proliferation by regulating the miR‑15b‑5p/Wnt3A axis. Molecular medicine reports 13 33760109
2019 Taurine Activates BMP-2/Wnt3a-Mediated Osteoblast Differentiation and Mineralization via Akt and MAPK Signaling. Iranian journal of public health 13 31970094
2017 MicroRNA-145 regulates disabled-2 and Wnt3a expression in cardiomyocytes under hyperglycaemia. European journal of clinical investigation 13 29178342
2017 Roles of Wnt3a and Dkk1 in experimental periodontitis. Journal of dental sciences 13 30895054

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