Affinage

WNT2

Protein Wnt-2 · UniProt P09544

Length
360 aa
Mass
40.4 kDa
Annotated
2026-06-11
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WNT2 is a secreted, N-linked glycosylated, cell surface-associated Wnt ligand with oncogenic transforming activity that orchestrates tissue morphogenesis and tumor-stromal communication, signaling principally through the canonical Wnt/beta-catenin pathway (PMID:1371336, PMID:12138115). It engages distinct Frizzled receptors in a cell-type-specific manner — Frizzled-9 (PMID:12138115), Frizzled-4 in hepatic sinusoidal endothelium (PMID:18302287), and Frizzled-8 in lung cancer cells and cancer-associated fibroblasts (PMID:23815780, PMID:28553956) — driving Dishevelled hyperphosphorylation, GSK-3beta inhibition, and beta-catenin nuclear accumulation that activates TCF target genes including cyclin D1 and c-Myc (PMID:12138115, PMID:21672941). WNT2 can also act through a noncanonical GSK-3beta/c-Jun/AP-1 route to induce MMP-7 and drive invasion independently of beta-catenin (PMID:15507471). Developmentally, WNT2/2b canonical signaling is required to specify lung endoderm progenitors, and its loss causes complete lung agenesis (PMID:19686689); it controls posterior second heart field morphogenesis in a feedforward loop with Gata6 (PMID:20159597), directs airway smooth muscle differentiation upstream of myocardin/Mrtf-B and Fgf10 (PMID:21704027), specifies endothelial and cardiomyocyte lineages (PMID:17098737), and is required for placental vascularization (PMID:8951051). WNT2 transcription is activated by GATA6, TBX5, CREB, and SOX4 and is epigenetically silenced by EZH2/PRC2-mediated H3K27me3 or DNMT1-mediated promoter methylation (PMID:16621466, PMID:30352852, PMID:16772171, PMID:37634009, PMID:26484565, PMID:30303745). In the tumor microenvironment WNT2 is produced predominantly by cancer-associated fibroblasts, where it promotes paracrine canonical Wnt activation, angiogenesis via a shifted pro-angiogenic secretome, and immune suppression by blocking dendritic cell differentiation through SOCS3/JAK2/STAT3 signaling (PMID:28553956, PMID:31667643, PMID:33692094). In hepatic endothelium WNT2 controls beta-catenin-dependent metabolic zonation and liver regeneration (PMID:36220068).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1992 High

    Established WNT2 as a secreted, glycosylated, cell-surface-associated protein with intrinsic oncogenic/transforming potential, defining it as a functional Wnt ligand.

    Evidence Cell transfection, conditioned medium and glycosylation analysis, and transformation assay in C57mg mammary epithelial cells

    PMID:1371336

    Open questions at the time
    • No receptor or downstream signaling pathway identified at this stage
    • Mechanism of transformation not resolved
  2. 1996 High

    Demonstrated an in vivo developmental requirement for Wnt2 in placental vascularization, the first organismal phenotype for the gene.

    Evidence Knockout mouse with histological analysis of placentas

    PMID:8951051

    Open questions at the time
    • Receptor and signaling pathway in placenta undefined
    • Cell-autonomous versus paracrine action not distinguished
  3. 2002 High

    Identified Frizzled-9 as a WNT2 receptor and placed WNT2 squarely in the canonical Wnt/beta-catenin pathway via Dishevelled and beta-catenin accumulation.

    Evidence Co-transfection in 293T cells, TCF reporter, receptor deletion mutants, beta-catenin/Dvl-1 Western blot

    PMID:12138115

    Open questions at the time
    • Physiological tissue context for Fzd9 usage not established
    • Other Frizzled receptors not yet tested
  4. 2004 High

    Revealed a noncanonical, Axin-insensitive GSK-3beta/c-Jun/AP-1 arm of WNT2 signaling that drives MMP-7 induction and invasion, distinguishing it from beta-catenin output.

    Evidence Stable overexpression, GSK-3beta siRNA, dominant-negative c-Jun, AP-1 reporter, collagen invasion assay

    PMID:15507471

    Open questions at the time
    • Receptor mediating noncanonical signaling not identified
    • Switch between canonical and noncanonical output not defined
  5. 2006 High

    Positioned WNT2 within mesoderm lineage commitment and cardiac/neuronal programs, and identified GATA6 and CREB as direct transcriptional activators.

    Evidence Wnt2-knockout ES cell embryoid bodies, SACO screen with neuronal CREB reporters, and GATA6 ChIP on the Wnt2 promoter

    PMID:16621466 PMID:16772171 PMID:17098737

    Open questions at the time
    • Receptor identity in cardiac mesoderm and neurons not established
    • Direct versus indirect lineage effects partly inferred
  6. 2008 High

    Identified Frizzled-4 as a WNT2 receptor in hepatic sinusoidal endothelium and linked WNT2 canonical signaling to VEGFR-2 upregulation, defining an autocrine angiogenic role.

    Evidence GST pull-down and co-IP for Fzd4 binding, siRNA knockdown, tube formation assay, Wnt inhibitors

    PMID:18302287

    Open questions at the time
    • Mechanism coupling WNT2 to VEGFR-2 transcription not detailed
    • Generality of Fzd4 usage beyond HSECs unknown
  7. 2009 High

    Established WNT2/2b canonical Wnt/beta-catenin signaling as necessary and sufficient for lung endoderm progenitor specification.

    Evidence Wnt2/2b double-knockout mice, endoderm beta-catenin conditional KO phenocopy, gain-of-function reprogramming

    PMID:19686689

    Open questions at the time
    • Receptor mediating endodermal response not identified
    • Downstream target genes of the specification step incompletely mapped
  8. 2010 High

    Defined WNT2 cellular roles in cardiac inflow tract morphogenesis (feedforward loop with Gata6, rescuable by GSK-3beta inhibition) and granulosa cell proliferation via beta-catenin.

    Evidence Wnt2-knockout mice with BrdU and Gsk-3beta inhibitor rescue; reciprocal siRNA/overexpression and beta-catenin epistasis in granulosa cells

    PMID:20107203 PMID:20159597

    Open questions at the time
    • Receptor in cardiac and ovarian contexts not defined
    • Direct transcriptional targets of the proliferative response not fully enumerated
  9. 2011 High

    Extended WNT2 function to airway smooth muscle differentiation, liver specification, intestinal anti-inflammatory regulation, and fibroblast-secreted tumor growth, including downstream effectors and an fzd5 receptor in liver.

    Evidence Wnt2-knockout/gain-of-function mice, zebrafish fzd5 epistasis, intestinal IL-8 and ubiquitination assays, and Wnt2-conditioned-medium oesophageal cancer assays

    PMID:21672941 PMID:21674728 PMID:21704027 PMID:21771809

    Open questions at the time
    • Receptor in smooth muscle and intestine not identified
    • Mechanism of ubiquitin-regulated WNT2 stability not detailed
  10. 2013 High

    Linked WNT2/beta-catenin to gap-junction (CX43) assembly in granulosa cells and identified Frizzled-8 as a WNT2 receptor in lung cancer with in vivo tumor relevance.

    Evidence Reciprocal WNT2/CTNNB1 knockdown with GJIC assays; TCF reporter with dominant-negative WNT2 and xenografts in lung cancer cells

    PMID:23815780 PMID:23843235

    Open questions at the time
    • FZD8 binding shown functionally but not by direct biochemical interaction
    • Connection between CX43 regulation and broader fertility function not resolved
  11. 2015 High

    Defined the transcriptional and epigenetic control of WNT2 (Hox5 upstream activation, EZH2/PRC2 H3K27me3 silencing) and a miR-199a-5p/WNT2/KLF4-myocardin axis governing smooth muscle phenotype.

    Evidence Hox5 triple-mutant mice with explant rescue, EZH2/H3K27me3 ChIP with WNT2 KO/antibody neutralization, and miRNA/WNT2 perturbations in SMCs

    PMID:25596533 PMID:26235626 PMID:26484565

    Open questions at the time
    • Signals triggering PRC2 release at the WNT2 promoter unclear
    • Receptor in the SMC phenotype-switch context not identified
  12. 2016 High

    Established WNT2 as a driver of vascular smooth muscle migration and neointimal thickening through beta-catenin/TCF-induced WISP-1 and integrin signaling.

    Evidence Recombinant WNT2, siRNA, Wnt2+/- carotid ligation mouse model, adenoviral WISP-1 rescue, migration assays

    PMID:27199447

    Open questions at the time
    • Receptor mediating VSMC migration not defined
    • Relationship between migration and proliferation programs not integrated
  13. 2017 High

    Identified FZD8 as the WNT2 receptor in cancer-associated fibroblasts and established CAF-derived WNT2 as a paracrine and autocrine driver of fibroblast invasiveness and cancer cell invasion.

    Evidence 7TGP canonical reporter, WNT2 siRNA in CAFs, 3D organotypic co-cultures, xenografts

    PMID:28553956

    Open questions at the time
    • Direct WNT2-FZD8 biochemical binding not shown
    • ECM remodeling effectors downstream of WNT2 not fully defined
  14. 2018 High

    Defined TBX5 as a direct transcriptional activator of Wnt2/2b in cardiopulmonary mesoderm enabling non-cell-autonomous lung specification, and identified DNMT1-mediated promoter methylation as a silencing mechanism affecting trophoblast invasion.

    Evidence TBX5 ChIP-seq with in vivo reporters and multi-organism KO; BPA/DNMT inhibitor placenta and trophoblast methylation studies

    PMID:30303745 PMID:30352852

    Open questions at the time
    • How TBX5 and Shh integrate at the Wnt2 locus mechanistically not fully resolved
    • DNMT1 study confined to a single lab
  15. 2019 High

    Established CAF-derived WNT2 as a tumor immunosuppressive and pro-angiogenic factor, acting via SOCS3/JAK2/STAT3 to block dendritic cell differentiation and via a shifted secretome (ANG-2, IL-6, G-CSF, PGF) to promote angiogenesis.

    Evidence Anti-WNT2 mAb and shRNA in syngeneic tumor models with RNA-seq/Western; mass spectrometry secretome profiling and angiogenesis assays in CRC xenografts

    PMID:31667643 PMID:33692094

    Open questions at the time
    • Receptor mediating immune-suppressive signaling on dendritic cells not identified
    • Direct versus indirect induction of secretome factors not fully separated
  16. 2021 Medium

    Implicated WNT2 (with Wnt4) in cardiac fibrosis through beta-catenin/NF-kappaB signaling using Frizzled4/Frizzled2 with LRP6 co-receptors under hypoxic conditions.

    Evidence siRNA in MI mouse model, NF-kappaB/beta-catenin pathway analysis in cardiac fibroblasts, patient ELISA, receptor expression analysis

    PMID:34911029

    Open questions at the time
    • Receptor assignment based on expression/knockdown, not direct binding
    • Single-lab study; relative contributions of Wnt2 versus Wnt4 unresolved
  17. 2022 High

    Established endothelial cell-derived WNT2 (with Wnt9b) as a controller of hepatic metabolic zonation and regeneration, with therapeutic rescue by a Wnt agonist.

    Evidence Spatial transcriptomics, EC-specific conditional Wnt2/Wnt9b KO, tetravalent antibody Wnt agonist in acetaminophen liver failure model

    PMID:36220068

    Open questions at the time
    • Relative contribution of Wnt2 versus Wnt9b not separated
    • Receptor on zone-3 hepatocytes not identified
  18. 2023 High

    Defined a WNT2-SOX4 positive feedback loop (via FZD8/beta-catenin) sustaining gastric cancer stem cell self-renewal, with anti-WNT2 antibody sensitizing tumors to chemotherapy.

    Evidence Reciprocal WNT2/SOX4 perturbations, TCF reporter, promoter analysis, anti-WNT2 mAb in xenografts

    PMID:37634009

    Open questions at the time
    • Direct WNT2-FZD8 interaction in this context not biochemically shown
    • Generality of the loop beyond gastric cancer unknown
  19. 2024 Medium

    Placed WNT2/Wnt11 downstream of mechanosensor Piezo1 in stiffness-driven skin fibrosis, linking mechanical signaling to CCL24 secretion.

    Evidence Piezo1 knockdown on variable-stiffness substrates, Wnt2/Wnt11 pathway and CCL24 analysis, AAV Piezo1 KD in mouse skin fibrosis

    PMID:38267432

    Open questions at the time
    • Limited mechanistic depth on WNT2 itself in this pathway
    • Receptor and beta-catenin involvement not defined; single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular determinants of WNT2 receptor selectivity across tissues and the switch between canonical beta-catenin and noncanonical GSK-3beta/AP-1 or NF-kappaB outputs remain unresolved.
  • No structural model of WNT2-Frizzled complexes in the corpus
  • Direct biochemical binding shown only for Fzd4; Fzd8/Fzd9 assignments largely functional
  • Mechanism determining canonical versus noncanonical signaling output undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 2
Partners
CTNNB1DVL1FZD2FZD4FZD8FZD9LRP6

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 WNT2 encodes a 33 kDa protein modified by N-linked glycosylation to a 35 kDa species. The secreted WNT2 protein is tightly associated with the cell surface (detectable in conditioned medium only after suramin treatment). Expression of WNT2 cDNA in mammary epithelial C57mg cells induces loss of density-inhibited growth and a transformed phenotype, demonstrating oncogenic/transforming potential similar to WNT1. CHO and AtT-20 cell transfection, conditioned medium analysis, glycosylation characterization, transformation assay in C57mg cells Oncogene High 1371336
1996 Loss of Wnt2 in mice results in placentation defects including oedema, tissue disruption, accumulation of maternal blood in large pools, decreased fetal capillaries, and increased fibrinoid material in the labyrinthine zone of the placenta, demonstrating that Wnt2 is required for proper vascularisation of the mouse placenta. Gene targeting (knockout mouse), histological analysis of placentas at 14.5 dpc Development High 8951051
2002 Frizzled-9 (Rfz9) is specifically activated by Wnt-2 (among several Wnt family members tested) in TCF-dependent transcription. Wnt-2 activation of Rfz9 requires the Wnt-binding domain and leads to hyperphosphorylation and membrane relocalization of Dishevelled-1 and cytosolic beta-catenin accumulation, placing WNT2 as a ligand that signals through the canonical Wnt/beta-catenin pathway via Frizzled-9. Co-transfection in 293T cells, TCF-dependent reporter assay, deletion mutant analysis of Rfz9, Western blot for beta-catenin and Dvl-1 The Journal of Biological Chemistry High 12138115
2004 The proinvasive activity of Wnt-2 is mediated through a noncanonical Wnt pathway involving GSK-3beta and c-Jun/AP-1 signaling. Wnt-2 induces MMP-7 (matrilysin) expression through an AP-1 binding site in its promoter, and invasion induced by Wnt-2 is not reversed by wild-type Axin (a canonical pathway inhibitor), distinguishing this from canonical beta-catenin signaling. Stable overexpression of Wnt-2, siRNA depletion of GSK-3beta, dominant-negative c-Jun (TAM67), AP-1 promoter reporter assay, collagen invasion assay, soluble FRP inhibition FASEB Journal High 15507471
2006 Wnt2 is required for proper commitment of mesoderm to endothelial and cardiac lineages during embryoid body (ES cell) differentiation; Wnt2 knockout increases Flk1+ hemangioblasts and hematopoietic progenitors but impairs endothelial and terminal cardiomyocyte differentiation, indicating Wnt2 acts as a negative regulator of hemangioblast/hematopoiesis and a positive regulator of endothelial and cardiomyocyte differentiation. Wnt2 knockout ES cell lines, embryoid body differentiation, flow cytometry for Flk1+ cells, blast colony-forming cell assays, gene expression analysis The Journal of Biological Chemistry High 17098737
2006 Neuronal activity drives dendritic arborization through a pathway involving CaMKK → CaMKI (gamma isoform) → Ras/MEK/ERK → CREB, and a SACO screen identified Wnt-2 as an activity-dependent CREB-responsive gene. Neuronal activity enhances CREB-dependent transcription of Wnt-2, and expression of Wnt-2 is sufficient to stimulate dendritic arborization in hippocampal neurons. Serial analysis of chromatin occupancy (SACO) screen, viral vector expression of Wnt-2 in hippocampal neurons and slices, CREB reporter assays, kinase inhibitors, dominant-negative constructs Neuron High 16772171
2006 GATA6 directly binds to cognate GATA-factor binding sites in the Wnt2 promoter and transcriptionally activates Wnt2 expression during early cardiogenesis, identifying Wnt2 as a direct downstream target of GATA6. Microarray screen in P19-CL6 cells with GATA6 overexpression, real-time RT-PCR validation, ChIP/promoter binding assay for GATA factors on the Wnt2 promoter Mechanisms of Development Medium 16621466
2008 Wnt2 acts as a cell type-specific autocrine growth factor in hepatic sinusoidal endothelial cells (HSECs). GST pull-down and co-immunoprecipitation assays identified Frizzled-4 (Fzd4) as a Wnt2 receptor in HSECs. Wnt2 signals through canonical beta-catenin (nuclear translocation) and cross-stimulates the VEGF pathway by upregulating VEGFR-2 expression. Wnt2 siRNA knockdown reduces HSEC proliferation and downregulates VEGFR-2. GST pull-down, co-immunoprecipitation, siRNA knockdown, quantitative RT-PCR, northern/western blotting, Matrigel tube formation assay, Wnt inhibitors (sFRP1, WIF) Hepatology High 18302287
2009 Wnt2/2b signaling through the canonical Wnt/beta-catenin pathway is required to specify lung endoderm progenitors within the anterior foregut. Embryos lacking Wnt2/2b exhibit complete lung agenesis without Nkx2.1 expression. Endoderm-restricted deletion of beta-catenin phenocopies this defect. Activation of canonical Wnt/beta-catenin signaling reprograms esophagus and stomach endoderm to a lung endoderm progenitor fate. Wnt2/2b double knockout mice, conditional beta-catenin knockout in endoderm, in situ hybridization, gain-of-function Wnt/beta-catenin activation Developmental Cell High 19686689
2010 Wnt2 is expressed specifically in the developing inflow tract mesoderm and is required for posterior pole heart development. Loss of Wnt2 reduces the number and proliferation of posterior second heart field progenitors, causing defects resembling complete common atrio-ventricular canal. Wnt2 works in a feedforward transcriptional loop with Gata6 to regulate posterior cardiac development. Pharmacological inhibition of Gsk-3beta rescues the Wnt2-/- cardiac defects, placing Gsk-3beta downstream of Wnt2. Wnt2 knockout mice, BrdU proliferation assays, pharmacological Gsk-3beta inhibition rescue experiment, gene expression analysis Developmental Cell High 20159597
2010 WNT2 promotes granulosa cell DNA synthesis (proliferation) through beta-catenin. WNT2 knockdown reduces beta-catenin expression and accumulates GSK-3beta in the cytoplasm; WNT2 overexpression reduces cytoplasmic GSK-3beta and induces nuclear translocation of beta-catenin. Beta-catenin knockdown inhibits DNA synthesis and neutralizes WNT2 overexpression effects, establishing a WNT2/beta-catenin signaling axis regulating granulosa cell proliferation. siRNA knockdown of WNT2 and beta-catenin, recombinant viral vector overexpression, [3H]-thymidine DNA synthesis assay, Western blot for GSK-3beta/beta-catenin localization, immunofluorescence Biology of Reproduction High 20107203
2011 Wnt2 signaling is necessary and sufficient to activate the airway smooth muscle program in the lung. Wnt2 loss-of-function impairs smooth muscle specification, and gain-of-function activates smooth muscle differentiation including upregulation of myocardin/Mrtf-B and the signaling factor Fgf10, placing Wnt2 upstream of myocardin/Mrtf-B and Fgf10 in a transcriptional hierarchy for lung airway smooth muscle development. Wnt2 knockout mice, conditional gain-of-function, qRT-PCR, in situ hybridization, immunostaining for smooth muscle markers Developmental Biology High 21704027
2011 Tumor fibroblast-secreted Wnt2 promotes oesophageal cancer cell growth by activating the canonical Wnt/beta-catenin signaling pathway and subsequently upregulates cyclin D1 and c-Myc expression. Wnt2 also enhances cancer cell motility and invasiveness by inducing epithelial-mesenchymal transition. Wnt2-secreting CHO conditioned medium, Western blotting for beta-catenin pathway components (cyclin D1, c-Myc), cell proliferation assays, cell motility/invasion assays, immunohistochemistry Gut Medium 21672941
2011 Sequential functions of Wnt2bb and Wnt2 control liver specification and proliferation in zebrafish, and fzd5 (frizzled-5) mediates part of hepatic competence. Genetic epistasis experiments show that fzd5 is required for early liver formation and interacts genetically with wnt2 and wnt2bb. Combined loss of both ligands causes liver agenesis and swim bladder agenesis. Zebrafish loss-of-function (morpholinos/mutants), genetic epistasis experiments, ectopic overexpression, in situ hybridization Development Medium 21771809
2011 Wnt2 inhibits enteric bacterial-induced inflammation in intestinal epithelial cells. Wnt2 knockdown enhances IL-8 secretion, while Wnt2 overexpression reduces bacterial-induced IL-8. Wnt2 protein stability is regulated through ubiquitination. The bacterial protein AvrA from Salmonella and E. coli stabilizes Wnt2 protein expression in vivo, linking a host-pathogen interaction to Wnt2 protein regulation. siRNA knockdown, Wnt2 overexpression, in vitro cell assays for IL-8 secretion, mouse Salmonella-colitis model, gnotobiotic mouse model, ubiquitination assay Inflammatory Bowel Diseases Medium 21674728
2013 WNT2/beta-catenin (CTNNB1) signaling regulates connexin43 (CX43) expression and gap-junctional intercellular communication (GJIC) in granulosa cells. WNT2 knockdown reduces CX43 expression, gap junction membrane extent, and GJIC. CTNNB1 knockdown similarly reduces CX43 expression and GJIC, and interferes with FSH-stimulated mobilization of CX43 into gap junctions, establishing that WNT2 acts through CTNNB1 to regulate gap junction assembly in an FSH-responsive manner. siRNA knockdown of WNT2 and CTNNB1, GJIC assay, immunofluorescence for CX43 and CTNNB1 localization, FSH treatment, Western blot Biology of Reproduction High 23843235
2013 Frizzled-8 (FZD8) is activated by Wnt-2 in non-small cell lung cancer cells. Co-expression of Wnt-2 and Frizzled-8 activates the canonical Wnt pathway (TCF reporter). A dominant-negative Wnt-2 construct inhibits Wnt-2/FZD8 signaling, reduces colony formation in vitro, and reduces tumor growth in a xenograft model. TCF TOP/FOP reporter assay in 293T/A549/A427 cells, RT-PCR in lung cancer tissues, dominant-negative Wnt-2 construct, colony formation assay, xenograft mouse model BMC Cancer Medium 23815780
2015 WNT2 expression is epigenetically silenced by EZH2-mediated H3K27me3 histone modification in non-CRC cells, and is de-repressed by loss of PRC2 promoter occupancy in colorectal cancer cells. Knockdown or knockout of endogenous WNT2 downregulates Wnt/beta-catenin target gene expression and inhibits CRC cell proliferation; neutralizing secreted Wnt2 similarly reduces target gene expression and proliferation. siRNA/CRISPR knockout of WNT2, neutralizing antibody against secreted WNT2, Wnt/beta-catenin target gene analysis, ChIP for EZH2/H3K27me3 on WNT2 promoter, cell proliferation assays Oncotarget High 26484565
2015 Hox5 paralogous genes act upstream of Wnt2/2b in the lung mesoderm; Hox5 triple-mutant embryos lose Wnt2/2b expression in the distal lung mesenchyme with downregulation of Wnt2/2b downstream targets Lef1, Axin2, and Bmp4. Wnt2/2b-enriched media rescue proper Sox2/Sox9 patterning and Bmp4 expression in Hox5 triple-mutant lung explants, establishing Hox5 genes as upstream mesenchymal regulators of the Wnt2/2b-Bmp4 axis. Hox5 triple-mutant mice, in situ hybridization, qRT-PCR, lung explant rescue with Wnt2/2b-enriched media Cell Reports High 26235626
2015 MiR-199a-5p directly targets WNT2. Inhibition of miR-199a-5p increases WNT2 expression and promotes smooth muscle cell (SMC) proliferation and reduced cell size, while overexpression of WNT2 or recombinant WNT2 treatment phenocopies miR-199a-5p inhibition. WNT2 knockdown in antimiR-expressing SMCs restores cell phenotype and proliferation rates, and WNT2/Wnt signaling suppresses myocardin while inducing Krüppel-like factor 4 (KLF4) in smooth muscle cells. Transcriptome analysis, antimiR/miRNA overexpression in SMCs, recombinant WNT2 treatment, shRNA knockdown of WNT2, Western blot, qRT-PCR, cell size/proliferation measurements The Journal of Biological Chemistry High 25596533
2016 WNT2 specifically promotes vascular smooth muscle cell (VSMC) migration. Recombinant Wnt2 induces VSMC migration in vitro. Wnt2 induces WISP-1 expression ~1.7-fold via beta-catenin/TCF signaling, and Wnt2-promoted migration is integrin-dependent and acts through WISP-1 as an intermediary. Wnt2+/- mice show reduced Wnt2 and WISP-1 levels and significantly suppressed intimal thickening after carotid artery ligation. Recombinant Wnt2 treatment, siRNA knockdown of Wnt2 and WISP-1, Wnt2+/- mice carotid ligation model, adenovirus-WISP-1, migration assays, beta-catenin/TCF reporter Arteriosclerosis, Thrombosis, and Vascular Biology High 27199447
2017 CAF-derived WNT2 activates canonical WNT signaling (using 7TGP reporter) in APC/beta-catenin wild-type colon cancer cells in a paracrine fashion. WNT2 activates autocrine canonical WNT signaling in primary fibroblasts, promoting a pro-migratory and pro-invasive phenotype. FZD8 is identified as the putative WNT2 receptor in cancer-associated fibroblasts (CAFs). WNT2-mediated fibroblast motility and ECM remodeling enhance cancer cell invasion in 3D organotypic co-cultures. 7TGP canonical WNT reporter construct, siRNA knockdown of WNT2 in CAFs, organotypic raft cultures, xenograft mouse model, fibroblast migration/invasion assays Oncogene High 28553956
2018 TBX5 directly drives Wnt2 and Wnt2b expression in cardiopulmonary mesoderm by binding to cis-regulatory elements at the Wnt2 locus (identified by TBX5 ChIP-seq). TBX5 is required for pulmonary specification non-cell-autonomously; this is mediated by Wnt2/2b signaling from mesoderm to endoderm. TBX5 cooperates with Shh signaling to drive Wnt2b expression for lung morphogenesis. TBX5 ChIP-sequencing, cis-regulatory element in vivo reporter assay, mouse and amphibian Tbx5 knockouts, in vitro mesoderm cell assays for Wnt2 expression Proceedings of the National Academy of Sciences USA High 30352852
2018 BPA exposure reduces WNT2 expression in placenta by increasing DNA methylation of the WNT2 promoter via upregulation of DNMT1. Inhibition of DNMT in HTR-8/SVneo trophoblast cells reduces WNT2 promoter methylation and restores WNT2 expression, establishing DNMT1-mediated promoter methylation as a mechanism of WNT2 epigenetic silencing with functional consequences for trophoblast invasion. BPA-treated pregnant mouse model, methylation analysis of WNT2 promoter, DNMT inhibitor treatment in HTR-8/SVneo cells, qRT-PCR, Western blot for DNMT1 and invasion-related genes FASEB Journal Medium 30303745
2019 CAF-derived WNT2 suppresses dendritic cell (DC) differentiation and DC-mediated antitumour T-cell responses via the SOCS3/p-JAK2/p-STAT3 signaling cascade. Anti-WNT2 monoclonal antibody or shRNA knockdown of WNT2 in CAFs restores DC differentiation and enhances anti-PD-1 efficacy in mouse OSCC and CRC syngeneic tumor models. Anti-WNT2 mAb treatment in syngeneic mouse models, shRNA knockdown of WNT2 in CAFs, RNA-sequencing, western blot for SOCS3/p-JAK2/p-STAT3, DC differentiation assays, T-cell response assays Gut High 33692094
2019 CAF-derived WNT2 promotes angiogenesis in colorectal cancer by shifting the secretome balance towards pro-angiogenic signals including ANG-2, IL-6, G-CSF, and PGF. WNT2 knockdown in CAFs reduces angiogenesis; WNT2 expression in skin fibroblasts increases angiogenesis. In CRC xenografts, WNT2 overexpression enhances vessel density and tumor volume. Secretome profiling by mass spectrometry and cytokine arrays identified the pro-angiogenic proteins elevated by WNT2. siRNA knockdown of WNT2 in CAFs, WNT2 overexpression in skin fibroblasts, CRC xenografts, mass spectrometry secretome profiling, cytokine arrays, angiogenesis assay Angiogenesis High 31667643
2021 Wnt2 and Wnt4 activate beta-catenin/NF-κB signaling to promote cardiac fibrosis through co-operation of Frizzled4 or Frizzled2 with LRP6 as co-receptors in cardiac fibroblasts. Hypoxia enhances secretion of Wnt2 and Wnt4 from cardiomyocytes and fibroblasts. WNT2 upregulates expression of Fzd2, Fzd4, and LRP6. Knockdown of Wnt2 and Wnt4 attenuates myocardial remodeling and cardiac dysfunction in experimental MI. siRNA knockdown in MI mouse model, in vitro NF-κB/beta-catenin pathway analysis in NRCFs, ELISA for Wnt2/Wnt4 in AMI patients, receptor expression analysis EBioMedicine Medium 34911029
2022 Endothelial cell-derived Wnt2 (and Wnt9b) controls hepatic metabolic zonation (LZ) and liver regeneration (LR). EC-specific elimination of Wnt2 and Wnt9b leads to loss of beta-catenin target gene expression in zone 3 and re-appearance of zone 1 genes in zone 3. A tetravalent antibody Wnt agonist rescues LZ and LR in the knockouts, and promotes LR in acetaminophen overdose acute liver failure. Single-cell spatial transcriptomics, endothelial cell-specific conditional KO of Wnt2 and Wnt9b, Wnt agonist (tetravalent antibody) treatment, acetaminophen liver failure model Cell Reports Medicine High 36220068
2023 WNT2 is positively regulated by the transcription factor SOX4, and in turn WNT2 (signaling via FZD8/beta-catenin) upregulates SOX4, forming an auto-regulatory positive feedback loop that maintains gastric cancer stem cell self-renewal and tumorigenicity. Blocking WNT2 with a monoclonal antibody disrupts this WNT2-SOX4 loop and enhances chemotherapeutic efficacy in GCSC-derived xenograft models. WNT2 overexpression/knockdown, SOX4 overexpression/knockdown, TCF/beta-catenin reporter, co-immunoprecipitation/promoter analysis, anti-WNT2 mAb in xenograft models, combination chemotherapy experiments Oncogene High 37634009
2024 Piezo1 acts upstream of Wnt2/Wnt11 in a mechanical stiffness-driven pathway promoting skin fibrosis. Piezo1 knockdown in dermal fibroblasts abolishes the fibroproliferative phenotype on stiff substrates. Piezo1 signals through the Wnt2/Wnt11 pathway to mechanically induce secretion of CCL24 (eotaxin-2), a pro-fibrotic cytokine. AAV-mediated Piezo1 knockdown ameliorates skin fibrosis in mice. Piezo1 knockdown on substrates of varying stiffness, Wnt2/Wnt11 pathway analysis, CCL24 secretion measurement, AAV-mediated Piezo1 KD in mouse skin fibrosis model Cell Death & Disease Medium 38267432

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annual review of nutrition 549 18489257
2004 Iron metabolism and the IRE/IRP regulatory system: an update. Annals of the New York Academy of Sciences 412 15105251
2006 Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2. Neuron 384 16772171
2009 Wnt2/2b and beta-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut. Developmental cell 354 19686689
1996 Targeted disruption of the Wnt2 gene results in placentation defects. Development (Cambridge, England) 309 8951051
2014 The IRP/IRE system in vivo: insights from mouse models. Frontiers in pharmacology 286 25120486
2019 Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer. Angiogenesis 247 31667643
1998 IRP-1 binding to ferritin mRNA prevents the recruitment of the small ribosomal subunit by the cap-binding complex eIF4F. Molecular cell 215 9774976
2008 Downregulation of Wnt2 and beta-catenin by siRNA suppresses malignant glioma cell growth. Cancer gene therapy 191 18949017
2017 Iron regulatory protein (IRP)-iron responsive element (IRE) signaling pathway in human neurodegenerative diseases. Molecular neurodegeneration 187 29061112
2021 Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity. Gut 165 33692094
2001 Evidence supporting WNT2 as an autism susceptibility gene. American journal of medical genetics 157 11449391
2001 Frequent up-regulation of WNT2 in primary gastric cancer and colorectal cancer. International journal of oncology 144 11605001
1997 Differences in the regulation of iron regulatory protein-1 (IRP-1) by extra- and intracellular oxidative stress. The Journal of biological chemistry 138 9092514
2002 Wnt signaling in the ovary: identification and compartmentalized expression of wnt-2, wnt-2b, and frizzled-4 mRNAs. Endocrinology 123 12072409
1997 Expression and hormone regulation of Wnt2, 3, 4, 5a, 7a, 7b and 10b in normal human endometrium and endometrial carcinoma. British journal of cancer 119 9099960
2021 CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles. Blood 114 34265052
2017 Autocrine WNT2 signaling in fibroblasts promotes colorectal cancer progression. Oncogene 114 28553956
2001 Differential regulation of WNT2 and WNT2B expression in human cancer. International journal of molecular medicine 114 11712082
2011 Wnt2 secreted by tumour fibroblasts promotes tumour progression in oesophageal cancer by activation of the Wnt/β-catenin signalling pathway. Gut 111 21672941
2010 Characterization and in vivo pharmacological rescue of a Wnt2-Gata6 pathway required for cardiac inflow tract development. Developmental cell 108 20159597
2007 Increased expression of Wnt2 and SFRP4 in Tsk mouse skin: role of Wnt signaling in altered dermal fibrillin deposition and systemic sclerosis. The Journal of investigative dermatology 106 17943183
2010 Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE/IRP dependent. Cell research 101 20125122
2010 Wnt2 expression and signaling is increased by different classes of antidepressant treatments. Biological psychiatry 99 20570247
1998 Mapping of chromosomal imbalances in gastric adenocarcinoma revealed amplified protooncogenes MYCN, MET, WNT2, and ERBB2. Genes, chromosomes & cancer 95 9824203
2003 WNT2 and human gastrointestinal cancer (review). International journal of molecular medicine 94 14533014
1995 Interleukin-1 beta-converting enzyme-related proteases (IRPs) and mammalian cell death: dissociation of IRP-induced oligonucleosomal endonuclease activity from morphological apoptosis in granulosa cells of the ovarian follicle. Endocrinology 93 7588240
1995 Differential modulation of the RNA-binding proteins IRP-1 and IRP-2 in response to iron. IRP-2 inactivation requires translation of another protein. The Journal of biological chemistry 88 7544791
2022 Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b. Cell reports. Medicine 87 36220068
2008 Stat5 regulates cellular iron uptake of erythroid cells via IRP-2 and TfR-1. Blood 86 18694996
2004 Lack of evidence for an association between WNT2 and RELN polymorphisms and autism. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 84 15048648
2002 Frizzled-9 is activated by Wnt-2 and functions in Wnt/beta -catenin signaling. The Journal of biological chemistry 84 12138115
1997 Cloning and expression of a rat brain interleukin-1beta-converting enzyme (ICE)-related protease (IRP) and its possible role in apoptosis of cultured cerebellar granule neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 84 9030616
2001 A study of genes that may modulate the expression of hereditary hemochromatosis: transferrin receptor-1, ferroportin, ceruloplasmin, ferritin light and heavy chains, iron regulatory proteins (IRP)-1 and -2, and hepcidin. Blood cells, molecules & diseases 83 11783942
2008 Wnt2 acts as a cell type-specific, autocrine growth factor in rat hepatic sinusoidal endothelial cells cross-stimulating the VEGF pathway. Hepatology (Baltimore, Md.) 82 18302287
2002 No association between the WNT2 gene and autistic disorder. American journal of medical genetics 79 11840514
2006 Effects of 12 metal ions on iron regulatory protein 1 (IRP-1) and hypoxia-inducible factor-1 alpha (HIF-1alpha) and HIF-regulated genes. Toxicology and applied pharmacology 78 16386771
2019 Cancer-associated fibroblasts secrete Wnt2 to promote cancer progression in colorectal cancer. Cancer medicine 76 31468733
2011 Wnt2 signaling is necessary and sufficient to activate the airway smooth muscle program in the lung by regulating myocardin/Mrtf-B and Fgf10 expression. Developmental biology 75 21704027
2017 The long non-coding RNA CRNDE acts as a ceRNA and promotes glioma malignancy by preventing miR-136-5p-mediated downregulation of Bcl-2 and Wnt2. Oncotarget 74 29152149
2015 Wnt2 complements Wnt/β-catenin signaling in colorectal cancer. Oncotarget 74 26484565
2018 Bisphenol A exposure alters placentation and causes preeclampsia-like features in pregnant mice involved in reprogramming of DNA methylation of WNT2. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 71 30303745
2004 Correlation of Wnt-2 expression and beta-catenin intracellular accumulation in Chinese gastric cancers: relevance with tumour dissemination. Cancer letters 71 15896469
2004 The proinvasive activity of Wnt-2 is mediated through a noncanonical Wnt pathway coupled to GSK-3beta and c-Jun/AP-1 signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 66 15507471
1995 Differential regulation of two related RNA-binding proteins, iron regulatory protein (IRP) and IRPB. RNA (New York, N.Y.) 66 7585245
1998 Structure and expression of Wnt13, a novel mouse Wnt2 related gene. Mechanisms of development 65 9545553
1992 The biochemical properties and transforming potential of human Wnt-2 are similar to Wnt-1. Oncogene 65 1371336
2012 Follicle-stimulating hormone regulation of estradiol production: possible involvement of WNT2 and β-catenin in bovine granulosa cells. Journal of animal science 63 22696613
2016 The antidepressant roles of Wnt2 and Wnt3 in stress-induced depression-like behaviors. Translational psychiatry 62 27622936
2013 Association of Wnt2 and sFRP4 expression in the third trimester placenta in women with severe preeclampsia. Reproductive sciences (Thousand Oaks, Calif.) 62 23322712
2006 Wnt2 coordinates the commitment of mesoderm to hematopoietic, endothelial, and cardiac lineages in embryoid bodies. The Journal of biological chemistry 62 17098737
2014 Activation of the Wnt pathway through Wnt2 promotes metastasis in pancreatic cancer. American journal of cancer research 60 25232495
2007 Wnt1 and Wnt5a affect endothelial proliferation and capillary length; Wnt2 does not. Growth factors (Chur, Switzerland) 60 17454147
2021 Circular RNA circLMO7 acts as a microRNA-30a-3p sponge to promote gastric cancer progression via the WNT2/β-catenin pathway. Journal of experimental & clinical cancer research : CR 59 33397440
2010 WNT2 regulates DNA synthesis in mouse granulosa cells through beta-catenin. Biology of reproduction 59 20107203
2024 Mechanical stiffness promotes skin fibrosis via Piezo1-Wnt2/Wnt11-CCL24 positive feedback loop. Cell death & disease 58 38267432
2015 MicroRNA MiR-199a-5p regulates smooth muscle cell proliferation and morphology by targeting WNT2 signaling pathway. The Journal of biological chemistry 58 25596533
2005 Wnt2 as a new therapeutic target in malignant pleural mesothelioma. International journal of cancer 58 15900580
2011 Interplay between Wnt2 and Wnt2bb controls multiple steps of early foregut-derived organ development. Development (Cambridge, England) 57 21771809
2015 Hox5 Genes Regulate the Wnt2/2b-Bmp4-Signaling Axis during Lung Development. Cell reports 56 26235626
2017 Involvement of c-Fos in cell proliferation, migration, and invasion in osteosarcoma cells accompanied by altered expression of Wnt2 and Fzd9. PloS one 55 28665975
1995 Ascorbic acid enhances ferritin mRNA translation by an IRP/aconitase switch. The Journal of biological chemistry 55 7642638
2018 Evolutionarily conserved Tbx5-Wnt2/2b pathway orchestrates cardiopulmonary development. Proceedings of the National Academy of Sciences of the United States of America 54 30352852
2022 Iron regulatory protein (IRP)-mediated iron homeostasis is critical for neutrophil development and differentiation in the bone marrow. Science advances 52 36197975
2021 Elevated Wnt2 and Wnt4 activate NF-κB signaling to promote cardiac fibrosis by cooperation of Fzd4/2 and LRP6 following myocardial infarction. EBioMedicine 51 34911029
2019 Long non-coding RNA LINC00968 attenuates drug resistance of breast cancer cells through inhibiting the Wnt2/β-catenin signaling pathway by regulating WNT2. Journal of experimental & clinical cancer research : CR 51 30791958
2016 Wnt2 and WISP-1/CCN4 Induce Intimal Thickening via Promotion of Smooth Muscle Cell Migration. Arteriosclerosis, thrombosis, and vascular biology 50 27199447
2015 Wnt2 promotes non-small cell lung cancer progression by activating WNT/β-catenin pathway. American journal of cancer research 50 26045984
2018 MiR-221 is involved in depression by regulating Wnt2/CREB/BDNF axis in hippocampal neurons. Cell cycle (Georgetown, Tex.) 49 30589396
1988 Recombinations between IRP and cystic fibrosis. American journal of human genetics 48 2902786
1998 Iron-regulatory protein-1 (IRP-1) is highly conserved in two invertebrate species--characterization of IRP-1 homologues in Drosophila melanogaster and Caenorhabditis elegans. European journal of biochemistry 47 9660175
1989 Isolation of a new DNA marker in linkage disequilibrium with cystic fibrosis, situated between J3.11 (D7S8) and IRP. American journal of human genetics 47 2565082
2007 Iron/IRP-1-dependent regulation of mRNA expression for transferrin receptor, DMT1 and ferritin during human erythroid differentiation. Experimental hematology 46 17533042
2011 WNT2 promoter methylation in human placenta is associated with low birthweight percentile in the neonate. Epigenetics 45 21474991
1997 Intracellular iron regulates iron absorption and IRP activity in intestinal epithelial (Caco-2) cells. The American journal of physiology 45 9277404
2019 SNHG9/miR-199a-5p/Wnt2 Axis Regulates Cell Growth and Aerobic Glycolysis in Glioblastoma. Journal of neuropathology and experimental neurology 43 31504670
2005 Generation of conditional alleles of the murine Iron Regulatory Protein (IRP)-1 and -2 genes. Genesis (New York, N.Y. : 2000) 42 16283625
2013 The canonical WNT2 pathway and FSH interact to regulate gap junction assembly in mouse granulosa cells. Biology of reproduction 41 23843235
2011 Wnt2 inhibits enteric bacterial-induced inflammation in intestinal epithelial cells. Inflammatory bowel diseases 41 21674728
2013 Frizzled-8 receptor is activated by the Wnt-2 ligand in non-small cell lung cancer. BMC cancer 38 23815780
2003 Alterations in cellular IRP-dependent iron regulation by in vitro manganese exposure in undifferentiated PC12 cells. Brain research 38 12729948
2004 Endogenous nitration of iron regulatory protein-1 (IRP-1) in nitric oxide-producing murine macrophages: further insight into the mechanism of nitration in vivo and its impact on IRP-1 functions. The Journal of biological chemistry 37 15258160
2018 Regulation of cellular iron metabolism: Iron-dependent degradation of IRP by SCFFBXL5 ubiquitin ligase. Free radical biology & medicine 36 30218771
2012 WNT2 locus is involved in genetic susceptibility of Peyronie's disease. The journal of sexual medicine 36 22489561
2001 An IRP-like protein from Plasmodium falciparum binds to a mammalian iron-responsive element. Blood 36 11588054
2019 Targeting FAT1 Inhibits Carcinogenesis, Induces Oxidative Stress and Enhances Cisplatin Sensitivity through Deregulation of LRP5/WNT2/GSS Signaling Axis in Oral Squamous Cell Carcinoma. Cancers 35 31783581
2018 microRNA-199a/b-5p enhance imatinib efficacy via repressing WNT2 signaling-mediated protective autophagy in imatinib-resistant chronic myeloid leukemia cells. Chemico-biological interactions 35 29890129
2011 Wnt2 accelerates cardiac myocyte differentiation from ES-cell derived mesodermal cells via non-canonical pathway. Journal of molecular and cellular cardiology 35 22146296
2014 The PTK7-related transmembrane proteins off-track and off-track 2 are co-receptors for Drosophila Wnt2 required for male fertility. PLoS genetics 34 25010066
2009 Overexpression of Wnt-2 in colorectal cancers. Neoplasma 34 19239325
2006 Wnt2 is a direct downstream target of GATA6 during early cardiogenesis. Mechanisms of development 34 16621466
2023 WNT2-SOX4 positive feedback loop promotes chemoresistance and tumorigenesis by inducing stem-cell like properties in gastric cancer. Oncogene 33 37634009
2003 Expression of a recombinant IRP-like Plasmodium falciparum protein that specifically binds putative plasmodial IREs. Molecular and biochemical parasitology 33 12615322
2014 Electrophoretic mobility shift assay (EMSA) for the study of RNA-protein interactions: the IRE/IRP example. Journal of visualized experiments : JoVE 32 25548934
2005 Neurochemical investigations of dopamine neuronal systems in iron-regulatory protein 2 (IRP-2) knockout mice. Brain research. Molecular brain research 32 16051392
2017 Deregulation of WNT2/FZD3/β-catenin pathway compromises the estrogen synthesis in cumulus cells from patients with polycystic ovary syndrome. Biochemical and biophysical research communications 31 28709873
2009 Association between autism and variants in the wingless-type MMTV integration site family member 2 ( WNT2) gene. The international journal of neuropsychopharmacology 31 19895723
2016 WNT2 Promotes Cervical Carcinoma Metastasis and Induction of Epithelial-Mesenchymal Transition. PloS one 30 27513465
2009 Responsiveness of Trichomonas vaginalis to iron concentrations: evidence for a post-transcriptional iron regulation by an IRE/IRP-like system. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 28 19539055
1998 Regulation of iron metabolism in the sanguivore lamprey Lampetra fluviatilis--molecular cloning of two ferritin subunits and two iron-regulatory proteins (IRP) reveals evolutionary conservation of the iron-regulatory element (IRE)/IRP regulatory system. European journal of biochemistry 28 9660174

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