Affinage

WNT2

Protein Wnt-2 · UniProt P09544

Length
360 aa
Mass
40.4 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WNT2 is a secreted, N-glycosylated, cell-surface-associated Wnt family ligand that signals primarily through the canonical Frizzled/β-catenin pathway—engaging receptors FZD4, FZD5, FZD8, FZD9, and co-receptor LRP6—to drive cell proliferation, fate specification, and tissue morphogenesis in contexts including lung endoderm specification, placental vascularization, cardiac inflow tract development, liver metabolic zonation and regeneration, smooth muscle differentiation, and granulosa cell proliferation (PMID:8951051, PMID:19686689, PMID:20159597, PMID:36220068, PMID:21704027, PMID:20107203). In specific contexts, WNT2 instead activates non-canonical JNK/AP-1 signaling to promote tumor invasion via MMP-7 induction or cardiomyocyte differentiation (PMID:15507471, PMID:22146296). WNT2 expression is transcriptionally controlled by TBX5 and CREB, and epigenetically regulated by EZH2-mediated H3K27me3 and DNMT1-dependent promoter methylation; its downstream canonical targets include cyclin D1, c-myc, WISP-1, VEGFR-2, and SOX4, the last forming a positive feedback loop that sustains cancer stem cell self-renewal (PMID:30352852, PMID:16772171, PMID:26484565, PMID:30303745, PMID:37634009). In the tumor microenvironment, cancer-associated fibroblast-secreted WNT2 promotes angiogenesis, fibroblast-mediated ECM remodeling, and immune evasion by suppressing dendritic cell differentiation via SOCS3/JAK2/STAT3 signaling (PMID:28553956, PMID:31667643, PMID:33692094).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1992 High

    Establishing WNT2 as a secreted, glycosylated, cell-surface-associated protein with transforming capacity answered whether WNT2 behaves biochemically like WNT1 and can drive oncogenic phenotypes.

    Evidence CHO/AtT-20 cell transfection with immunoprecipitation, suramin release, and C57mg transformation assay

    PMID:1371336

    Open questions at the time
    • No receptor identified
    • No signaling pathway defined
    • In vivo relevance not tested
  2. 1996 High

    The first loss-of-function model revealed that WNT2 is required for placental labyrinthine vascularization, establishing a non-redundant developmental role.

    Evidence Wnt2 knockout mouse with histological analysis of placenta

    PMID:8951051

    Open questions at the time
    • Downstream pathway not identified
    • Whether defect is cell-autonomous unknown
    • Redundancy with Wnt2b not explored
  3. 1998 High

    Demonstrating that WNT2 elevates cytosolic β-catenin without activating MAP kinase resolved which Wnt signaling branch WNT2 engages.

    Evidence NIH3T3 stable transfection with β-catenin and MAPK western blots

    PMID:9652750

    Open questions at the time
    • Receptor identity unknown
    • Whether non-canonical signaling occurs in other contexts untested
  4. 2002 High

    Identification of FZD9 as a WNT2 receptor—with deletion mutants confirming the ligand-binding domain requirement—answered how WNT2 engages the canonical pathway at the receptor level.

    Evidence 293T co-transfection, TCF reporter, FZD9 deletion mutants, Dvl-1/Axin relocalization

    PMID:12138115

    Open questions at the time
    • Whether additional Frizzled receptors serve as WNT2 receptors unknown
    • Co-receptor requirement not addressed
  5. 2004 High

    Discovery that WNT2-driven invasion uses a non-canonical GSK-3β/c-Jun/AP-1 pathway to induce MMP-7 revealed that WNT2 can bifurcate between canonical and non-canonical signaling depending on cellular context.

    Evidence Collagen invasion assay, siRNA, AP-1 reporter, dominant-negative c-Jun, Axin overexpression controls

    PMID:15507471

    Open questions at the time
    • What determines canonical vs. non-canonical pathway choice unknown
    • Receptor mediating non-canonical signaling not identified
  6. 2006 High

    Two studies established WNT2 as a critical signal in neuronal and mesodermal lineage decisions: CREB-dependent transcription of WNT2 drives activity-dependent dendritic arborization in hippocampal neurons, while Wnt2 knockout in ES cells showed opposing roles in hematopoietic vs. endothelial/cardiac differentiation.

    Evidence Hippocampal neuron culture with kinase cascades and SACO; ES cell Wnt2 KO with embryoid body differentiation and flow cytometry

    PMID:16772171 PMID:17098737

    Open questions at the time
    • Whether Wnt2 acts cell-autonomously in neurons vs. mesoderm not fully resolved
    • Receptor identity in neurons unknown
  7. 2008 High

    Identification of FZD4 as a WNT2 receptor in hepatic sinusoidal endothelial cells, with VEGFR-2 as a downstream transcriptional target, defined the first autocrine WNT2 signaling circuit in a differentiated cell type.

    Evidence GST pull-down, reciprocal co-IP, Wnt2 siRNA, VEGFR-2 expression profiling in HSECs

    PMID:18302287

    Open questions at the time
    • Whether LRP5/6 co-receptors participate not tested
    • Mechanism of VEGFR-2 transcriptional activation unknown
  8. 2009 High

    Double knockout of Wnt2/Wnt2b causing complete lung agenesis—phenocopied by endoderm-specific β-catenin deletion—proved that mesenchymal WNT2 signals through canonical β-catenin to specify lung endoderm progenitors.

    Evidence Wnt2/Wnt2b double knockout and conditional β-catenin deletion in mouse, Nkx2.1 expression

    PMID:19686689

    Open questions at the time
    • Relative contribution of Wnt2 vs. Wnt2b not separable
    • Direct Wnt2 receptor on endoderm not identified
  9. 2010 High

    Wnt2 knockout cardiac phenotypes (AV canal defects, reduced SHF progenitor proliferation) rescued by GSK-3β inhibition established WNT2 as a canonical pathway ligand in cardiac inflow tract morphogenesis with a Gata6 feedforward loop.

    Evidence Wnt2 KO mouse, SHF analysis, GSK-3β inhibitor rescue, Gata6 epistasis

    PMID:20159597

    Open questions at the time
    • Which Frizzled receptor operates in SHF progenitors unknown
    • Whether Wnt2b compensates partially unclear
  10. 2010 High

    WNT2 was shown to control granulosa cell proliferation via β-catenin nuclear translocation, extending the canonical pathway model to the ovarian follicle.

    Evidence Bidirectional WNT2 manipulation (siRNA/overexpression) with β-catenin localization and DNA synthesis assay

    PMID:20107203

    Open questions at the time
    • Receptor identity in granulosa cells unknown
    • In vivo fertility phenotype not assessed
  11. 2011 High

    Multiple studies in 2011 expanded WNT2's biological repertoire: fibroblast-secreted WNT2 drives esophageal cancer growth via cyclin D1/c-myc, WNT2 specifies lung smooth muscle via myocardin/Mrtf-B, zebrafish Wnt2/Wnt2bb control liver specification through FZD5, WNT2 non-canonically promotes cardiomyocyte differentiation via JNK/AP-1, and WNT2 protein stability is regulated by ubiquitination during intestinal infection.

    Evidence CHO conditioned medium with cancer cell assays; mouse lung GOF/LOF; zebrafish genetics with fzd5 epistasis; ES cell JNK inhibitor assays; ubiquitination assays in intestinal cells

    PMID:21672941 PMID:21674728 PMID:21704027 PMID:21771809 PMID:22146296

    Open questions at the time
    • Ubiquitin ligase mediating WNT2 degradation not identified
    • Whether JNK vs. β-catenin pathway selection is receptor-determined remains open
  12. 2015 High

    Epigenetic regulation of WNT2 was defined: EZH2/H3K27me3 silences WNT2 in normal tissues while de-repression sustains CRC proliferation, and miR-199a-5p post-transcriptionally represses WNT2 in smooth muscle cells to control the proliferation-differentiation switch via KLF4.

    Evidence ChIP for H3K27me3/EZH2, CRISPR KO, neutralizing antibody (CRC); antimiR/miR overexpression with WNT2 shRNA rescue (SMC)

    PMID:25596533 PMID:26484565

    Open questions at the time
    • Whether DNMT1 and EZH2 cooperate at WNT2 promoter not tested
    • KLF4 binding site on myocardin-regulated genes not mapped
  13. 2017 High

    CAF-derived WNT2 was found to act both in paracrine (on cancer cells) and autocrine (on fibroblasts via FZD8) canonical modes, remodeling the tumor stroma to promote invasion.

    Evidence 7TGP Wnt reporter, siRNA in CAFs, organotypic cultures, xenograft

    PMID:28553956

    Open questions at the time
    • Other Wnt ligands from CAFs not controlled for
    • Whether WNT2 antibody blocks stromal remodeling not tested in this study
  14. 2018 High

    TBX5 ChIP-seq identified direct cis-regulatory elements at the Wnt2 locus, and DNMT1-mediated promoter methylation was shown to silence WNT2 in placental trophoblasts, together establishing the upstream transcriptional and epigenetic control architecture of WNT2.

    Evidence TBX5 ChIP-seq with in vivo enhancer validation; bisulfite sequencing with DNMT inhibitor rescue in trophoblasts

    PMID:30303745 PMID:30352852

    Open questions at the time
    • Whether TBX5 and CREB co-regulate WNT2 in the same cells unknown
    • Full enhancer landscape of WNT2 not mapped outside cardiopulmonary mesoderm
  15. 2021 High

    CAF-secreted WNT2 was shown to suppress dendritic cell differentiation via SOCS3/JAK2/STAT3, defining WNT2 as an immunosuppressive factor in the tumor microenvironment; anti-WNT2 mAb synergized with anti-PD-1 therapy.

    Evidence shRNA, anti-WNT2 mAb, RNA-seq, western blot for SOCS3/JAK2/STAT3, syngeneic tumor models

    PMID:33692094

    Open questions at the time
    • Whether SOCS3 induction is β-catenin-dependent or non-canonical not resolved
    • Human clinical validation absent
  16. 2022 High

    Endothelial Wnt2 (with Wnt9b) was shown to be the zonating signal that establishes pericentral liver identity and supports regeneration, resolved by EC-specific conditional knockout and rescue with a tetravalent Wnt agonist antibody.

    Evidence Single-cell spatial transcriptomics, EC-specific Wnt2/Wnt9b conditional KO, Wnt agonist antibody, APAP liver injury model

    PMID:36220068

    Open questions at the time
    • Relative contribution of Wnt2 vs. Wnt9b not individually quantified
    • Whether hepatocyte FZD receptors distinguish Wnt2 from Wnt9b unknown
  17. 2023 High

    A WNT2–FZD8–β-catenin–SOX4 positive feedback loop was mechanistically dissected using ChIP and shown to maintain gastric cancer stem cell self-renewal and chemoresistance.

    Evidence WNT2 OE/KD, FZD8/β-catenin reporter, ChIP for SOX4 at WNT2 promoter, anti-WNT2 mAb in GCSC xenograft

    PMID:37634009

    Open questions at the time
    • Whether this loop operates in non-gastric cancers unknown
    • SOX4 ChIP-seq at genome-wide scale not performed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: what determines canonical vs. non-canonical pathway choice downstream of WNT2 in different cell types; the structural basis for WNT2 receptor selectivity across FZD4/5/8/9; the identity of the E3 ubiquitin ligase controlling WNT2 protein turnover; and whether anti-WNT2 therapeutic antibodies have efficacy in human cancer immunotherapy trials.
  • No structural data for WNT2–Frizzled complexes
  • Ubiquitin ligase for WNT2 unidentified
  • Human clinical data for anti-WNT2 antibody absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 5 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 12 R-HSA-1266738 Developmental Biology 7 R-HSA-1643685 Disease 7 R-HSA-168256 Immune System 1
Partners
CTNNB1DVL1FZD4FZD5FZD8FZD9LRP6SOX4

Evidence

Reading pass · 33 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 protein is tightly associated with the cell surface (detectable in medium only after suramin treatment); expression in mammary epithelial cells induces loss of density-inhibited growth and a transformed phenotype similar to WNT1. CHO and AtT-20 cell transfection, immunoprecipitation, suramin treatment, C57mg mammary epithelial cell transformation assay Oncogene High 1371336
1996 Targeted disruption of Wnt2 in mice results in placentation defects primarily in the labyrinthine zone, including oedema, reduced fetal capillaries, and increased fibrinoid material, indicating Wnt2 is required for proper placental vascularization. Gene targeting (knockout mouse), histological analysis of placentas Development High 8951051
1998 Wnt-1 and Wnt-2 overexpression in NIH3T3 fibroblasts increases cytosolic (uncomplexed) beta-catenin without activating MAP kinase, demonstrating that WNT2 signals through the beta-catenin pathway rather than through the Ras/MAP kinase pathway. Stable NIH3T3 transfection, beta-catenin and MAP kinase western blot, transient transfection assays Oncogene High 9652750
2002 Frizzled-9 functions as a receptor for Wnt-2: Wnt-2 specifically activates Frizzled-9 in TCF-dependent transcription, induces hyperphosphorylation and relocalization of Dishevelled-1, and leads to cytosolic beta-catenin accumulation; deletion of the Wnt-binding domain of Frizzled-9 abolishes Wnt-2-dependent TCF transcription. 293T cell transfection, TCF reporter assay, co-transfection of deletion mutants, immunofluorescence of Dvl-1 and Axin relocalization The Journal of Biological Chemistry High 12138115
2004 The pro-invasive activity of Wnt-2 is mediated through a non-canonical Wnt pathway requiring GSK-3beta and c-Jun/AP-1 signaling, not through canonical beta-catenin/Axin signaling; Wnt-2 induces MMP-7 (matrilysin) expression via the AP-1 binding site in its promoter, and invasion is blocked by soluble FRP or dominant-negative c-Jun (TAM67) but not by wild-type Axin. Collagen invasion assay, siRNA knockdown of GSK-3beta, AP-1 promoter-reporter assay, dominant-negative constructs, MMP-7 protein measurement FASEB Journal High 15507471
2006 Activity-dependent dendritic arborization in hippocampal neurons is mediated through NMDA receptor/Ca2+/CaMKK/CaMKI/MEK/ERK/CREB signaling that drives CREB-dependent transcription of Wnt-2, with enhanced Wnt-2 synthesis and secretion stimulating dendritic outgrowth and branching. Serial analysis of chromatin occupancy (SACO), hippocampal neuron culture, dominant-negative/constitutively-active kinase constructs, CREB reporter assays, Wnt-2 overexpression Neuron High 16772171
2006 Wnt2 acts as a negative regulator of hemangioblast differentiation and hematopoiesis but as a positive regulator of endothelial and terminal cardiomyocyte differentiation during mesoderm commitment in embryoid bodies; loss of Wnt2 increases Flk1+ progenitors yet impairs downstream endothelial and cardiac differentiation while enhancing hematopoietic output. ES cell Wnt2 knockout, embryoid body differentiation, flow cytometry, blast colony-forming cell assay, gene expression analysis The Journal of Biological Chemistry High 17098737
2008 Wnt2 acts as a cell type-specific autocrine growth factor in hepatic sinusoidal endothelial cells (HSECs): it signals via canonical Wnt/beta-catenin (nuclear translocation) and GST pull-down/co-immunoprecipitation identified Frizzled-4 (Fzd4) as a Wnt2 receptor in HSECs; Wnt2 signaling upregulates VEGFR-2 as a downstream target. GST pull-down, co-immunoprecipitation, Wnt2 siRNA knockdown, exogenous Wnt2 treatment, gene expression profiling, tube formation assay Hepatology High 18302287
2009 Wnt2 and Wnt2b signaling through the canonical Wnt/beta-catenin pathway is required to specify lung endoderm progenitors in the anterior foregut; embryos lacking Wnt2/2b show complete lung agenesis without Nkx2.1 expression, and endoderm-specific beta-catenin deletion recapitulates this phenotype; activation of canonical Wnt/beta-catenin reprograms esophagus/stomach endoderm to a lung fate. Wnt2/Wnt2b double knockout mouse, conditional beta-catenin deletion in endoderm, gain-of-function beta-catenin activation, Nkx2.1 expression analysis Developmental Cell High 19686689
2010 Wnt2 is expressed in developing inflow tract mesoderm and is required for posterior cardiac second heart field progenitor proliferation; loss of Wnt2 causes atrio-ventricular canal defects; Wnt2 works in a feedforward transcriptional loop with Gata6; GSK-3beta pharmacological inhibition rescues the cardiac defects in Wnt2−/− mice. Wnt2 knockout mouse, second heart field progenitor analysis, GSK-3beta inhibitor rescue, Gata6 epistasis analysis Developmental Cell High 20159597
2010 Wnt2 increases expression and signaling in hippocampus following antidepressant treatment; viral vector-mediated overexpression of Wnt2 specifically in the hippocampus is sufficient to produce antidepressant-like behavioral effects in mouse depression models. Focused microarray, viral vector Wnt2 overexpression, behavioral tests (depression models) Biological Psychiatry Medium 20570247
2010 WNT2 regulates DNA synthesis (proliferation) in mouse granulosa cells via beta-catenin: WNT2 knockdown reduces beta-catenin expression and DNA synthesis, while WNT2 overexpression promotes nuclear translocation of beta-catenin and enhances proliferation; beta-catenin knockdown abolishes the effect of WNT2 overexpression. siRNA knockdown, viral vector overexpression, immunostaining of beta-catenin localization, DNA synthesis assay, GSK3B western blot Biology of Reproduction High 20107203
2011 Wnt2 is secreted by tumor fibroblasts and promotes esophageal cancer cell growth and invasion by activating the canonical Wnt/beta-catenin signaling pathway, subsequently upregulating cyclin D1 and c-myc, and inducing epithelial-mesenchymal transition. CHO cell Wnt2-secreting system, conditioned medium assays, western blot for beta-catenin/cyclin D1/c-myc, proliferation and invasion assays Gut High 21672941
2011 Wnt2 signaling is necessary and sufficient to activate the lung airway smooth muscle transcriptional program by regulating expression of myocardin/Mrtf-B and Fgf10; Wnt2 is placed high in the smooth muscle specification hierarchy in the lung mesenchyme. Wnt2 loss-of-function and gain-of-function mouse models, lung smooth muscle marker expression analysis Developmental Biology High 21704027
2011 In zebrafish, Wnt2bb and Wnt2 control liver specification and proliferation sequentially; their combined loss causes liver agenesis; excess wnt2bb or wnt2 induces ectopic liver at the expense of pancreatic/intestinal tissue; Frizzled-5 (fzd5) mediates hepatic competence and interacts genetically with both wnt2 and wnt2bb; combined loss also causes swim bladder agenesis. Zebrafish loss-of-function genetics, ectopic expression assays, epistasis with fzd5 Development High 21771809
2011 Wnt2 is elevated in intestinal epithelial cells after bacterial infection and contributes to host defense by inhibiting apoptosis and inflammatory IL-8 secretion; Wnt2 protein stability is regulated through ubiquitination; the bacterial protein AvrA from Salmonella stabilizes Wnt2 protein expression in vivo. siRNA knockdown, Wnt2 overexpression in epithelial cells, IL-8 ELISA, ubiquitination assay, gnotobiotic mouse model Inflammatory Bowel Diseases Medium 21674728
2013 The WNT2/beta-catenin (CTNNB1) canonical pathway regulates connexin43 (CX43) expression and gap-junctional intercellular communication (GJIC) in granulosa cells; WNT2 knockdown reduces CX43 expression and GJIC; CTNNB1 knockdown interferes with FSH-promoted CX43 mobilization into gap junctions. siRNA knockdown of WNT2 and CTNNB1, CX43 immunostaining, GJIC assay, FSH stimulation Biology of Reproduction High 23843235
2013 Frizzled-8 functions as a receptor activated by Wnt-2 in non-small cell lung cancer: co-expression of Wnt-2 and Frizzled-8 activates the canonical Wnt pathway (TCF reporter), and a dominant-negative Wnt-2 construct inhibits Wnt-2/Frizzled-8 signaling, reduces colony formation, and reduces xenograft tumor growth. TCF reporter assay, dominant-negative Wnt-2 construct, colony formation assay, xenograft mouse model, RT-PCR in patient samples BMC Cancer Medium 23815780
2014 In Drosophila, the PTK7-related co-receptors Off-track (Otk) and Off-track 2 (Otk2) bind to each other and form complexes with Frizzled, Frizzled2, and Wnt2, functioning as Wnt2 co-receptors required for morphogenesis of the ejaculatory duct (male fertility); flies lacking both otk and otk2 are male sterile due to defective genital tract development. Co-immunoprecipitation, double knockout fly genetics, fertility assays PLoS Genetics High 25010066
2015 WNT2 expression is transcriptionally silenced by EZH2-mediated H3K27me3 histone modification in non-CRC cells; in colorectal cancer cells, WNT2 is de-repressed by loss of PRC2 promoter occupancy; WNT2 complements canonical Wnt/beta-catenin signaling by sustaining target gene expression and CRC cell proliferation. siRNA/CRISPR knockout, neutralizing antibody against secreted Wnt2, ChIP for H3K27me3/EZH2, TCF reporter assay Oncotarget High 26484565
2015 miR-199a-5p directly targets WNT2 in smooth muscle cells; inhibition of miR-199a-5p upregulates WNT2, increases SMC proliferation, and reduces cell size; overexpression of WNT2 or recombinant WNT2 treatment mimics miR-199a-5p inhibition; shRNA knockdown of WNT2 in antimiR-expressing SMCs restores normal proliferation phenotype; WNT2 activates KLF4 to repress myocardin-dependent differentiation genes. AntimiR treatment, miR-199a-5p overexpression, WNT2 overexpression, shRNA knockdown, transcriptome analysis The Journal of Biological Chemistry High 25596533
2015 Hox5 genes act upstream of Wnt2/2b in the lung mesoderm: Hoxa5/Hoxb5/Hoxc5 triple-mutant embryos lack Wnt2/2b expression in distal lung mesenchyme and show downregulated Lef1, Axin2, and Bmp4; Wnt2/2b-enriched media rescues Sox2/Sox9 patterning and Bmp4 expression in triple-mutant lung explants. Triple-knockout mouse genetics, lung explant rescue with Wnt2/2b-conditioned media, gene expression analysis Cell Reports High 26235626
2016 Wnt2 promotes vascular smooth muscle cell (VSMC) migration and intimal thickening via induction of WISP-1/CCN4 through beta-catenin/TCF signaling; Wnt2 and WISP-1 effects on migration are integrin-dependent and not additive; Wnt2+/- and WISP-1-/- mice show reduced intimal thickening after carotid artery ligation. Wnt2+/- mouse, WISP-1-/- mouse, recombinant Wnt2 treatment, siRNA knockdown, carotid ligation model, beta-catenin reporter assay Arteriosclerosis, Thrombosis, and Vascular Biology High 27199447
2017 CAF-derived WNT2 activates canonical Wnt/beta-catenin signaling in APC/beta-catenin wild-type colon cancer cells (paracrine), and activates autocrine canonical Wnt signaling in fibroblasts via FZD8 receptor, promoting a pro-migratory and pro-invasive fibroblast phenotype; WNT2-mediated fibroblast motility and ECM remodeling enhance cancer cell invasion. 7TGP canonical Wnt reporter, siRNA knockdown in CAFs, organotypic raft cultures, xenograft mouse model, FZD8 identification Oncogene High 28553956
2018 TBX5 directly drives Wnt2 and Wnt2b expression in cardiopulmonary mesoderm; TBX5 ChIP-sequencing identified cis-regulatory elements at Wnt2 sufficient for endogenous Wnt2 expression in vivo; Tbx5 cooperates with Shh signaling to drive Wnt2b expression; Tbx5 haploinsufficiency decreases mesodermal-to-endodermal Wnt signaling required for pulmonary specification and cardiac septation. TBX5 ChIP-seq, cis-regulatory element validation in vivo, Tbx5 conditional knockout, Shh epistasis PNAS High 30352852
2018 BPA exposure down-regulates WNT2 expression in placental trophoblasts via DNMT1-mediated DNA methylation of the WNT2 promoter; inhibition of DNMT in HTR-8/SVneo cells reduces WNT2 promoter methylation and restores WNT2 expression; reduced WNT2/beta-catenin signaling impairs trophoblast invasion and placental vessel remodeling. Mouse BPA exposure model, bisulfite sequencing/DNA methylation assay, DNMT inhibitor treatment, HTR-8/SVneo cell culture FASEB Journal Medium 30303745
2019 CAF-derived WNT2 promotes angiogenesis in colorectal cancer by enhancing endothelial cell migration/invasion and by shifting the secretome toward pro-angiogenic factors including ANG-2, IL-6, G-CSF, and PGF; WNT2 knockdown in CAFs reduces angiogenesis; WNT2 overexpression in xenografts increases vessel density and tumor volume. CAF siRNA knockdown, angiogenesis assay, secretome profiling (mass spectrometry and cytokine arrays), CRC xenograft model Angiogenesis High 31667643
2021 CAF-secreted WNT2 suppresses dendritic cell differentiation and DC-mediated antitumour T-cell responses via the SOCS3/p-JAK2/p-STAT3 signalling cascade; anti-WNT2 monoclonal antibody restores DC-mediated immunity and enhances anti-PD-1 efficacy in mouse tumour models. shRNA knockdown, anti-WNT2 monoclonal antibody, RNA-sequencing, western blot for SOCS3/JAK2/STAT3, syngeneic mouse tumour models Gut High 33692094
2021 Elevated Wnt2 activates beta-catenin/NF-κB signaling to promote cardiac fibrosis via cooperation of Fzd4 and LRP6 co-receptors in cardiac fibroblasts; Wnt2 upregulates Fzd2, Fzd4, and LRP6 expression; Wnt2 knockdown attenuates myocardial remodeling and cardiac dysfunction after experimental MI. Wnt2/Wnt4 knockdown in MI mouse model, NF-κB and beta-catenin western blot, receptor expression analysis, ELISA in patients EBioMedicine Medium 34911029
2022 Endothelial cell-specific Wnt2 and Wnt9b (zone 3) control liver metabolic zonation via beta-catenin signaling; EC-specific knockout of both Wnt2 and Wnt9b abolishes zone 3 beta-catenin target genes and re-expresses zone 1 genes in zone 3; impaired liver regeneration in knockouts phenocopies defective hepatic Wnt signaling; a tetravalent Wnt agonist antibody rescues zonation and regeneration. Single-cell spatial transcriptomics, EC-specific conditional knockout, Wnt agonist antibody treatment, acetaminophen liver failure model Cell Reports Medicine High 36220068
2023 WNT2 signals through FZD8/beta-catenin to transcriptionally upregulate SOX4, which in turn acts as a transcription factor to positively regulate WNT2 expression, forming an auto-regulatory positive feedback loop that maintains gastric cancer stem cell self-renewal and chemoresistance; anti-WNT2 monoclonal antibody disrupts this loop and enhances chemotherapy efficacy in xenograft models. WNT2 overexpression/knockdown, FZD8/beta-catenin reporter assays, ChIP for SOX4 at WNT2 promoter, anti-WNT2 mAb treatment, GCSC xenograft model Oncogene High 37634009
2024 Piezo1 mechanosensitive ion channel acts through the Wnt2/Wnt11 pathway to drive secretion of CCL24 (eotaxin-2) in dermal fibroblasts, promoting skin fibrosis; Piezo1 knockdown by AAV reduces skin fibrosis and stiffness in mice, establishing a Piezo1–Wnt2/Wnt11–CCL24 positive feedback loop in fibrosis. Piezo1 knockdown (AAV), fibroblast stiffness substrate assays, CCL24 secretion measurement, mouse skin fibrosis model Cell Death & Disease Medium 38267432
2011 Wnt2 accelerates cardiomyocyte differentiation from ES-cell-derived mesodermal cells through a non-canonical Wnt pathway using JNK/AP-1 signaling (not canonical beta-catenin); Wnt2 knockdown reduces cardiomyocyte differentiation efficiency and exogenous Wnt2 increases it in a temporally restricted manner. ES cell differentiation, Wnt2 siRNA knockdown, exogenous Wnt2 addition, JNK/AP-1 pathway inhibitor assays, canonical pathway reporter assay Journal of Molecular and Cellular Cardiology Medium 22146296

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 546 18489257
2004 Iron metabolism and the IRE/IRP regulatory system: an update. Annals of the New York Academy of Sciences 408 15105251
2006 Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2. Neuron 383 16772171
2009 Wnt2/2b and beta-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut. Developmental cell 353 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 282 25120486
2019 Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer. Angiogenesis 245 31667643
2008 Downregulation of Wnt2 and beta-catenin by siRNA suppresses malignant glioma cell growth. Cancer gene therapy 190 18949017
2017 Iron regulatory protein (IRP)-iron responsive element (IRE) signaling pathway in human neurodegenerative diseases. Molecular neurodegeneration 181 29061112
2021 Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity. Gut 161 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
2001 Differential regulation of WNT2 and WNT2B expression in human cancer. International journal of molecular medicine 114 11712082
2017 Autocrine WNT2 signaling in fibroblasts promotes colorectal cancer progression. Oncogene 113 28553956
2021 CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles. Blood 111 34265052
2011 Wnt2 secreted by tumour fibroblasts promotes tumour progression in oesophageal cancer by activation of the Wnt/β-catenin signalling pathway. Gut 109 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 100 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
2008 Stat5 regulates cellular iron uptake of erythroid cells via IRP-2 and TfR-1. Blood 84 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
2022 Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b. Cell reports. Medicine 79 36220068
2002 No association between the WNT2 gene and autistic disorder. American journal of medical genetics 79 11840514
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