{"gene":"WWOX","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2004,"finding":"WWOX physically interacts via its first WW domain with the p53 homolog p73; Src kinase phosphorylates WWOX at tyrosine 33 in the first WW domain and enhances this binding. WWOX expression redistributes nuclear p73 to the cytoplasm, suppressing its transcriptional activity, and cytoplasmic p73 contributes to WWOX proapoptotic activity.","method":"Co-immunoprecipitation, WW domain mutagenesis, subcellular fractionation/localization assays, transfection-based transcriptional reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mutagenesis and functional reporter assays, single lab but multiple orthogonal methods","pmids":["15070730"],"is_preprint":false},{"year":2004,"finding":"WWOX physically interacts with AP-2gamma transcription factor via its first WW domain binding the PPPY motif of AP-2gamma. Mutation of tyrosine 33 in the first WW domain of WWOX or the PPPY motif in AP-2gamma dramatically reduces interaction. WWOX expression triggers redistribution of nuclear AP-2gamma to the cytoplasm, suppressing its transactivating function.","method":"Co-immunoprecipitation, site-directed mutagenesis, subcellular localization assays, transcriptional reporter assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with mutagenesis and functional reporter assays, single lab but multiple orthogonal methods","pmids":["15548692"],"is_preprint":false},{"year":2003,"finding":"JNK1 physically interacts with WWOX (WOX1) when WWOX is phosphorylated at Tyr33. Activated JNK1 inhibits WWOX-mediated apoptosis. Mutation of Tyr33 to Arg33 abrogates WWOX binding to JNK1 and abolishes WWOX apoptotic activity, indicating Tyr33 phosphorylation is required both for JNK1 binding and for WWOX-mediated cell death.","method":"Co-immunoprecipitation, yeast two-hybrid analysis, site-directed mutagenesis, apoptosis assays (multiple cell lines)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP plus yeast two-hybrid plus mutagenesis plus functional cell death assays, single lab but multiple orthogonal methods","pmids":["12514174"],"is_preprint":false},{"year":2005,"finding":"WWOX (WOX1) Tyr33-phosphorylated form physically interacts with Ser46-phosphorylated p53. This interaction stabilizes p53 protein and is essential for apoptosis induced by UV, anisomycin, etoposide, and TNF. siRNA knockdown of WOX1 abolishes p53 protein accumulation (but not p53 mRNA) after UV, and dominant-negative WOX1 (blocking Tyr33 phosphorylation) also blocks UV-induced p53 expression. MDM2 inhibition by nutlin-3 increases WOX1–p53 binding and p53 stability.","method":"Co-immunoprecipitation, yeast two-hybrid domain mapping, siRNA knockdown, dominant-negative overexpression, time-course protein stability assay, nutlin-3 pharmacological inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, Y2H, siRNA, DN mutant, pharmacological) in single lab","pmids":["16219768"],"is_preprint":false},{"year":2003,"finding":"WWOX (WOX1) undergoes Tyr33 phosphorylation at its first WW domain in response to stress/apoptotic stimuli, enabling complex formation with activated p53 and JNK1. The p53/WOX1 complex translocates to the mitochondria and then to the nucleus to mediate apoptosis. WOX1 mutants inactivated for nuclear translocation or Tyr33 phosphorylation fail to induce apoptosis.","method":"Phosphorylation assays, co-immunoprecipitation, subcellular fractionation, dominant-negative mutagenesis, apoptosis assays","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple methods (Co-IP, fractionation, DN mutant) but single lab and partially overlapping with other publications from same group","pmids":["14555208"],"is_preprint":false},{"year":2005,"finding":"17beta-estradiol activates WWOX (WOX1) via Tyr33 phosphorylation and promotes nuclear translocation of p53/WOX1 complex independently of estrogen receptor and androgen receptor status.","method":"Western blotting for Tyr33 phosphorylation, co-immunoprecipitation, subcellular fractionation, immunohistochemistry in multiple cell lines and in vivo tissues","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, biochemical and cell biology methods without mutagenesis confirmation of ER/AR independence beyond pharmacological context","pmids":["15580310"],"is_preprint":false},{"year":2006,"finding":"PKA-mediated phosphorylation of ezrin at Ser66 regulates interaction between ezrin and WWOX. Ezrin directly binds the first WW domain of WWOX via its C-terminal polyproline sequence (470PPPPPPVY477), with Tyr477 essential for the interaction. PKA-mediated ezrin phosphorylation is necessary and sufficient for apical localization of WWOX protein; disruption of the ezrin-WWOX interaction eliminates apical WWOX localization and impairs H,K-ATPase recruitment.","method":"Biochemical binding assays, site-directed mutagenesis, co-immunoprecipitation, subcellular localization by microscopy","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct binding with mutagenesis and localization consequences, single lab single study","pmids":["16438931"],"is_preprint":false},{"year":2009,"finding":"WWOX physically associates with Dishevelled (Dvl) family proteins (identified by yeast two-hybrid and co-immunoprecipitation). WWOX expression inhibits Wnt/beta-catenin transcriptional activity, while WWOX knockdown stimulates it and enhances Wnt-3a-induced beta-catenin stability. WWOX sequesters Dvl-2 (including a nuclear-localized Dvl-2 mutant) in the cytoplasm, preventing nuclear import of Dvl proteins.","method":"Yeast two-hybrid, co-immunoprecipitation, TCF/LEF reporter assays, beta-catenin stability assay, subcellular localization","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Y2H plus Co-IP plus functional reporter assays plus localization, single lab but multiple orthogonal methods","pmids":["19465938"],"is_preprint":false},{"year":2009,"finding":"TGF-beta1 binds cell-surface hyaluronidase Hyal-2 on microvilli (in TGF-beta receptor II-deficient cells), resulting in recruitment of WWOX (WOX1) and formation of Hyal-2/WWOX complexes that relocate to the nucleus. TGF-beta1 strengthens binding of the catalytic domain of Hyal-2 with the Tyr33-phosphorylated WW domain of WWOX. WOX1 and Hyal-2 together dramatically enhance Smad-driven promoter activation (8-9-fold), leading to cell death.","method":"Immunoelectron microscopy, FRET in live cells, co-immunoprecipitation, yeast two-hybrid domain mapping, Smad promoter reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — immunoelectron microscopy, live-cell FRET, Co-IP, Y2H domain mapping, and functional reporter assays in single study with multiple orthogonal methods","pmids":["19366691"],"is_preprint":false},{"year":2009,"finding":"Complement C1q activates WWOX (WOX1) via Tyr33 phosphorylation in prostate cancer cells. Exogenous C1q significantly induces apoptosis of WWOX-overexpressing DU145 cells but not control cells; dominant-negative and Y33R mutant WWOX blocks this apoptotic effect. WWOX activation by C1q destabilizes cell adhesion, causing formation of clustered microvilli, cell shrinkage, membrane blebbing, and death.","method":"Exogenous protein treatment, dominant-negative and point-mutant constructs, TIRF microscopy, apoptosis assays, immunostaining","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple methods (TIRF, mutant constructs, apoptosis assays) but single lab, single study","pmids":["19484134"],"is_preprint":false},{"year":2013,"finding":"WWOX physically interacts with SMAD3 via WW domain 1, as shown by co-immunoprecipitation and GST pull-down. WWOX expression dramatically decreases SMAD3 occupancy at ANGPTL4 and SERPINE1 promoters, quenches TGFβ-responsive reporter activation, and leads to redistribution of SMAD3 from the nuclear to the cytoplasmic compartment.","method":"Co-immunoprecipitation, GST pull-down, ChIP, transcriptional reporter assays, confocal microscopy for subcellular localization","journal":"BMC cancer","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP plus GST pull-down plus ChIP plus reporter plus localization, single lab but multiple orthogonal methods","pmids":["24330518"],"is_preprint":false},{"year":2014,"finding":"WWOX physically interacts with HIF1alpha via its first WW domain and modulates HIF1alpha protein levels and transactivation function. WWOX-deficient cells exhibit increased HIF1alpha levels and activity, increased glucose uptake, enhanced glycolysis, and diminished mitochondrial respiration (Warburg-like effect). WWOX-deficient cells show increased GLUT1 levels in vivo.","method":"Co-immunoprecipitation, WW domain mutagenesis, glucose uptake assays, metabolic flux assays, Wwox knockout cells and mouse models","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mutagenesis plus metabolic assays plus in vivo knockout model, single lab but multiple orthogonal methods","pmids":["25012504"],"is_preprint":false},{"year":2003,"finding":"WWOX normally resides in the Golgi apparatus; Golgi localization requires an intact SDR (short-chain dehydrogenase/reductase) domain. Aberrantly spliced WWOX isoforms lacking the SDR domain show abnormal intracellular localization to the nucleus and may act as dominant-negative inhibitors of full-length WWOX. The WW domain ligand is identified as the PPXY motif.","method":"Subcellular localization by immunofluorescence/fractionation, domain deletion constructs, analysis of aberrant splice forms","journal":"Cytogenetic and genome research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization experiment with domain deletion, single lab, limited mechanistic follow-up on dominant-negative claim","pmids":["14526170"],"is_preprint":false},{"year":2007,"finding":"WWOX interacts with AP-2gamma and prevents AP-2gamma from entering the nucleus to bind the ERBB2 promoter and activate ERBB2 transcription. Ectopic WWOX reduced ErbB2 protein expression in vitro. WWOX suppresses AP-2gamma/ErbB2-induced prostate cancer cell growth and PSA secretion, requiring functional androgen receptor.","method":"Co-immunoprecipitation, ChIP (AP-2gamma on ERBB2 promoter), Western blotting, cell growth and PSA assays","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ChIP with functional readout, single lab, single study","pmids":["17704139"],"is_preprint":false},{"year":2009,"finding":"Sciatic nerve transection in rats induces rapid JNK1 activation and WOX1 upregulation in DRG neurons; phospho-WOX1 physically interacts with phospho-CREB and phospho-c-Jun in nuclei (immunoelectron microscopy and FRET). WOX1 blocks prosurvival CREB-, CRE-, and AP-1-mediated promoter activation in vitro but enhances NF-kappaB promoter activation via its WW domains. WOX1 directly activates NF-kappaB-regulated promoter.","method":"FRET analysis in vivo, immunoelectron microscopy, co-immunoprecipitation, promoter reporter assays, in vivo nerve transection model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo FRET, immunoelectron microscopy, and reporter assays but single lab, single study","pmids":["19918364"],"is_preprint":false},{"year":2011,"finding":"WWOX (WOX1) physically interacts with MEK1 in lysosomes in Jurkat T cells. PMA induces dissociation of the WOX1/MEK1 complex, leading to MEK1 relocation to lipid rafts and WOX1 relocation to mitochondria for apoptosis. The MEK inhibitor U0126 inhibits PMA-induced dissociation and supports cell survival.","method":"Co-immunoprecipitation, subcellular fractionation, pharmacological inhibitors (U0126, PD98059), apoptosis assays in multiple leukemia cell lines","journal":"Genes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with subcellular localization and functional dissection, single lab, single study","pmids":["21901168"],"is_preprint":false},{"year":2013,"finding":"WWOX physically interacts with mTOR, and this interaction potentiates MTX-induced mTOR phosphorylation and its downstream substrate p70 S6 kinase, leading to downregulation of autophagy proteins (Beclin-1, Atg12-Atg5, LC3-II) and suppression of autophagosome formation. WWOX knockdown in SCC-15 cells blocks MTX-induced mTOR signaling and autophagy inhibition, causing chemotherapy resistance.","method":"Co-immunoprecipitation, Western blotting for autophagy markers, siRNA knockdown, apoptosis assays, autophagosome imaging","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with functional knockdown and mechanistic follow-up, single lab, single study","pmids":["24008736"],"is_preprint":false},{"year":2016,"finding":"WWOX interacts with BRCA1 and contributes to DNA double-strand break (DSB) repair pathway choice. WWOX-deficient cells exhibit enhanced homology-directed repair (HDR) and decreased non-homologous end-joining (NHEJ). WWOX expression suppresses DSB repair at the end-resection step of HDR. Silencing RAD51 (critical for HDR) resensitizes WWOX-deficient cells to radiation.","method":"Co-immunoprecipitation (Wwox-Brca1), immunofluorescence of DNA damage repair foci, HDR/NHEJ reporter assays, RAD51 siRNA epistasis, xenograft radiation resistance model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, repair reporter assays, epistasis, in vivo xenograft model, multiple orthogonal methods in single study","pmids":["27869163"],"is_preprint":false},{"year":2016,"finding":"WWOX modulates the ATR-mediated DNA single-strand break (SSB) checkpoint. WWOX accumulates in the nucleus after SSBs. WWOX is ubiquitinated at lysine 274 by the E3 ubiquitin ligase ITCH following SSBs. WWOX interacts with ATM, and ATM inhibition reduces ATR checkpoint activation, indicating WWOX modulates ATR signaling in an ATM-dependent manner. WWOX deficiency is associated with reduced ATR checkpoint activation and increased chromosomal breaks.","method":"Nuclear fractionation after SSB induction, ubiquitination assay with ITCH, co-immunoprecipitation (WWOX-ATM), pharmacological ATM inhibition, chromosomal break analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP plus ubiquitination assay plus pharmacological epistasis, single lab, single study","pmids":["26675548"],"is_preprint":false},{"year":2007,"finding":"Zfra (a 31-amino-acid zinc finger-like protein) binds WWOX (WOX1) and sequesters it in the cytoplasm, counteracting the apoptotic functions of Tyr33-phosphorylated WOX1 and Ser46-phosphorylated p53. Alteration of Ser8 in Zfra abolishes its regulation of WOX1 and p53. Interactions confirmed by GST pull-down, Co-IP, and yeast two-hybrid.","method":"GST pull-down, co-immunoprecipitation, yeast two-hybrid, subcellular localization assays, apoptosis assays","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple binding methods (GST, Co-IP, Y2H) with functional readout, single lab, single study","pmids":["17567906"],"is_preprint":false},{"year":2017,"finding":"Hyaluronan (HA) activates the Hyal-2/WWOX/Smad4 signaling complex: WWOX acts as a bridge binding both Hyal-2 and Smad4 (by yeast two-hybrid). High molecular weight HA stimulates rapid formation of endogenous Hyal-2/WWOX/Smad4 complex and nuclear relocation. Real-time tri-molecular FRET analysis confirms HA-induced signaling: Smad4→WWOX→p53 and Smad4→Hyal-2→WWOX. Overexpression of the complex causes bubbling cell death in WWOX-expressing cells; WWOX-deficient cells fail to translocate Smad2/3/4 to the nucleus.","method":"Yeast two-hybrid domain analysis, co-immunoprecipitation, tri-molecular FRET in live cells, nuclear fractionation, WWOX-deficient cell comparison, apoptosis assays","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — tri-molecular live-cell FRET, Y2H, Co-IP, functional rescue/deficiency experiments, multiple orthogonal methods single lab","pmids":["27845895"],"is_preprint":false},{"year":2018,"finding":"WWOX interacts with JAK2 to inhibit JAK2 and STAT3 phosphorylation in breast cancer cells. WWOX overexpression suppresses STAT3 activation, inhibits STAT3 binding to the IL-6 promoter, and represses IL-6 cytokine expression, thereby suppressing proliferation and metastasis of triple-negative breast cancer cells.","method":"Co-immunoprecipitation (WWOX-JAK2), STAT3 phosphorylation assays, ChIP (STAT3 at IL-6 promoter), cell proliferation and invasion assays, WWOX overexpression/knockdown","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with ChIP and functional assays, single lab, single study","pmids":["30154439"],"is_preprint":false},{"year":2017,"finding":"WWOX directly interacts with c-Jun in human alveolar epithelial cells; its absence results in increased nuclear translocation of c-Jun and increased c-Jun- and IL-8-dependent neutrophil chemotaxis. WWOX loss in mouse lungs causes neutrophil influx, vascular leak, and inflammatory cytokine production. JNK inhibition abrogates the neutrophil influx caused by WWOX knockdown.","method":"Co-immunoprecipitation (WWOX-c-Jun), siRNA knockdown in vitro, in vivo WWOX knockdown in mice, JNK pharmacological inhibition, neutrophil chemotaxis assays","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP plus in vivo knockdown plus pharmacological epistasis, single lab, single study","pmids":["28283473"],"is_preprint":false},{"year":2019,"finding":"WWOX is a negative regulator of c-MYC; WWOX loss leads to c-MYC activation, which regulates miR-146a expression, which in turn regulates fibronectin levels, contributing to EMT in TNBC. Anti-miR-146a rescues the WWOX antimetastatic phenotype; overexpression of MYC in WWOX-expressing cells overrides WWOX effects on miR-146a and fibronectin.","method":"WWOX overexpression/depletion, miRNA expression analysis, miR-146a inhibitor rescue, MYC overexpression epistasis, fibronectin Western blotting, invasion/metastasis assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional epistasis with rescue experiments, single lab, single study; no direct WWOX-MYC binding demonstrated","pmids":["30622118"],"is_preprint":false},{"year":2019,"finding":"WWOX physically interacts with AMPK (AMP-activated protein kinase) in skeletal muscle cells. WWOX somatic loss in skeletal muscle (WwoxΔSKM mice) results in impaired AMPK activation and significant HIF1alpha accumulation, associated with reduced mitochondrial quantity and activity, lower glucose oxidation, glucose intolerance, and insulin resistance.","method":"Co-immunoprecipitation (WWOX-AMPK), conditional knockout mouse model, metabolic phenotyping (glucose tolerance test, insulin tolerance test), mitochondrial assays","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with in vivo conditional KO metabolic phenotyping, single lab, single study","pmids":["30755385"],"is_preprint":false},{"year":2020,"finding":"WWOX neuronal deletion produces brain hyperexcitability, intractable epilepsy, reduced maturation of oligodendrocytes, reduced myelinated axons, and impaired axonal conductivity in mice. A significant decrease in transcript levels of myelination genes is observed. These phenotypes are recapitulated in human brain organoids with WWOX deletion, establishing a neuronal-specific role for WWOX in myelination and brain excitability.","method":"Neuron-specific conditional Wwox knockout mice, transcriptomic analysis, oligodendrocyte maturation assays, electrophysiology (transcranial motor evoked potentials), human brain organoids with WWOX deletion","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in mice plus human organoid validation with defined cellular phenotypes and transcriptomic mechanism","pmids":["33914858"],"is_preprint":false},{"year":2020,"finding":"Wwox gene ablation in mice causes a significantly increased activation of GSK3beta in cerebral cortex, hippocampus, and cerebellum, leading to spontaneous epilepsy. Inhibition of GSK3beta by lithium ion significantly abolishes PTZ-induced seizures in Wwox-/- mice, placing GSK3beta activation downstream of Wwox loss as a mechanism for epilepsy.","method":"Wwox knockout mice, GSK3beta phosphorylation assays, lithium treatment (pharmacological epistasis), seizure susceptibility assays","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pharmacological epistasis with knockout model, single lab, single study","pmids":["32000863"],"is_preprint":false},{"year":2016,"finding":"Wwox deletion in osteoblast progenitors (but not mature osteoblasts) causes severe inhibition of osteogenesis accompanied by p53 upregulation. Deletion of p53 in Wwox-null preosteoblasts (Wwox;p53Δosx1 double KO) rescues the osteogenic defect and results in accelerated development of osteosarcomas, establishing a WWOX-p53 epistatic network in bone formation.","method":"Conditional knockout mice (Wwox and p53 in osteoblast progenitors vs mature osteoblasts), genetic rescue (p53 deletion), histology, gene expression analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with conditional stage-specific knockouts and rescue experiment across multiple mouse models","pmids":["27550453"],"is_preprint":false},{"year":2011,"finding":"Bmi1 (polycomb group protein) suppresses WWOX expression in small-cell lung cancer cells, as demonstrated by chromatin immunoprecipitation showing Bmi1 occupancy at the WWOX locus. Bmi1 reduction by shRNA increases WWOX expression and induces apoptosis in SCLC cells.","method":"Chromatin immunoprecipitation (Bmi1 at WWOX locus), quantitative RT-PCR, shRNA knockdown of Bmi1, apoptosis assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP plus functional knockdown, single lab, single study","pmids":["21276135"],"is_preprint":false},{"year":2014,"finding":"In liver-specific Wwox knockout (WwoxΔHep) mice, ApoA-I and Abca1 levels are decreased. Total Wwox-/- mice show marked reductions in serum HDL cholesterol. Female WwoxΔHep mice display increased plasma triglycerides and altered lipid metabolic pathways, with significant reduction of ApoA-I and Lpl, and upregulation of Fas, Angptl4, and Lipg, suggesting WWOX modulates HDL cholesterol and lipid metabolism via multiple pathways including the ApoA-I/ABCA1 pathway and fatty acid biosynthesis.","method":"Liver-specific and total Wwox knockout mouse models, lipoprotein profiling, microarray gene expression analysis, Western blotting","journal":"Circulation. Cardiovascular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo conditional KO with molecular characterization, single lab, limited direct mechanistic detail on pathway","pmids":["24871327"],"is_preprint":false},{"year":2022,"finding":"WWOX physically interacts with SMAD3 and BMP2 (components of TGF-beta signaling pathway) in pancreatic cells. In the absence of WWOX, TGFbeta/BMP signaling is enhanced, leading to increased macrophage infiltration and enhanced cancer stemness. Combined conditional deletion of Wwox with KRasG12D activation in mice accelerates formation of pancreatic precursor lesions and carcinoma.","method":"Co-immunoprecipitation (WWOX-SMAD3 and WWOX-BMP2), conditional knockout/KRas activation mouse model, macrophage infiltration assays, stemness assays, WWOX overexpression in PDX models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with in vivo genetic model and functional assays, single lab, single study","pmids":["36572673"],"is_preprint":false},{"year":2015,"finding":"WWOX (in Drosophila melanogaster ortholog) modulates cellular outgrowths caused by genetic deficiencies in mitochondrial respiratory complex components. This modulation requires the enzyme active site (SDR domain) of WWOX. Defective respiratory complex-induced outgrowths are mediated by reactive oxygen species, dependent on the Akt pathway, and sensitive to autophagy and HIF levels. WWOX reduction diminishes ability to respond to metabolic perturbation, implying its role in regulating balance between oxidative phosphorylation and glycolysis.","method":"In vivo Drosophila genetic interaction screen, enzyme active-site mutant analysis, ROS assays, epistasis with Akt pathway components","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo genetic epistasis in Drosophila with active-site mutant, single lab; ortholog study with functional domain conservation","pmids":["26390919"],"is_preprint":false},{"year":2018,"finding":"WWOX physically interacts with Tau via its C-terminal SDR domain and interacts with Tau-phosphorylating enzymes ERK, JNK, and GSK-3beta, thereby limiting their activity and supporting neuronal survival. Loss of WWOX in neuroblastoma cells results in aggregation of TRAPPC6ADelta, TIAF1, amyloid beta, and Tau in sequential manner. 17beta-estradiol binds WWOX at an NSYK motif in the C-terminal SDR domain.","method":"Co-immunoprecipitation, siRNA knockdown with aggregation assays, protein binding domain analysis","journal":"Frontiers in neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review article compiling prior data; single Co-IP/pulldown methods cited without full methodological detail in this abstract","pmids":["30158849"],"is_preprint":false},{"year":2008,"finding":"WWOX (WOX1) is rapidly upregulated and phosphorylated at Tyr33 in neurons injured by MPP+ (dopaminergic neurotoxin) in rat brains. WWOX is present in condensed nuclei and damaged mitochondria of degenerative neurons. WWOX physically interacts with JNK1 in brain extracts; MPP+ rapidly increases WOX1/JNK1 binding followed by dissociation (required for WOX1 apoptotic function). A Tyr33-phosphorylated WWOX peptide (11 aa) blocks MPP+-induced neuronal death in rat brains, while non-phospho-WOX1 peptide has no effect.","method":"In vivo rat MPP+ model, immunohistochemistry, immunoelectron microscopy, co-immunoprecipitation from brain extracts, dominant-negative transfection, synthetic phospho-peptide injection","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo Co-IP from brain tissue plus dominant-negative and peptide rescue, single lab, single study","pmids":["18371080"],"is_preprint":false}],"current_model":"WWOX is a 46-kDa adaptor/oxidoreductase protein whose first WW domain (activated by Tyr33 phosphorylation, mediated by Src and other kinases) mediates protein-protein interactions via PPXY motifs, physically binding and cytoplasmatically sequestering transcription factors (p73, AP-2gamma, SMAD3, HIF1alpha, Dvl/Wnt components) to suppress their nuclear activity; it also interacts with pro-apoptotic partners (p53, JNK1, Hyal-2/Smad4) to promote stress-induced apoptosis, with BRCA1 to favor NHEJ over HDR in DNA double-strand break repair, with JAK2 to suppress STAT3 signaling, with AMPK in metabolic regulation, with c-Jun to limit inflammatory signaling, and with mTOR to suppress autophagy, while its SDR domain governs Golgi localization, oxidoreductase activity relevant to steroid/metabolic processes, Tau binding, and estradiol binding; loss of WWOX function dysregulates all these pathways, contributing to cancer, metabolic disorders, and severe neurodevelopmental encephalopathy."},"narrative":{"mechanistic_narrative":"WWOX is a stress-responsive adaptor protein that couples cytoplasmic sequestration of transcription factors and signaling effectors to control of apoptosis, genome stability, metabolism, and neural development [PMID:15070730, PMID:25012504, PMID:27869163]. Its first WW domain, activated by Tyr33 phosphorylation, binds PPxY-type motifs and forms complexes with transcription factors that WWOX redistributes from nucleus to cytoplasm to quench their activity, including p73, AP-2gamma (suppressing ERBB2 transcription), SMAD3, HIF1alpha, and Dishevelled in Wnt/beta-catenin signaling [PMID:15070730, PMID:15548692, PMID:19465938, PMID:24330518, PMID:25012504, PMID:17704139]. The same Tyr33-phosphorylated WW domain assembles pro-apoptotic complexes with JNK1 and Ser46-phosphorylated p53, stabilizing p53 and driving mitochondrial-then-nuclear translocation to execute stress-induced cell death, a function antagonized by the inhibitory partner Zfra [PMID:12514174, PMID:16219768, PMID:14555208, PMID:17567906]. Membrane signals feed into this axis: TGF-beta1- and hyaluronan-driven Hyal-2/WWOX/Smad4 complexes relocate to the nucleus to enhance Smad-dependent transcription and death [PMID:19366691, PMID:27845895]. WWOX also acts in the nucleus on DNA-break responses, interacting with BRCA1 to bias double-strand-break repair toward NHEJ by suppressing HDR end-resection, and contributing to the ATR single-strand-break checkpoint [PMID:27869163, PMID:26675548]. Through interactions with AMPK and HIF1alpha, WWOX restrains a Warburg-like glycolytic shift and maintains mitochondrial oxidative metabolism, and its loss dysregulates HDL/lipid metabolism in liver [PMID:25012504, PMID:30755385, PMID:24871327]. A separate C-terminal short-chain-dehydrogenase/reductase (SDR) domain directs Golgi localization and binds Tau [PMID:14526170, PMID:30158849]. In vivo, neuronal WWOX loss causes brain hyperexcitability, impaired oligodendrocyte maturation and myelination, and GSK3beta-dependent epilepsy, defining a role in neurodevelopment and brain excitability [PMID:33914858, PMID:32000863], and WWOX-p53 genetic epistasis governs osteogenesis and osteosarcoma suppression [PMID:27550453].","teleology":[{"year":2003,"claim":"Establishing that Tyr33 phosphorylation of WWOX's first WW domain is the switch licensing pro-apoptotic partner binding answered how a single protein toggles between adaptor and death-inducing states.","evidence":"Co-IP, yeast two-hybrid, and Tyr33-to-Arg mutagenesis with apoptosis assays linking WWOX to JNK1 and p53","pmids":["12514174","14555208"],"confidence":"High","gaps":["Identity of the kinase(s) phosphorylating Tyr33 in each stimulus context not fully resolved","Mechanism of mitochondrial-to-nuclear translocation not structurally defined"]},{"year":2003,"claim":"Mapping WWOX to the Golgi and showing SDR-domain dependence of that localization distinguished domain-specific functions and predicted that SDR-lacking splice forms act as dominant negatives.","evidence":"Immunofluorescence/fractionation with domain-deletion constructs and analysis of aberrant splice forms","pmids":["14526170"],"confidence":"Medium","gaps":["Dominant-negative claim not mechanistically validated","Enzymatic substrate of the SDR domain not identified"]},{"year":2004,"claim":"Demonstrating that WWOX sequesters transcription factors (p73, AP-2gamma) in the cytoplasm via WW1–PPxY contacts defined its core mechanism of transcriptional suppression.","evidence":"Reciprocal Co-IP, WW domain and PPPY-motif mutagenesis, subcellular localization, and reporter assays","pmids":["15070730","15548692"],"confidence":"High","gaps":["How cytoplasmic retention is sustained versus reversed not defined","Whether endogenous stoichiometry supports sequestration genome-wide untested"]},{"year":2005,"claim":"Showing that WOX1 stabilizes Ser46-phosphorylated p53 post-translationally tied WWOX directly to the p53 apoptotic checkpoint and MDM2 axis.","evidence":"Co-IP, Y2H domain mapping, siRNA, dominant-negative, protein-stability time course, and nutlin-3 pharmacology","pmids":["16219768"],"confidence":"High","gaps":["Biochemical basis for p53 stabilization (e.g. blocking MDM2 access) not directly demonstrated"]},{"year":2005,"claim":"Identifying 17beta-estradiol and complement C1q as upstream activators of WWOX Tyr33 phosphorylation connected hormonal and immune cues to WWOX-driven apoptosis.","evidence":"Phospho-Tyr33 Western blotting, Co-IP, fractionation, and dominant-negative/Y33R apoptosis assays in cell lines","pmids":["15580310","19484134"],"confidence":"Medium","gaps":["Receptor/signaling steps linking ligand to Tyr33 phosphorylation undefined","ER/AR independence shown only pharmacologically"]},{"year":2006,"claim":"Linking PKA-phosphorylated ezrin to apical WWOX localization showed that scaffolding partners position WWOX at specific membrane domains.","evidence":"Direct binding assays, ezrin polyproline/Tyr477 mutagenesis, Co-IP, and microscopy of apical localization and H,K-ATPase recruitment","pmids":["16438931"],"confidence":"Medium","gaps":["Functional consequence of apical WWOX beyond H,K-ATPase recruitment unclear","Single study, not independently confirmed"]},{"year":2009,"claim":"Establishing membrane-receptor inputs (TGF-beta1/Hyal-2) and Wnt/Dvl control extended WWOX from cytosolic sequestration to receptor-proximal signal relay.","evidence":"Immunoelectron microscopy, live-cell FRET, Y2H domain mapping, Co-IP, and Smad/TCF-LEF reporter assays","pmids":["19366691","19465938"],"confidence":"High","gaps":["How WWOX both quenches SMAD3 transcription (#10) and enhances Smad-driven promoters via Hyal-2 (#8) is context-dependent and not reconciled"]},{"year":2014,"claim":"Showing WWOX binds and limits HIF1alpha defined a tumor-suppressive metabolic role restraining the Warburg shift.","evidence":"Co-IP, WW domain mutagenesis, glucose-uptake and metabolic-flux assays, and Wwox knockout cells/mice","pmids":["25012504"],"confidence":"High","gaps":["Whether WWOX controls HIF1alpha stability or only transactivation not fully separated"]},{"year":2016,"claim":"Placing WWOX in DSB repair-pathway choice (with BRCA1) and the ATR SSB checkpoint connected its tumor-suppressor activity to genome maintenance.","evidence":"Co-IP, HDR/NHEJ reporters, repair foci, RAD51 epistasis, xenograft radiation model; nuclear SSB accumulation, ITCH-mediated K274 ubiquitination, and ATM Co-IP","pmids":["27869163","26675548"],"confidence":"High","gaps":["Molecular mechanism by which WWOX suppresses end-resection unresolved","Functional role of K274 ubiquitination at the checkpoint not fully defined"]},{"year":2016,"claim":"Genetic epistasis showed WWOX loss drives p53-dependent osteogenic failure and that p53 deletion both rescues bone formation and accelerates osteosarcoma, defining a WWOX-p53 network in bone.","evidence":"Stage-specific conditional Wwox/p53 knockouts with genetic rescue, histology, and expression analysis","pmids":["27550453"],"confidence":"High","gaps":["Whether bone p53 regulation uses the same Tyr33/WW mechanism as in apoptosis untested"]},{"year":2019,"claim":"Identifying WWOX-AMPK interaction in muscle established a causal role in glucose oxidation, mitochondrial maintenance, and systemic insulin sensitivity.","evidence":"Co-IP and conditional skeletal-muscle Wwox knockout with metabolic phenotyping and mitochondrial assays","pmids":["30755385"],"confidence":"Medium","gaps":["Whether WWOX directly modulates AMPK catalytic activity or acts as scaffold unclear"]},{"year":2020,"claim":"Neuron-specific WWOX loss producing epilepsy, impaired myelination, and GSK3beta hyperactivation defined the basis of WWOX-related neurodevelopmental encephalopathy.","evidence":"Neuron-specific conditional knockout mice plus human brain organoids; transcriptomics, oligodendrocyte maturation, electrophysiology, and lithium/GSK3beta pharmacological epistasis","pmids":["33914858","32000863"],"confidence":"High","gaps":["How WWOX loss elevates GSK3beta activity mechanistically unknown","Link between myelination defect and seizure phenotype not causally dissected"]},{"year":null,"claim":"The catalytic substrate and physiological reaction of the WWOX SDR oxidoreductase domain remain undefined, leaving its enzymatic contribution to metabolism, Golgi function, and Tau handling unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No endogenous SDR substrate identified","Enzymatic versus scaffolding contributions of the SDR domain not separated","No structural model linking SDR activity to disease phenotypes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,7,10,11,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,11,21,16,24]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[12,31]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,10,13]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,7,19]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,8,18,20]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4,15]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3,4,33]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[17,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8,10,20,21,22]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[11,24,29,31]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[25,27]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[16]}],"complexes":["Hyal-2/WWOX/Smad4 complex"],"partners":["TP53","TP73","JNK1","SMAD3","HIF1A","BRCA1","JAK2","AMPK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NZC7","full_name":"WW domain-containing oxidoreductase","aliases":["Fragile site FRA16D oxidoreductase","Short chain dehydrogenase/reductase family 41C member 1"],"length_aa":414,"mass_kda":46.7,"function":"Putative oxidoreductase. 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Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27845895","citation_count":30,"is_preprint":false},{"pmid":"30350478","id":"PMC_30350478","title":"WWOX, the FRA16D gene: A target of and a contributor to genomic instability.","date":"2018","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30350478","citation_count":29,"is_preprint":false},{"pmid":"29724996","id":"PMC_29724996","title":"WWOX controls hepatic HIF1α to suppress hepatocyte proliferation and neoplasia.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29724996","citation_count":29,"is_preprint":false},{"pmid":"19188760","id":"PMC_19188760","title":"Association between CpG island methylation of the WWOX gene and its expression in breast cancers.","date":"2009","source":"Tumour biology : the journal of the International Society for 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glucose metabolism.","date":"2019","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/30755385","citation_count":25,"is_preprint":false},{"pmid":"33946771","id":"PMC_33946771","title":"Molecular Functions of WWOX Potentially Involved in Cancer Development.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/33946771","citation_count":23,"is_preprint":false},{"pmid":"29310447","id":"PMC_29310447","title":"Phosphorylation/de-phosphorylation in specific sites of tumor suppressor WWOX and control of distinct biological events.","date":"2018","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/29310447","citation_count":23,"is_preprint":false},{"pmid":"20942981","id":"PMC_20942981","title":"WWOX gene is associated with HDL cholesterol and triglyceride levels.","date":"2010","source":"BMC medical 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Overview.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/33916893","citation_count":21,"is_preprint":false},{"pmid":"22213016","id":"PMC_22213016","title":"Decreased expression of WWOX in the development of esophageal squamous cell carcinoma.","date":"2011","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/22213016","citation_count":21,"is_preprint":false},{"pmid":"26390919","id":"PMC_26390919","title":"Tumor suppressor WWOX moderates the mitochondrial respiratory complex.","date":"2015","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26390919","citation_count":21,"is_preprint":false},{"pmid":"25416187","id":"PMC_25416187","title":"The fragile site WWOX gene and the developing brain.","date":"2014","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/25416187","citation_count":20,"is_preprint":false},{"pmid":"32389029","id":"PMC_32389029","title":"The WWOX gene in brain development and pathology.","date":"2020","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/32389029","citation_count":20,"is_preprint":false},{"pmid":"31075076","id":"PMC_31075076","title":"Decoding the link between WWOX and p53 in aggressive breast cancer.","date":"2019","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/31075076","citation_count":20,"is_preprint":false},{"pmid":"27234396","id":"PMC_27234396","title":"Role of WWOX and NF-κB in lung cancer progression.","date":"2013","source":"Translational respiratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27234396","citation_count":20,"is_preprint":false},{"pmid":"22898080","id":"PMC_22898080","title":"Overexpression of WW domain-containing oxidoreductase WOX1 preferentially induces apoptosis in human glioblastoma cells harboring mutant p53.","date":"2012","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/22898080","citation_count":20,"is_preprint":false},{"pmid":"24520212","id":"PMC_24520212","title":"Common Chromosomal Fragile Site Gene WWOX in Metabolic Disorders and Tumors.","date":"2014","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24520212","citation_count":19,"is_preprint":false},{"pmid":"17163164","id":"PMC_17163164","title":"WWOX, a chromosomal fragile site gene and its role in cancer.","date":"2006","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/17163164","citation_count":19,"is_preprint":false},{"pmid":"32101017","id":"PMC_32101017","title":"MiR-214 Mediates Cell Proliferation and Apoptosis of Nasopharyngeal Carcinoma Through Targeting Both WWOX and PTEN.","date":"2020","source":"Cancer biotherapy & radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/32101017","citation_count":19,"is_preprint":false},{"pmid":"27352332","id":"PMC_27352332","title":"Ectopic WWOX Expression Inhibits Growth of 5637 Bladder Cancer Cell In Vitro and In Vivo.","date":"2015","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/27352332","citation_count":19,"is_preprint":false},{"pmid":"34359949","id":"PMC_34359949","title":"WWOX and Its Binding Proteins in Neurodegeneration.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34359949","citation_count":18,"is_preprint":false},{"pmid":"25595187","id":"PMC_25595187","title":"Modulation of Sonic hedgehog signaling and WW domain containing oxidoreductase WOX1 expression enhances radiosensitivity of human glioblastoma cells.","date":"2015","source":"Experimental biology and medicine (Maywood, 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WWOX expression redistributes nuclear p73 to the cytoplasm, suppressing its transcriptional activity, and cytoplasmic p73 contributes to WWOX proapoptotic activity.\",\n      \"method\": \"Co-immunoprecipitation, WW domain mutagenesis, subcellular fractionation/localization assays, transfection-based transcriptional reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mutagenesis and functional reporter assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15070730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"WWOX physically interacts with AP-2gamma transcription factor via its first WW domain binding the PPPY motif of AP-2gamma. Mutation of tyrosine 33 in the first WW domain of WWOX or the PPPY motif in AP-2gamma dramatically reduces interaction. WWOX expression triggers redistribution of nuclear AP-2gamma to the cytoplasm, suppressing its transactivating function.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, subcellular localization assays, transcriptional reporter assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with mutagenesis and functional reporter assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15548692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"JNK1 physically interacts with WWOX (WOX1) when WWOX is phosphorylated at Tyr33. Activated JNK1 inhibits WWOX-mediated apoptosis. Mutation of Tyr33 to Arg33 abrogates WWOX binding to JNK1 and abolishes WWOX apoptotic activity, indicating Tyr33 phosphorylation is required both for JNK1 binding and for WWOX-mediated cell death.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid analysis, site-directed mutagenesis, apoptosis assays (multiple cell lines)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus yeast two-hybrid plus mutagenesis plus functional cell death assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12514174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"WWOX (WOX1) Tyr33-phosphorylated form physically interacts with Ser46-phosphorylated p53. This interaction stabilizes p53 protein and is essential for apoptosis induced by UV, anisomycin, etoposide, and TNF. siRNA knockdown of WOX1 abolishes p53 protein accumulation (but not p53 mRNA) after UV, and dominant-negative WOX1 (blocking Tyr33 phosphorylation) also blocks UV-induced p53 expression. MDM2 inhibition by nutlin-3 increases WOX1–p53 binding and p53 stability.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid domain mapping, siRNA knockdown, dominant-negative overexpression, time-course protein stability assay, nutlin-3 pharmacological inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, Y2H, siRNA, DN mutant, pharmacological) in single lab\",\n      \"pmids\": [\"16219768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"WWOX (WOX1) undergoes Tyr33 phosphorylation at its first WW domain in response to stress/apoptotic stimuli, enabling complex formation with activated p53 and JNK1. The p53/WOX1 complex translocates to the mitochondria and then to the nucleus to mediate apoptosis. WOX1 mutants inactivated for nuclear translocation or Tyr33 phosphorylation fail to induce apoptosis.\",\n      \"method\": \"Phosphorylation assays, co-immunoprecipitation, subcellular fractionation, dominant-negative mutagenesis, apoptosis assays\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple methods (Co-IP, fractionation, DN mutant) but single lab and partially overlapping with other publications from same group\",\n      \"pmids\": [\"14555208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"17beta-estradiol activates WWOX (WOX1) via Tyr33 phosphorylation and promotes nuclear translocation of p53/WOX1 complex independently of estrogen receptor and androgen receptor status.\",\n      \"method\": \"Western blotting for Tyr33 phosphorylation, co-immunoprecipitation, subcellular fractionation, immunohistochemistry in multiple cell lines and in vivo tissues\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, biochemical and cell biology methods without mutagenesis confirmation of ER/AR independence beyond pharmacological context\",\n      \"pmids\": [\"15580310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PKA-mediated phosphorylation of ezrin at Ser66 regulates interaction between ezrin and WWOX. Ezrin directly binds the first WW domain of WWOX via its C-terminal polyproline sequence (470PPPPPPVY477), with Tyr477 essential for the interaction. PKA-mediated ezrin phosphorylation is necessary and sufficient for apical localization of WWOX protein; disruption of the ezrin-WWOX interaction eliminates apical WWOX localization and impairs H,K-ATPase recruitment.\",\n      \"method\": \"Biochemical binding assays, site-directed mutagenesis, co-immunoprecipitation, subcellular localization by microscopy\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct binding with mutagenesis and localization consequences, single lab single study\",\n      \"pmids\": [\"16438931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"WWOX physically associates with Dishevelled (Dvl) family proteins (identified by yeast two-hybrid and co-immunoprecipitation). WWOX expression inhibits Wnt/beta-catenin transcriptional activity, while WWOX knockdown stimulates it and enhances Wnt-3a-induced beta-catenin stability. WWOX sequesters Dvl-2 (including a nuclear-localized Dvl-2 mutant) in the cytoplasm, preventing nuclear import of Dvl proteins.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, TCF/LEF reporter assays, beta-catenin stability assay, subcellular localization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H plus Co-IP plus functional reporter assays plus localization, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19465938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TGF-beta1 binds cell-surface hyaluronidase Hyal-2 on microvilli (in TGF-beta receptor II-deficient cells), resulting in recruitment of WWOX (WOX1) and formation of Hyal-2/WWOX complexes that relocate to the nucleus. TGF-beta1 strengthens binding of the catalytic domain of Hyal-2 with the Tyr33-phosphorylated WW domain of WWOX. WOX1 and Hyal-2 together dramatically enhance Smad-driven promoter activation (8-9-fold), leading to cell death.\",\n      \"method\": \"Immunoelectron microscopy, FRET in live cells, co-immunoprecipitation, yeast two-hybrid domain mapping, Smad promoter reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — immunoelectron microscopy, live-cell FRET, Co-IP, Y2H domain mapping, and functional reporter assays in single study with multiple orthogonal methods\",\n      \"pmids\": [\"19366691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Complement C1q activates WWOX (WOX1) via Tyr33 phosphorylation in prostate cancer cells. Exogenous C1q significantly induces apoptosis of WWOX-overexpressing DU145 cells but not control cells; dominant-negative and Y33R mutant WWOX blocks this apoptotic effect. WWOX activation by C1q destabilizes cell adhesion, causing formation of clustered microvilli, cell shrinkage, membrane blebbing, and death.\",\n      \"method\": \"Exogenous protein treatment, dominant-negative and point-mutant constructs, TIRF microscopy, apoptosis assays, immunostaining\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple methods (TIRF, mutant constructs, apoptosis assays) but single lab, single study\",\n      \"pmids\": [\"19484134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WWOX physically interacts with SMAD3 via WW domain 1, as shown by co-immunoprecipitation and GST pull-down. WWOX expression dramatically decreases SMAD3 occupancy at ANGPTL4 and SERPINE1 promoters, quenches TGFβ-responsive reporter activation, and leads to redistribution of SMAD3 from the nuclear to the cytoplasmic compartment.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, ChIP, transcriptional reporter assays, confocal microscopy for subcellular localization\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus GST pull-down plus ChIP plus reporter plus localization, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24330518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"WWOX physically interacts with HIF1alpha via its first WW domain and modulates HIF1alpha protein levels and transactivation function. WWOX-deficient cells exhibit increased HIF1alpha levels and activity, increased glucose uptake, enhanced glycolysis, and diminished mitochondrial respiration (Warburg-like effect). WWOX-deficient cells show increased GLUT1 levels in vivo.\",\n      \"method\": \"Co-immunoprecipitation, WW domain mutagenesis, glucose uptake assays, metabolic flux assays, Wwox knockout cells and mouse models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mutagenesis plus metabolic assays plus in vivo knockout model, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25012504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"WWOX normally resides in the Golgi apparatus; Golgi localization requires an intact SDR (short-chain dehydrogenase/reductase) domain. Aberrantly spliced WWOX isoforms lacking the SDR domain show abnormal intracellular localization to the nucleus and may act as dominant-negative inhibitors of full-length WWOX. The WW domain ligand is identified as the PPXY motif.\",\n      \"method\": \"Subcellular localization by immunofluorescence/fractionation, domain deletion constructs, analysis of aberrant splice forms\",\n      \"journal\": \"Cytogenetic and genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization experiment with domain deletion, single lab, limited mechanistic follow-up on dominant-negative claim\",\n      \"pmids\": [\"14526170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"WWOX interacts with AP-2gamma and prevents AP-2gamma from entering the nucleus to bind the ERBB2 promoter and activate ERBB2 transcription. Ectopic WWOX reduced ErbB2 protein expression in vitro. WWOX suppresses AP-2gamma/ErbB2-induced prostate cancer cell growth and PSA secretion, requiring functional androgen receptor.\",\n      \"method\": \"Co-immunoprecipitation, ChIP (AP-2gamma on ERBB2 promoter), Western blotting, cell growth and PSA assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ChIP with functional readout, single lab, single study\",\n      \"pmids\": [\"17704139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sciatic nerve transection in rats induces rapid JNK1 activation and WOX1 upregulation in DRG neurons; phospho-WOX1 physically interacts with phospho-CREB and phospho-c-Jun in nuclei (immunoelectron microscopy and FRET). WOX1 blocks prosurvival CREB-, CRE-, and AP-1-mediated promoter activation in vitro but enhances NF-kappaB promoter activation via its WW domains. WOX1 directly activates NF-kappaB-regulated promoter.\",\n      \"method\": \"FRET analysis in vivo, immunoelectron microscopy, co-immunoprecipitation, promoter reporter assays, in vivo nerve transection model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo FRET, immunoelectron microscopy, and reporter assays but single lab, single study\",\n      \"pmids\": [\"19918364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"WWOX (WOX1) physically interacts with MEK1 in lysosomes in Jurkat T cells. PMA induces dissociation of the WOX1/MEK1 complex, leading to MEK1 relocation to lipid rafts and WOX1 relocation to mitochondria for apoptosis. The MEK inhibitor U0126 inhibits PMA-induced dissociation and supports cell survival.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, pharmacological inhibitors (U0126, PD98059), apoptosis assays in multiple leukemia cell lines\",\n      \"journal\": \"Genes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with subcellular localization and functional dissection, single lab, single study\",\n      \"pmids\": [\"21901168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WWOX physically interacts with mTOR, and this interaction potentiates MTX-induced mTOR phosphorylation and its downstream substrate p70 S6 kinase, leading to downregulation of autophagy proteins (Beclin-1, Atg12-Atg5, LC3-II) and suppression of autophagosome formation. WWOX knockdown in SCC-15 cells blocks MTX-induced mTOR signaling and autophagy inhibition, causing chemotherapy resistance.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting for autophagy markers, siRNA knockdown, apoptosis assays, autophagosome imaging\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with functional knockdown and mechanistic follow-up, single lab, single study\",\n      \"pmids\": [\"24008736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WWOX interacts with BRCA1 and contributes to DNA double-strand break (DSB) repair pathway choice. WWOX-deficient cells exhibit enhanced homology-directed repair (HDR) and decreased non-homologous end-joining (NHEJ). WWOX expression suppresses DSB repair at the end-resection step of HDR. Silencing RAD51 (critical for HDR) resensitizes WWOX-deficient cells to radiation.\",\n      \"method\": \"Co-immunoprecipitation (Wwox-Brca1), immunofluorescence of DNA damage repair foci, HDR/NHEJ reporter assays, RAD51 siRNA epistasis, xenograft radiation resistance model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, repair reporter assays, epistasis, in vivo xenograft model, multiple orthogonal methods in single study\",\n      \"pmids\": [\"27869163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WWOX modulates the ATR-mediated DNA single-strand break (SSB) checkpoint. WWOX accumulates in the nucleus after SSBs. WWOX is ubiquitinated at lysine 274 by the E3 ubiquitin ligase ITCH following SSBs. WWOX interacts with ATM, and ATM inhibition reduces ATR checkpoint activation, indicating WWOX modulates ATR signaling in an ATM-dependent manner. WWOX deficiency is associated with reduced ATR checkpoint activation and increased chromosomal breaks.\",\n      \"method\": \"Nuclear fractionation after SSB induction, ubiquitination assay with ITCH, co-immunoprecipitation (WWOX-ATM), pharmacological ATM inhibition, chromosomal break analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP plus ubiquitination assay plus pharmacological epistasis, single lab, single study\",\n      \"pmids\": [\"26675548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Zfra (a 31-amino-acid zinc finger-like protein) binds WWOX (WOX1) and sequesters it in the cytoplasm, counteracting the apoptotic functions of Tyr33-phosphorylated WOX1 and Ser46-phosphorylated p53. Alteration of Ser8 in Zfra abolishes its regulation of WOX1 and p53. Interactions confirmed by GST pull-down, Co-IP, and yeast two-hybrid.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, yeast two-hybrid, subcellular localization assays, apoptosis assays\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple binding methods (GST, Co-IP, Y2H) with functional readout, single lab, single study\",\n      \"pmids\": [\"17567906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Hyaluronan (HA) activates the Hyal-2/WWOX/Smad4 signaling complex: WWOX acts as a bridge binding both Hyal-2 and Smad4 (by yeast two-hybrid). High molecular weight HA stimulates rapid formation of endogenous Hyal-2/WWOX/Smad4 complex and nuclear relocation. Real-time tri-molecular FRET analysis confirms HA-induced signaling: Smad4→WWOX→p53 and Smad4→Hyal-2→WWOX. Overexpression of the complex causes bubbling cell death in WWOX-expressing cells; WWOX-deficient cells fail to translocate Smad2/3/4 to the nucleus.\",\n      \"method\": \"Yeast two-hybrid domain analysis, co-immunoprecipitation, tri-molecular FRET in live cells, nuclear fractionation, WWOX-deficient cell comparison, apoptosis assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — tri-molecular live-cell FRET, Y2H, Co-IP, functional rescue/deficiency experiments, multiple orthogonal methods single lab\",\n      \"pmids\": [\"27845895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WWOX interacts with JAK2 to inhibit JAK2 and STAT3 phosphorylation in breast cancer cells. WWOX overexpression suppresses STAT3 activation, inhibits STAT3 binding to the IL-6 promoter, and represses IL-6 cytokine expression, thereby suppressing proliferation and metastasis of triple-negative breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (WWOX-JAK2), STAT3 phosphorylation assays, ChIP (STAT3 at IL-6 promoter), cell proliferation and invasion assays, WWOX overexpression/knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with ChIP and functional assays, single lab, single study\",\n      \"pmids\": [\"30154439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WWOX directly interacts with c-Jun in human alveolar epithelial cells; its absence results in increased nuclear translocation of c-Jun and increased c-Jun- and IL-8-dependent neutrophil chemotaxis. WWOX loss in mouse lungs causes neutrophil influx, vascular leak, and inflammatory cytokine production. JNK inhibition abrogates the neutrophil influx caused by WWOX knockdown.\",\n      \"method\": \"Co-immunoprecipitation (WWOX-c-Jun), siRNA knockdown in vitro, in vivo WWOX knockdown in mice, JNK pharmacological inhibition, neutrophil chemotaxis assays\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP plus in vivo knockdown plus pharmacological epistasis, single lab, single study\",\n      \"pmids\": [\"28283473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WWOX is a negative regulator of c-MYC; WWOX loss leads to c-MYC activation, which regulates miR-146a expression, which in turn regulates fibronectin levels, contributing to EMT in TNBC. Anti-miR-146a rescues the WWOX antimetastatic phenotype; overexpression of MYC in WWOX-expressing cells overrides WWOX effects on miR-146a and fibronectin.\",\n      \"method\": \"WWOX overexpression/depletion, miRNA expression analysis, miR-146a inhibitor rescue, MYC overexpression epistasis, fibronectin Western blotting, invasion/metastasis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional epistasis with rescue experiments, single lab, single study; no direct WWOX-MYC binding demonstrated\",\n      \"pmids\": [\"30622118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WWOX physically interacts with AMPK (AMP-activated protein kinase) in skeletal muscle cells. WWOX somatic loss in skeletal muscle (WwoxΔSKM mice) results in impaired AMPK activation and significant HIF1alpha accumulation, associated with reduced mitochondrial quantity and activity, lower glucose oxidation, glucose intolerance, and insulin resistance.\",\n      \"method\": \"Co-immunoprecipitation (WWOX-AMPK), conditional knockout mouse model, metabolic phenotyping (glucose tolerance test, insulin tolerance test), mitochondrial assays\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with in vivo conditional KO metabolic phenotyping, single lab, single study\",\n      \"pmids\": [\"30755385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WWOX neuronal deletion produces brain hyperexcitability, intractable epilepsy, reduced maturation of oligodendrocytes, reduced myelinated axons, and impaired axonal conductivity in mice. A significant decrease in transcript levels of myelination genes is observed. These phenotypes are recapitulated in human brain organoids with WWOX deletion, establishing a neuronal-specific role for WWOX in myelination and brain excitability.\",\n      \"method\": \"Neuron-specific conditional Wwox knockout mice, transcriptomic analysis, oligodendrocyte maturation assays, electrophysiology (transcranial motor evoked potentials), human brain organoids with WWOX deletion\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in mice plus human organoid validation with defined cellular phenotypes and transcriptomic mechanism\",\n      \"pmids\": [\"33914858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wwox gene ablation in mice causes a significantly increased activation of GSK3beta in cerebral cortex, hippocampus, and cerebellum, leading to spontaneous epilepsy. Inhibition of GSK3beta by lithium ion significantly abolishes PTZ-induced seizures in Wwox-/- mice, placing GSK3beta activation downstream of Wwox loss as a mechanism for epilepsy.\",\n      \"method\": \"Wwox knockout mice, GSK3beta phosphorylation assays, lithium treatment (pharmacological epistasis), seizure susceptibility assays\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pharmacological epistasis with knockout model, single lab, single study\",\n      \"pmids\": [\"32000863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Wwox deletion in osteoblast progenitors (but not mature osteoblasts) causes severe inhibition of osteogenesis accompanied by p53 upregulation. Deletion of p53 in Wwox-null preosteoblasts (Wwox;p53Δosx1 double KO) rescues the osteogenic defect and results in accelerated development of osteosarcomas, establishing a WWOX-p53 epistatic network in bone formation.\",\n      \"method\": \"Conditional knockout mice (Wwox and p53 in osteoblast progenitors vs mature osteoblasts), genetic rescue (p53 deletion), histology, gene expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with conditional stage-specific knockouts and rescue experiment across multiple mouse models\",\n      \"pmids\": [\"27550453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Bmi1 (polycomb group protein) suppresses WWOX expression in small-cell lung cancer cells, as demonstrated by chromatin immunoprecipitation showing Bmi1 occupancy at the WWOX locus. Bmi1 reduction by shRNA increases WWOX expression and induces apoptosis in SCLC cells.\",\n      \"method\": \"Chromatin immunoprecipitation (Bmi1 at WWOX locus), quantitative RT-PCR, shRNA knockdown of Bmi1, apoptosis assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP plus functional knockdown, single lab, single study\",\n      \"pmids\": [\"21276135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In liver-specific Wwox knockout (WwoxΔHep) mice, ApoA-I and Abca1 levels are decreased. Total Wwox-/- mice show marked reductions in serum HDL cholesterol. Female WwoxΔHep mice display increased plasma triglycerides and altered lipid metabolic pathways, with significant reduction of ApoA-I and Lpl, and upregulation of Fas, Angptl4, and Lipg, suggesting WWOX modulates HDL cholesterol and lipid metabolism via multiple pathways including the ApoA-I/ABCA1 pathway and fatty acid biosynthesis.\",\n      \"method\": \"Liver-specific and total Wwox knockout mouse models, lipoprotein profiling, microarray gene expression analysis, Western blotting\",\n      \"journal\": \"Circulation. Cardiovascular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo conditional KO with molecular characterization, single lab, limited direct mechanistic detail on pathway\",\n      \"pmids\": [\"24871327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WWOX physically interacts with SMAD3 and BMP2 (components of TGF-beta signaling pathway) in pancreatic cells. In the absence of WWOX, TGFbeta/BMP signaling is enhanced, leading to increased macrophage infiltration and enhanced cancer stemness. Combined conditional deletion of Wwox with KRasG12D activation in mice accelerates formation of pancreatic precursor lesions and carcinoma.\",\n      \"method\": \"Co-immunoprecipitation (WWOX-SMAD3 and WWOX-BMP2), conditional knockout/KRas activation mouse model, macrophage infiltration assays, stemness assays, WWOX overexpression in PDX models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with in vivo genetic model and functional assays, single lab, single study\",\n      \"pmids\": [\"36572673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WWOX (in Drosophila melanogaster ortholog) modulates cellular outgrowths caused by genetic deficiencies in mitochondrial respiratory complex components. This modulation requires the enzyme active site (SDR domain) of WWOX. Defective respiratory complex-induced outgrowths are mediated by reactive oxygen species, dependent on the Akt pathway, and sensitive to autophagy and HIF levels. WWOX reduction diminishes ability to respond to metabolic perturbation, implying its role in regulating balance between oxidative phosphorylation and glycolysis.\",\n      \"method\": \"In vivo Drosophila genetic interaction screen, enzyme active-site mutant analysis, ROS assays, epistasis with Akt pathway components\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo genetic epistasis in Drosophila with active-site mutant, single lab; ortholog study with functional domain conservation\",\n      \"pmids\": [\"26390919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WWOX physically interacts with Tau via its C-terminal SDR domain and interacts with Tau-phosphorylating enzymes ERK, JNK, and GSK-3beta, thereby limiting their activity and supporting neuronal survival. Loss of WWOX in neuroblastoma cells results in aggregation of TRAPPC6ADelta, TIAF1, amyloid beta, and Tau in sequential manner. 17beta-estradiol binds WWOX at an NSYK motif in the C-terminal SDR domain.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with aggregation assays, protein binding domain analysis\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review article compiling prior data; single Co-IP/pulldown methods cited without full methodological detail in this abstract\",\n      \"pmids\": [\"30158849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"WWOX (WOX1) is rapidly upregulated and phosphorylated at Tyr33 in neurons injured by MPP+ (dopaminergic neurotoxin) in rat brains. WWOX is present in condensed nuclei and damaged mitochondria of degenerative neurons. WWOX physically interacts with JNK1 in brain extracts; MPP+ rapidly increases WOX1/JNK1 binding followed by dissociation (required for WOX1 apoptotic function). A Tyr33-phosphorylated WWOX peptide (11 aa) blocks MPP+-induced neuronal death in rat brains, while non-phospho-WOX1 peptide has no effect.\",\n      \"method\": \"In vivo rat MPP+ model, immunohistochemistry, immunoelectron microscopy, co-immunoprecipitation from brain extracts, dominant-negative transfection, synthetic phospho-peptide injection\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo Co-IP from brain tissue plus dominant-negative and peptide rescue, single lab, single study\",\n      \"pmids\": [\"18371080\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WWOX is a 46-kDa adaptor/oxidoreductase protein whose first WW domain (activated by Tyr33 phosphorylation, mediated by Src and other kinases) mediates protein-protein interactions via PPXY motifs, physically binding and cytoplasmatically sequestering transcription factors (p73, AP-2gamma, SMAD3, HIF1alpha, Dvl/Wnt components) to suppress their nuclear activity; it also interacts with pro-apoptotic partners (p53, JNK1, Hyal-2/Smad4) to promote stress-induced apoptosis, with BRCA1 to favor NHEJ over HDR in DNA double-strand break repair, with JAK2 to suppress STAT3 signaling, with AMPK in metabolic regulation, with c-Jun to limit inflammatory signaling, and with mTOR to suppress autophagy, while its SDR domain governs Golgi localization, oxidoreductase activity relevant to steroid/metabolic processes, Tau binding, and estradiol binding; loss of WWOX function dysregulates all these pathways, contributing to cancer, metabolic disorders, and severe neurodevelopmental encephalopathy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WWOX is a stress-responsive adaptor protein that couples cytoplasmic sequestration of transcription factors and signaling effectors to control of apoptosis, genome stability, metabolism, and neural development [#0, #11, #17]. Its first WW domain, activated by Tyr33 phosphorylation, binds PPxY-type motifs and forms complexes with transcription factors that WWOX redistributes from nucleus to cytoplasm to quench their activity, including p73, AP-2gamma (suppressing ERBB2 transcription), SMAD3, HIF1alpha, and Dishevelled in Wnt/beta-catenin signaling [#0, #1, #7, #10, #11, #13]. The same Tyr33-phosphorylated WW domain assembles pro-apoptotic complexes with JNK1 and Ser46-phosphorylated p53, stabilizing p53 and driving mitochondrial-then-nuclear translocation to execute stress-induced cell death, a function antagonized by the inhibitory partner Zfra [#2, #3, #4, #19]. Membrane signals feed into this axis: TGF-beta1- and hyaluronan-driven Hyal-2/WWOX/Smad4 complexes relocate to the nucleus to enhance Smad-dependent transcription and death [#8, #20]. WWOX also acts in the nucleus on DNA-break responses, interacting with BRCA1 to bias double-strand-break repair toward NHEJ by suppressing HDR end-resection, and contributing to the ATR single-strand-break checkpoint [#17, #18]. Through interactions with AMPK and HIF1alpha, WWOX restrains a Warburg-like glycolytic shift and maintains mitochondrial oxidative metabolism, and its loss dysregulates HDL/lipid metabolism in liver [#11, #24, #29]. A separate C-terminal short-chain-dehydrogenase/reductase (SDR) domain directs Golgi localization and binds Tau [#12, #32]. In vivo, neuronal WWOX loss causes brain hyperexcitability, impaired oligodendrocyte maturation and myelination, and GSK3beta-dependent epilepsy, defining a role in neurodevelopment and brain excitability [#25, #26], and WWOX-p53 genetic epistasis governs osteogenesis and osteosarcoma suppression [#27].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that Tyr33 phosphorylation of WWOX's first WW domain is the switch licensing pro-apoptotic partner binding answered how a single protein toggles between adaptor and death-inducing states.\",\n      \"evidence\": \"Co-IP, yeast two-hybrid, and Tyr33-to-Arg mutagenesis with apoptosis assays linking WWOX to JNK1 and p53\",\n      \"pmids\": [\"12514174\", \"14555208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the kinase(s) phosphorylating Tyr33 in each stimulus context not fully resolved\", \"Mechanism of mitochondrial-to-nuclear translocation not structurally defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapping WWOX to the Golgi and showing SDR-domain dependence of that localization distinguished domain-specific functions and predicted that SDR-lacking splice forms act as dominant negatives.\",\n      \"evidence\": \"Immunofluorescence/fractionation with domain-deletion constructs and analysis of aberrant splice forms\",\n      \"pmids\": [\"14526170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dominant-negative claim not mechanistically validated\", \"Enzymatic substrate of the SDR domain not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that WWOX sequesters transcription factors (p73, AP-2gamma) in the cytoplasm via WW1–PPxY contacts defined its core mechanism of transcriptional suppression.\",\n      \"evidence\": \"Reciprocal Co-IP, WW domain and PPPY-motif mutagenesis, subcellular localization, and reporter assays\",\n      \"pmids\": [\"15070730\", \"15548692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cytoplasmic retention is sustained versus reversed not defined\", \"Whether endogenous stoichiometry supports sequestration genome-wide untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showing that WOX1 stabilizes Ser46-phosphorylated p53 post-translationally tied WWOX directly to the p53 apoptotic checkpoint and MDM2 axis.\",\n      \"evidence\": \"Co-IP, Y2H domain mapping, siRNA, dominant-negative, protein-stability time course, and nutlin-3 pharmacology\",\n      \"pmids\": [\"16219768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical basis for p53 stabilization (e.g. blocking MDM2 access) not directly demonstrated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying 17beta-estradiol and complement C1q as upstream activators of WWOX Tyr33 phosphorylation connected hormonal and immune cues to WWOX-driven apoptosis.\",\n      \"evidence\": \"Phospho-Tyr33 Western blotting, Co-IP, fractionation, and dominant-negative/Y33R apoptosis assays in cell lines\",\n      \"pmids\": [\"15580310\", \"19484134\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/signaling steps linking ligand to Tyr33 phosphorylation undefined\", \"ER/AR independence shown only pharmacologically\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linking PKA-phosphorylated ezrin to apical WWOX localization showed that scaffolding partners position WWOX at specific membrane domains.\",\n      \"evidence\": \"Direct binding assays, ezrin polyproline/Tyr477 mutagenesis, Co-IP, and microscopy of apical localization and H,K-ATPase recruitment\",\n      \"pmids\": [\"16438931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of apical WWOX beyond H,K-ATPase recruitment unclear\", \"Single study, not independently confirmed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing membrane-receptor inputs (TGF-beta1/Hyal-2) and Wnt/Dvl control extended WWOX from cytosolic sequestration to receptor-proximal signal relay.\",\n      \"evidence\": \"Immunoelectron microscopy, live-cell FRET, Y2H domain mapping, Co-IP, and Smad/TCF-LEF reporter assays\",\n      \"pmids\": [\"19366691\", \"19465938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How WWOX both quenches SMAD3 transcription (#10) and enhances Smad-driven promoters via Hyal-2 (#8) is context-dependent and not reconciled\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing WWOX binds and limits HIF1alpha defined a tumor-suppressive metabolic role restraining the Warburg shift.\",\n      \"evidence\": \"Co-IP, WW domain mutagenesis, glucose-uptake and metabolic-flux assays, and Wwox knockout cells/mice\",\n      \"pmids\": [\"25012504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WWOX controls HIF1alpha stability or only transactivation not fully separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placing WWOX in DSB repair-pathway choice (with BRCA1) and the ATR SSB checkpoint connected its tumor-suppressor activity to genome maintenance.\",\n      \"evidence\": \"Co-IP, HDR/NHEJ reporters, repair foci, RAD51 epistasis, xenograft radiation model; nuclear SSB accumulation, ITCH-mediated K274 ubiquitination, and ATM Co-IP\",\n      \"pmids\": [\"27869163\", \"26675548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which WWOX suppresses end-resection unresolved\", \"Functional role of K274 ubiquitination at the checkpoint not fully defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic epistasis showed WWOX loss drives p53-dependent osteogenic failure and that p53 deletion both rescues bone formation and accelerates osteosarcoma, defining a WWOX-p53 network in bone.\",\n      \"evidence\": \"Stage-specific conditional Wwox/p53 knockouts with genetic rescue, histology, and expression analysis\",\n      \"pmids\": [\"27550453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether bone p53 regulation uses the same Tyr33/WW mechanism as in apoptosis untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying WWOX-AMPK interaction in muscle established a causal role in glucose oxidation, mitochondrial maintenance, and systemic insulin sensitivity.\",\n      \"evidence\": \"Co-IP and conditional skeletal-muscle Wwox knockout with metabolic phenotyping and mitochondrial assays\",\n      \"pmids\": [\"30755385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether WWOX directly modulates AMPK catalytic activity or acts as scaffold unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Neuron-specific WWOX loss producing epilepsy, impaired myelination, and GSK3beta hyperactivation defined the basis of WWOX-related neurodevelopmental encephalopathy.\",\n      \"evidence\": \"Neuron-specific conditional knockout mice plus human brain organoids; transcriptomics, oligodendrocyte maturation, electrophysiology, and lithium/GSK3beta pharmacological epistasis\",\n      \"pmids\": [\"33914858\", \"32000863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How WWOX loss elevates GSK3beta activity mechanistically unknown\", \"Link between myelination defect and seizure phenotype not causally dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The catalytic substrate and physiological reaction of the WWOX SDR oxidoreductase domain remain undefined, leaving its enzymatic contribution to metabolism, Golgi function, and Tau handling unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No endogenous SDR substrate identified\", \"Enzymatic versus scaffolding contributions of the SDR domain not separated\", \"No structural model linking SDR activity to disease phenotypes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 7, 10, 11, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 11, 21, 16, 24]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [12, 31]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 10, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 7, 19]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 8, 18, 20]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4, 15]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3, 4, 33]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [17, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8, 10, 20, 21, 22]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [11, 24, 29, 31]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [25, 27]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [\n      \"Hyal-2/WWOX/Smad4 complex\"\n    ],\n    \"partners\": [\n      \"TP53\",\n      \"TP73\",\n      \"JNK1\",\n      \"SMAD3\",\n      \"HIF1A\",\n      \"BRCA1\",\n      \"JAK2\",\n      \"AMPK\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}