Affinage

WWC3

Protein WWC3 · UniProt Q9ULE0

Length
1216 aa
Mass
136.6 kDa
Annotated
2026-06-11
9 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WWC3 is a scaffolding protein that functions as a tumor suppressor by linking the Hippo and Wnt signaling pathways (PMID:28543074, PMID:29780251). Through its WW domain, WWC3 binds LATS1 to promote LATS1 and YAP phosphorylation, retaining YAP in the cytoplasm and thereby restraining cell proliferation, invasion, and epithelial-mesenchymal transition in lung cancer cells and vascular smooth muscle cells (PMID:29780251, PMID:29393412). In parallel, WWC3 suppresses Wnt/β-catenin signaling: via its WW and C-terminal PDZ-binding domains it engages Dishevelled proteins, preventing casein kinase 1ε from phosphorylating Dvl and blocking β-catenin nuclear translocation, and it additionally binds the β-catenin partner TCF4 to inhibit β-catenin-driven transcription (PMID:28543074, PMID:29115863). The same domains that drive Hippo activation are points of competition, integrating these pathways: Dvl binding to WWC3 reduces the WWC3-LATS1 interaction (PMID:28543074), WBP2 competitively occupies the WW domain through its PPxY motifs to displace LATS1 and activate YAP (PMID:33837178), and FRMPD1 binds the C-terminal PDZ-binding motif to strengthen LATS1 phosphorylation and Hippo output (PMID:31114375). WWC3 expression is itself controlled post-transcriptionally by microRNAs including miR-10b-5p and miR-4504, whose suppression of WWC3 inactivates Hippo signaling (PMID:32892482, PMID:35494512).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2017 High

    Established WWC3 as a dual-pathway scaffold that simultaneously suppresses Wnt and modulates Hippo signaling, defining its core mechanism as a competitive partner exchange between Dvl and LATS1.

    Evidence Co-immunoprecipitation, ΔWW and ΔPDZ-binding domain deletion mutants, and in vitro/in vivo functional assays

    PMID:28543074

    Open questions at the time
    • Stoichiometry and kinetics of the Dvl-versus-LATS1 binding competition not resolved
    • Direct demonstration that CK1ε exclusion is structural rather than steric not provided
  2. 2017 Medium

    Extended WWC3's Wnt suppression to a second mechanism by showing it binds TCF4 to block β-catenin transcriptional activity in glioma cells.

    Evidence Co-immunoprecipitation, immunoblotting, overexpression and knockdown assays in glioma cells

    PMID:29115863

    Open questions at the time
    • Single Co-IP without domain mapping of the TCF4 interaction
    • Relationship between TCF4-binding and Dvl-binding mechanisms not integrated
  3. 2018 High

    Confirmed the WW domain as the functional unit for LATS1 binding and YAP phosphorylation, tying WWC3-mediated Hippo activation directly to suppression of EMT in lung cancer.

    Evidence Co-immunoprecipitation, ΔWW mutant, shRNA knockdown, and invasion/wound-healing assays in lung cancer cells

    PMID:29780251

    Open questions at the time
    • Whether WWC3 directly enhances LATS1 catalytic activity or acts as a passive scaffold not distinguished
  4. 2018 Medium

    Demonstrated the WWC3-LATS1-YAP axis operates outside cancer in vascular smooth muscle cells, where WWC3 is downregulated by proliferative stimuli.

    Evidence Co-IP, WW domain deletion, siRNA knockdown, and overexpression in a rat balloon injury model with PDGF-BB stimulation

    PMID:29393412

    Open questions at the time
    • Upstream signal coupling PDGF-BB/injury to WWC3 repression not defined
    • Single lab
  5. 2019 Medium

    Identified FRMPD1 as a positive scaffolding partner that strengthens WWC3-driven Hippo activation through the C-terminal PDZ-binding motif.

    Evidence Co-IP, dual-luciferase assay, immunofluorescence, and in vitro/in vivo functional assays in lung cancer

    PMID:31114375

    Open questions at the time
    • Mechanism by which FRMPD1 enhances LATS1 phosphorylation (recruitment vs. stabilization) not resolved
  6. 2021 High

    Revealed WBP2 as a competitive antagonist that displaces LATS1 from the WWC3 WW domain, providing a switch for YAP activation and pro-tumorigenic signaling.

    Evidence Competitive Co-IP with PPxY-motif domain mapping, gain/loss-of-function, and xenograft validation in lung cancer

    PMID:33837178

    Open questions at the time
    • What governs the balance between WBP2 and LATS1 occupancy in vivo not established
  7. 2022 Medium

    Placed WWC3 under post-transcriptional control by microRNAs, showing miR-10b-5p and miR-4504 repress WWC3 to inactivate Hippo signaling, with lncRNA TSLNC8 acting as a sponge to relieve repression.

    Evidence Dual-luciferase reporter assays, qRT-PCR, immunoblotting, knockdown/overexpression, and xenograft models in glioma and colorectal carcinoma

    PMID:32892482 PMID:35494512

    Open questions at the time
    • Endogenous physiological contexts driving these miRNA programs not defined
    • Single lab per miRNA

Open questions

Synthesis pass · forward-looking unresolved questions
  • How WWC3 integrates competing inputs (Dvl, WBP2, FRMPD1) into a unified output and whether it directly stimulates LATS1 kinase activity versus acting purely as a scaffold remains unresolved.
  • No structural model of the WWC3-LATS1 or WWC3-Dvl complexes
  • No reconstituted biochemical assay distinguishing scaffolding from catalytic enhancement
  • No reported Mendelian disease linkage

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4
Partners
DVLFRMPD1LATS1TCF4WBP2

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 WWC3 interacts with Dishevelled (Dvl) proteins via its WW and C-terminal PDZ-binding domains, prevents casein kinase 1ε from phosphorylating Dvls, and inhibits β-catenin nuclear translocation to suppress the Wnt pathway. Simultaneously, WWC3 interaction with Dvls reduces WWC3-LATS1 interaction and decreases LATS1 phosphorylation, increasing YAP nuclear import and attenuating the Hippo pathway. Domain deletion experiments (ΔWW, ΔPDZ-binding) confirmed domain requirements. Co-immunoprecipitation, domain deletion mutagenesis, immunoblotting, in vitro and in vivo functional assays The Journal of pathology High 28543074
2017 WWC3 interacts with TCF4, a binding partner of β-catenin, and this interaction inhibits the transcriptional activation of β-catenin, thereby suppressing Wnt/β-catenin signaling and glioma cell proliferation. Co-immunoprecipitation, immunoblotting, overexpression and knockdown functional assays DNA and cell biology Medium 29115863
2018 WWC3 activates the Hippo pathway via its WW domain to promote LATS1 and YAP phosphorylation, thereby inhibiting EMT in lung cancer cells; deletion of the WW domain (WWC3-ΔWW) abrogates these effects. WWC3-LATS1 interaction was confirmed by co-immunoprecipitation. Co-immunoprecipitation, domain deletion mutagenesis (ΔWW), immunoblotting, shRNA knockdown, cell invasion/wound healing assays OncoTargets and therapy High 29780251
2018 WWC3 interacts with LATS1 via its WW domain to promote LATS1 phosphorylation and YAP phosphorylation, suppressing YAP nuclear translocation in vascular smooth muscle cells (VSMCs). Deletion of the WW domain abolishes this effect. WWC3 expression is suppressed in VSMCs following PDGF-BB stimulation or balloon injury, and knockdown of WWC3 reduces LATS1 and YAP phosphorylation. Co-immunoprecipitation, WW domain deletion mutagenesis, immunoblotting, siRNA knockdown, overexpression in rat balloon injury model Molecular medicine reports Medium 29393412
2021 WBP2 competitively binds to the WW domain of WWC3 via its PPxY motifs, displacing LATS1 from the WWC3-LATS1 complex, reducing LATS1 phosphorylation, and promoting YAP nuclear translocation to activate pro-tumorigenic signaling in lung cancer. Co-immunoprecipitation, domain competition assays, gain- and loss-of-function experiments, immunoblotting, in vivo xenograft Cell death & disease High 33837178
2019 FRMPD1 interacts with the C-terminal PDZ-binding motif of WWC3 via its PDZ domain, and this interaction promotes LATS1 phosphorylation and inhibits YAP nuclear translocation, thereby activating the Hippo pathway and suppressing lung cancer cell proliferation and invasion. Co-immunoprecipitation, immunoblotting, dual-luciferase assay, immunofluorescence, in vivo and in vitro functional assays Cancer management and research Medium 31114375
2020 miR-10b-5p suppresses WWC3 expression, and WWC3 levels regulate Hippo signaling activity in glioma cells. The lncRNA TSLNC8 sequesters miR-10b-5p, relieving suppression of WWC3 and activating the Hippo pathway. Luciferase reporter assay, qRT-PCR, immunoblotting, knockdown/overexpression, xenograft model Molecular oncology Medium 32892482
2022 WWC3 is a direct target of miR-4504; reduction of WWC3 by miR-4504 inactivates Hippo signaling by inhibiting LATS1 phosphorylation and promoting YAP activity in colorectal carcinoma cells. Dual-luciferase reporter assay, western blot, knockdown experiments, in vivo xenograft Journal of healthcare engineering Medium 35494512

Source papers

Stage 0 corpus · 9 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 WWC3 regulates the Wnt and Hippo pathways via Dishevelled proteins and large tumour suppressor 1, to suppress lung cancer invasion and metastasis. The Journal of pathology 67 28543074
2018 WWC3 inhibits epithelial-mesenchymal transition of lung cancer by activating Hippo-YAP signaling. OncoTargets and therapy 26 29780251
2017 WWC3 Inhibits Glioma Cell Proliferation Through Suppressing the Wnt/β-Catenin Signaling Pathway. DNA and cell biology 24 29115863
2021 WBP2 negatively regulates the Hippo pathway by competitively binding to WWC3 with LATS1 to promote non-small cell lung cancer progression. Cell death & disease 17 33837178
2020 Interaction of BACH2 with FUS promotes malignant progression of glioma cells via the TSLNC8-miR-10b-5p-WWC3 pathway. Molecular oncology 15 32892482
2019 FRMPD1 activates the Hippo pathway via interaction with WWC3 to suppress the proliferation and invasiveness of lung cancer cells. Cancer management and research 14 31114375
2021 Circ_WWC3 overexpression decelerates the progression of osteosarcoma by regulating miR-421/PDE7B axis. Open life sciences 7 33817314
2018 WWC3 inhibits intimal proliferation following vascular injury via the Hippo signaling pathway. Molecular medicine reports 6 29393412
2022 Antitumor Activity of lncRNA NBAT-1 via Inhibition of miR-4504 to Target to WWC3 in Oxaliplatin-Resistant Colorectal Carcinoma. Journal of healthcare engineering 5 35494512

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