Affinage

FZD2

Frizzled-2 · UniProt Q14332

Length
565 aa
Mass
63.6 kDa
Annotated
2026-04-28
24 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FZD2 is a Frizzled-family seven-transmembrane Wnt receptor that integrates canonical Wnt/β-catenin and multiple noncanonical signaling branches to control cell fate, tissue morphogenesis, and homeostasis across diverse developmental and adult contexts. In canonical mode, FZD2 activates β-catenin with sustained kinetics that favor paraxial mesoderm specification over lateral mesoderm, requires Dishevelled interaction and cooperation with co-receptors such as ROR2/LRP, and drives endothelial proliferation and lung vascular development; in noncanonical mode it transduces WNT5A/PCP signals that orient chondrocytes during digit elongation, activates FYN/STAT3 to promote epithelial–mesenchymal transition and metastasis, and engages PI3K–AKT to maintain alveolar fibroblast identity and prevent fibrotic transition (PMID:18215320, PMID:36867021, PMID:39824186, PMID:41257888, PMID:34450691). FZD2 surface availability is controlled by ER scramblases VMP1/TMEM41B, which are required for its maturation and trafficking, while WNT2 ligand stabilizes FZD2 post-translationally by attenuating its ubiquitination, and the methyl-CpG-binding protein MBD2 epigenetically promotes FZD2 transcription (PMID:39968886, PMID:32766155, PMID:40081619). Pathogenic missense mutations in FZD2 cause Robinow syndrome through dominant-negative disruption of both canonical and noncanonical Wnt branches, with at least one variant (P142K) selectively abolishing WNT5A-dependent noncanonical signaling (PMID:38967226, PMID:36867021).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2008 Medium

    The question of whether FZD2 participates in canonical Wnt signaling and how co-receptors modulate it was addressed by showing that ROR2 cooperates with FZD2 (but not FZD7) to potentiate Wnt3a-induced canonical signaling in an LRP-dependent manner.

    Evidence Co-transfection and STF reporter assays with domain deletion mutants and Dkk1/Krm1 inhibitors in H441 lung carcinoma cells

    PMID:18215320

    Open questions at the time
    • No in vivo validation of the ROR2–FZD2 cooperative mechanism
    • Downstream pathway components beyond β-catenin not mapped
    • Specificity of CRD interaction not structurally resolved
  2. 2014 Medium

    The identification of a noncanonical FZD2 signaling axis was advanced by demonstrating that WNT5A/FZD2 activates FYN kinase and STAT3 to drive EMT and metastasis, establishing FZD2 as a mediator of tumor invasion distinct from canonical β-catenin signaling.

    Evidence Functional cell-based assays and pathway analysis in cancer cells

    PMID:34450691

    Open questions at the time
    • Detailed upstream mechanism linking FZD2 to FYN activation unresolved
    • Independence from canonical pathway not fully dissected
  3. 2020 Medium

    The range of noncanonical effectors downstream of FZD2 was broadened by showing it binds WNT5A/B and WNT3 to activate IL-6/STAT3, YAP1, and TGF-β1/SMAD3, and that WNT2 stabilizes FZD2 protein by reducing its ubiquitination, providing the first evidence of ligand-dependent post-translational regulation of FZD2.

    Evidence Co-IP for ligand binding, ubiquitination/phosphorylation assays, mammosphere formation, xenograft models in breast and esophageal cancer cells

    PMID:31907106 PMID:32766155

    Open questions at the time
    • E3 ligase responsible for FZD2 ubiquitination not identified
    • Relative contributions of individual Wnt ligands to each downstream branch unclear
    • Mechanistic link from FZD2 to YAP1 activation not delineated
  4. 2021 Medium

    The connection between FZD2 and Notch signaling was established by showing that FZD2 knockdown inactivates Notch and suppresses TGF-β1-induced EMT in breast cancer, adding Notch as another downstream effector.

    Evidence siRNA knockdown, western blot for EMT/Notch markers, xenograft

    PMID:33832493

    Open questions at the time
    • Direct versus indirect link between FZD2 and Notch pathway components unresolved
    • Mechanism of Notch activation by FZD2 unknown
  5. 2022 Medium

    The WNT5A/FZD2 noncanonical axis was shown to drive enzalutamide resistance in prostate cancer by maintaining constitutive AR signaling, extending FZD2's role to therapy resistance.

    Evidence siRNA knockdown, BERA-WNT5A construct, xenograft, AR reporter assays in prostate cancer cells

    PMID:35930737

    Open questions at the time
    • Intermediary signaling steps between FZD2 and AR activation not identified
    • Whether FZD2 directly complexes with AR pathway components unknown
  6. 2023 High

    A long-standing question about how FZD2 coordinates both canonical and noncanonical limb development was resolved by a CRISPR knock-in mouse carrying a Dishevelled-interacting-domain frameshift, which disrupted β-catenin-dependent proliferation and WNT5A/PCP-dependent chondrocyte polarity, recapitulating Robinow syndrome/OMOD2.

    Evidence CRISPR/Cas9 knock-in mouse (Fzd2em1Smill), β-catenin reporter, PCP readouts, skeletal phenotyping

    PMID:36867021

    Open questions at the time
    • Whether other Frizzled receptors partially compensate in vivo not tested
    • Signaling intermediates between FZD2 and PCP effectors in chondrocytes not mapped
  7. 2024 High

    Variant-specific pathogenicity of FZD2 was established: the P142K Robinow-associated mutation selectively ablates noncanonical WNT5A responsiveness while both P142K and G434V act as dominant negatives on canonical signaling, providing the first evidence that a single amino-acid change in a Frizzled receptor can selectively alter ligand-binding specificity.

    Evidence Retroviral overexpression in chicken frontonasal mass, SOX9 and Wnt reporter assays, β-catenin nuclear localization

    PMID:38967226

    Open questions at the time
    • Structural basis for selective WNT5A binding loss not determined
    • Whether P142K affects binding of other noncanonical Wnt ligands untested
  8. 2024 Medium

    FZD2 was placed upstream of YAP in adult cardiomyocytes, where its deletion causes cardiomegaly and cell-cycle re-entry through a mechanism independent of both canonical β-catenin transcription and LATS-mediated Hippo signaling, revealing a novel non-canonical route to YAP suppression.

    Evidence (preprint) Conditional Fzd2 knockout in adult mouse cardiomyocytes, YAP/LATS epistasis experiments, MI injury model

    PMID:bio_10.1101_2024.07.26.605158

    Open questions at the time
    • Preprint; not yet peer-reviewed
    • Molecular intermediary between FZD2 and YAP unknown
    • Whether this mechanism operates in non-cardiac tissues untested
  9. 2025 Medium

    Receptor-selective agonism revealed that FZD2 activates β-catenin with sustained kinetics distinct from FZD7, promoting paraxial mesoderm while suppressing lateral mesoderm, demonstrating non-redundant roles among Frizzled family members in human stem cell fate decisions.

    Evidence Selective antibody agonists against FZD2 and FZD7, hPSC directed differentiation, β-catenin signaling kinetics, flow cytometry

    PMID:39824186

    Open questions at the time
    • Mechanism generating sustained versus transient β-catenin kinetics through FZD2 versus FZD7 unresolved
    • Whether kinetic difference depends on co-receptors unknown
  10. 2025 High

    The cell-type-specific duality of FZD2 signaling was resolved in the lung: FZD2 drives canonical β-catenin in endothelial cells and noncanonical/PI3K-AKT in mesenchymal cells, where it maintains fibroblast identity and prevents fibrotic transition, and its transcription is epigenetically regulated by MBD2.

    Evidence Cell-type-specific conditional knockouts, bleomycin injury model, scRNA-seq, PI3K-AKT analysis; MBD2 ChIP-seq/knockout in alveolar epithelial cells

    PMID:39968886 PMID:40081619 PMID:41257888

    Open questions at the time
    • How cell-type context switches FZD2 between canonical and noncanonical modes mechanistically unknown
    • Whether PI3K-AKT engagement is direct or requires adaptor proteins not determined
    • MBD2 regulation of FZD2 shown only in lung epithelium; generalizability untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) the structural basis for FZD2's selective ligand recognition and how single mutations alter it, (2) the molecular mechanism by which cellular context dictates canonical versus noncanonical output, and (3) the identity of the intermediary that connects FZD2 to YAP suppression independently of LATS and β-catenin.
  • No crystal or cryo-EM structure of FZD2 in complex with any Wnt ligand
  • Context-dependent pathway switching mechanism undefined
  • FZD2-to-YAP intermediary unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3
Partners
FYNMBD2ROR2TMEM41BVMP1WNT2WNT3WNT5A

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Ror2 positively modulates Wnt3a-activated canonical Wnt signaling in lung carcinoma cells through cooperative interaction with Fzd2 (but not Fzd7); this requires the extracellular CRD of Ror2 and is Lrp-dependent (inhibited by Dkk1/Krm1). Co-transfection, reporter assay (STF), domain deletion mutants, inhibitor treatment in H441 cells BMC molecular biology Medium 18215320
2014 FZD2 and WNT5A drive epithelial-to-mesenchymal transition (EMT) and metastasis via a noncanonical signaling pathway involving FYN kinase and STAT3. Functional cell-based assays, pathway analysis (reported in Cancer Discovery summary) Cancer discovery Medium 34450691
2020 FZD2 modulates noncanonical Wnt signaling by binding Wnt5a/b and Wnt3 ligands to activate oncogenic IL-6/STAT3, YAP1, and TGF-β1/Smad3 pathways, promoting breast cancer cell mesenchymal stemness and drug resistance. FZD2 knockdown/overexpression, co-immunoprecipitation (binding with Wnt ligands), mammosphere formation, pathway reporter assays Oncology research Medium 31907106
2020 WNT2 ligand stabilizes and phosphorylates the FZD2 receptor by attenuating FZD2 ubiquitination, leading to activation of STAT3 signaling and promotion of esophageal cancer cell metastasis. Co-immunoprecipitation, ubiquitination assay, phosphorylation assay, knockdown/overexpression with migration/invasion readouts, in vivo xenograft Frontiers in oncology Medium 32766155
2021 FZD2 promotes TGF-β1-induced EMT in breast cancer cells through activation of the Notch signaling pathway; FZD2 knockdown leads to Notch inactivation and suppression of EMT markers. siRNA knockdown, western blot for EMT and Notch pathway markers, in vivo xenograft, immunofluorescence Cancer cell international Medium 33832493
2022 Wnt5a/FZD2-mediated noncanonical Wnt pathway activation drives enzalutamide resistance in prostate cancer; blocking this pathway suppresses constitutively activated androgen receptor (AR) and AR variants. siRNA knockdown, BERA-Wnt5a siRNA construct, in vivo tumor xenograft, AR pathway reporter assays Molecular cancer therapeutics Medium 35930737
2023 FZD2 controls limb development by mediating both canonical Wnt/β-catenin signaling (required for limb mesenchyme proliferation) and noncanonical WNT5A/planar cell polarity (PCP) signaling (required for digit chondrocyte elongation and orientation); frameshift mutation in the Dishevelled-interacting domain causes shortened limbs resembling Robinow syndrome/OMOD2. CRISPR/Cas9 knock-in mouse model (Fzd2em1Smill), conditional FZD function disruption in limb mesenchyme, β-catenin reporter assay, PCP pathway readouts, skeletal analysis Disease models & mechanisms High 36867021
2024 Two pathogenic FZD2 missense variants (G434V; P142K) associated with Robinow syndrome inhibit chondrogenesis, increase nuclear β-catenin shuttling and TWIST1 expression; the P142K variant selectively fails to activate non-canonical Wnt signaling and is unresponsive to WNT5A, representing the first single amino-acid change shown to selectively alter ligand binding in a FZD receptor. Both variants act as dominant negatives on wild-type FZD2 in canonical Wnt reporter assays. Retroviral overexpression in chicken embryo frontonasal mass, primary cell cultures, SOX9 and canonical/non-canonical Wnt luciferase reporters, β-catenin nuclear localization assay Disease models & mechanisms High 38967226
2024 FZD2 suppresses YAP activity and prevents adult cardiomyocytes from re-entering the cell cycle through a mechanism independent of canonical Wnt/β-catenin transcription and LATS1/2-mediated Hippo signaling; FZD2 deletion leads to cardiomegaly with increased proliferation markers and upregulation of YAP target genes Mycl and Bcl2l1. Conditional knockout (Fzd2 CKO) in adult mouse cardiomyocytes, YAP knockdown/overexpression epistasis, β-catenin knockdown, LATS-site YAP mutant, neonatal ventricular CM gain/loss-of-function, MI model bioRxivpreprint Medium bio_10.1101_2024.07.26.605158
2025 FZD2 activation by selective antibody-based agonists triggers β-catenin signaling with sustained kinetics that promotes paraxial mesoderm differentiation while blocking lateral mesoderm in human pluripotent stem cells, revealing a non-redundant role distinct from FZD7. Selective FZD2 and FZD7 antibody agonists, directed differentiation of hPSCs, β-catenin signaling kinetics assay, flow cytometry for mesoderm markers Stem cell reports Medium 39824186
2025 ER-resident scramblases VMP1 and TMEM41B are required for proper maturation, stability, and secretion/trafficking of FZD2, which is essential for WNT signaling during primitive endoderm specification in mouse embryonic stem cells. Vmp1/Tmem41b CRISPR knockout in mouse ESCs, differentiation assays, western blot for FZD2 protein stability, WNT signaling readouts Autophagy Medium 39968886
2025 Fzd2 mediates canonical Wnt/β-catenin signaling in lung endothelial cells (required for endothelial proliferation and vascular development) and non-canonical Wnt signaling in mesenchymal cells (required for proliferation and survival); additionally, Fzd2 in mesenchymal cells mediates PI3K-AKT signaling to maintain alveolar fibroblast 1 (AF1) identity and prevent fibrotic AF2 transition. Conditional knockout mouse models (cell type-specific Fzd2 deletion), bleomycin injury model, single-cell RNA-seq, β-catenin reporter assay, PI3K-AKT pathway analysis Cell communication and signaling High 41257888
2025 MBD2 promotes EMT and pulmonary fibrosis by modulating FZD2 expression; MBD2 binds the FZD2 locus (identified by ChIP-seq) and MBD2 knockout reduces FZD2 levels and alleviates TGF-β-induced EMT in alveolar epithelial cells. MBD2 knockout mice, RNA-seq, ChIP assay, TGF-β-induced EMT model in MLE-12 cells, western blot for EMT markers Biochimica et biophysica acta. Molecular basis of disease Medium 40081619

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Ror2 modulates the canonical Wnt signaling in lung epithelial cells through cooperation with Fzd2. BMC molecular biology 79 18215320
2013 Expression of Wnt5a and its receptor Fzd2 is changed in the spinal cord of adult amyotrophic lateral sclerosis transgenic mice. International journal of clinical and experimental pathology 35 23826406
2020 Fzd2 Contributes to Breast Cancer Cell Mesenchymal-Like Stemness and Drug Resistance. Oncology research 26 31907106
2019 FZD2 regulates cell proliferation and invasion in tongue squamous cell carcinoma. International journal of biological sciences 25 31595151
2013 Immunoreactivity of Wnt5a, Fzd2, Fzd6, and Ryk in glioblastoma: evaluative methodology for DAB chromogenic immunostaining. Brain tumor pathology 22 23748645
2022 Bioengineered BERA-Wnt5a siRNA Targeting Wnt5a/FZD2 Signaling Suppresses Advanced Prostate Cancer Tumor Growth and Enhances Enzalutamide Treatment. Molecular cancer therapeutics 21 35930737
2020 WNT2-Mediated FZD2 Stabilization Regulates Esophageal Cancer Metastasis via STAT3 Signaling. Frontiers in oncology 20 32766155
2018 Nonsense mutations in FZD2 cause autosomal-dominant omodysplasia: Robinow syndrome-like phenotypes. American journal of medical genetics. Part A 20 29383834
2015 FZD2 inhibits the cell growth and migration of salivary adenoid cystic carcinomas. Oncology reports 17 25695658
2021 FZD2 promotes TGF-β-induced epithelial-to-mesenchymal transition in breast cancer via activating notch signaling pathway. Cancer cell international 15 33832493
2019 Casiopeina II‑gly acts on lncRNA MALAT1 by miR‑17‑5p to inhibit FZD2 expression via the Wnt signaling pathway during the treatment of cervical carcinoma. Oncology reports 14 31524268
2017 A Novel de novo FZD2 Mutation in a Patient with Autosomal Dominant Omodysplasia. Molecular syndromology 12 29230162
2024 Total Flavonoids of Aurantii Fructus Immaturus Regulate miR-5100 to Improve Constipation by Targeting Fzd2 to Alleviate Calcium Balance and Autophagy in Interstitial Cells of Cajal. Molecular neurobiology 8 38244148
2023 FZD2 regulates limb development by mediating β-catenin-dependent and -independent Wnt signaling pathways. Disease models & mechanisms 7 36867021
2024 Interference of FZD2 suppresses proliferation, vasculogenic mimicry and stemness in glioma cells via blocking the Notch/NF‑κB signaling pathway. Experimental and therapeutic medicine 4 39091630
2025 MBD2 promotes epithelial-to-mesenchymal transition (EMT) and ARDS-related pulmonary fibrosis by modulating FZD2. Biochimica et biophysica acta. Molecular basis of disease 3 40081619
2014 Noncanonical FZD2 Signaling Induces EMT and Tumor Progression. Cancer discovery 3 34450691
2025 Selective activation of FZD2 and FZD7 reveals non-redundant function during mesoderm differentiation. Stem cell reports 2 39824186
2024 Craniofacial studies in chicken embryos confirm the pathogenicity of human FZD2 variants associated with Robinow syndrome. Disease models & mechanisms 2 38967226
2025 Bioinspired nanoparticles prevent blue-light-induced skin hyperpigmentation via FZD2-TYR-melanin pathway. Materials today. Bio 1 40978162
2025 Scrambling stem cell development: VMP1 and TMEM41B regulate FZD2/FRIZZLED2 secretion during primitive endoderm specification. Autophagy 0 39968886
2025 [Omodysplasia Type II - first publication of de novo Mutation in FZD2 Gene]. Zeitschrift fur Geburtshilfe und Neonatologie 0 41022130
2025 Fzd2 orchestrates canonical and non-canonical Wnt signaling to regulate lung development and fibrosis. Cell communication and signaling : CCS 0 41257888
2017 [Relationship between Wound Age and the Expression of Fzd2 in Rats Skeletal Muscle after Contusion]. Fa yi xue za zhi 0 29219261