{"gene":"WBP2","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2010,"finding":"The WW domain of TAZ binds WBP2 through interaction with the PPXY-containing C-terminal region of WBP2. Point mutations in the WW domain of TAZ abolished interaction with WBP2 and abolished TAZ-driven transformation and transcriptional activation of ITGB2. Forced fusion of WBP2 (or its TAZ-interacting C-terminal domain) to WW-mutant TAZ rescued transforming and transcription-promoting ability, establishing that WW domain–WBP2 interaction is required for TAZ oncogenic activity.","method":"Proteomic interaction screen, co-immunoprecipitation, WW domain point mutagenesis, cell transformation assay, transcription reporter assay, RNAi knockdown, overexpression","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, rescue experiment, and multiple functional readouts in a single rigorous study","pmids":["20972459"],"is_preprint":false},{"year":2011,"finding":"Drosophila Wbp2 interacts with Yorkie (the fly ortholog of YAP/TAZ) in a WW domain- and PY motif-dependent manner, enhances Yorkie's transcriptional co-activator properties, is required for normal wing growth, and genetically suppresses overgrowth caused by loss of the warts tumor suppressor gene, placing Wbp2 as a downstream component of the Salvador-Warts-Hippo pathway.","method":"Co-immunoprecipitation, genetic epistasis (warts loss-of-function suppression), in vivo tissue growth assay, transcription reporter assay in Drosophila","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis, Co-IP, and multiple in vivo functional readouts independently support pathway placement","pmids":["21311569"],"is_preprint":false},{"year":2012,"finding":"The WW1 domain of WWOX tumor suppressor binds PPXY motifs within WBP2 in a physiologically relevant manner; the WW2 domain shows no affinity for these motifs due to chemically distinct residues (E66/Y85 vs. R25/W44). Introduction of E66R/Y85W double substitution into WW2 confers gain-of-function binding to WBP2, stronger than wild-type WW1. WW1 is structurally disordered and folds upon ligand binding, while WW2 is pre-structured and acts as a chaperone to stabilize and augment WW1 ligand binding.","method":"Isothermal titration calorimetry, circular dichroism, molecular modeling, site-directed mutagenesis (E66R/Y85W gain-of-function)","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biophysical methods plus mutagenesis establishing binding mechanism","pmids":["22634283"],"is_preprint":false},{"year":2011,"finding":"The WW1 and WW2 domains of YAP2 both recognize PPXY motifs within WBP1 and WBP2 in a promiscuous manner; both WW domains strictly require the consensus PPXY sequence; a PPXYXG motif (glycine one residue C-terminal of the consensus tyrosine) is bound with highest affinity by both domains. Binding interactions are highly dynamic with rapid nanosecond-scale conformational fluctuations.","method":"Isothermal titration calorimetry, circular dichroism, molecular modeling, molecular dynamics simulation","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biophysical methods plus computational dynamics characterizing binding determinants","pmids":["21981024"],"is_preprint":false},{"year":2016,"finding":"WBP2 protein stability is controlled by the E3 ubiquitin ligase ITCH, which binds WBP2 and targets it for ubiquitin-dependent proteasomal degradation. Wnt3A signaling stabilizes WBP2 by disrupting ITCH–WBP2 interaction via EGFR-mediated tyrosine phosphorylation of WBP2 and competitive binding of TAZ/YAP. Stabilized nuclear WBP2 interacts with β-catenin and activates TCF-mediated transcription. ITCH silencing elevates WBP2 levels; ITCH-mediated WBP2 degradation inhibits TCF/β-catenin transcription, in vitro transformation, and in vivo tumorigenesis.","method":"Co-immunoprecipitation, RNAi knockdown, proteasome inhibitor treatment, in vitro transformation assay, in vivo xenograft, tyrosine phosphorylation analysis, somatic mutation analysis of ITCH","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional rescue, in vivo model, multiple orthogonal methods establishing ITCH-WBP2-β-catenin axis","pmids":["27578003"],"is_preprint":false},{"year":2016,"finding":"WBP2 acts as a transcriptional coactivator for estrogen receptor α (ESR1) and progesterone receptor (PGR) in the cochlea; loss of Wbp2 expression in mice leads to progressive high-frequency hearing loss with a primary defect at inner hair cell afferent (glutamatergic) synapses.","method":"Mouse knockout (Wbp2-deficient), auditory function testing, electron microscopy of cochlear synapses, histology","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined synaptic phenotype, but molecular mechanism linking WBP2/ESR1/PGR to synapse biology not fully dissected in the abstract","pmids":["26881968"],"is_preprint":false},{"year":2017,"finding":"WBP2 functions as a co-factor of YAP that enhances YAP/TEAD-mediated gene transcription in epidermal stem cells. WBP2 deletion in mouse skin reduces proliferation in neonatal and wounded adult epidermis. In reconstituted epidermis, YAP/WBP2 activity is controlled by intercellular adhesion rather than canonical Hippo signaling.","method":"Genome-wide pooled RNAi screen, mouse conditional knockout, immunofluorescence, TEAD reporter assay, reconstituted epidermis model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen, mouse KO with defined proliferative phenotype, and mechanistic epistasis placing WBP2 downstream of adhesion/YAP","pmids":["28332498"],"is_preprint":false},{"year":2004,"finding":"WBP-2 binds Pax8 (a thyroid-specific transcription factor) in vitro via pulldown and in vivo via co-immunoprecipitation; the interaction is mediated by a novel protein-interacting domain in the C-terminal portion of Pax8 (not a WW domain). WBP-2 does not act as a transcriptional co-activator of Pax8 but behaves as an adaptor molecule in this context.","method":"Immunological/yeast screening, GST pulldown, co-immunoprecipitation, transcription assay (negative result for co-activation)","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pulldown and Co-IP from a single lab; co-activation explicitly shown to be negative","pmids":["14531730"],"is_preprint":false},{"year":2018,"finding":"WBP2 interacts with ERα (estrogen receptor α) and directly modulates MDR1 (ABCB1) transcription through binding to ERα; chromatin immunoprecipitation confirmed ERα occupancy at the MDR1 promoter is WBP2-dependent, increasing chemoresistance to doxorubicin.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), RNAi knockdown, overexpression, MTT cell viability, flow cytometry, in vivo xenograft","journal":"British journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ChIP directly demonstrating WBP2-ERα-MDR1 promoter axis, with in vivo validation","pmids":["29937544"],"is_preprint":false},{"year":2018,"finding":"WBP2 primes TNBC cells for Wnt responses by upregulating GPS1 and TNIK; GPS1 activates the JNK/Jun pathway, which forms a positive feedback loop with TNIK to mediate Wnt-induced AXIN2 expression. WBP2 is required for expression of core Wnt target genes including AXIN2, which is essential for Wnt/WBP2-driven cancer growth and migration.","method":"RNAi coupled with RNA-Seq and mass spectrometry, functional rescue, migration and growth assays, pathway inhibitor studies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with RNA-Seq and MS from a single lab; mechanistic pathway placement validated by rescue experiments","pmids":["30442712"],"is_preprint":false},{"year":2018,"finding":"USF-1 (upstream stimulatory factor 1) is a key transcription factor that directly drives WBP2 transcription via an E-box motif in the WBP2 minimal promoter; AKT-mediated phosphorylation of USF-1 (stimulated by insulin/PI3K signaling) enhances USF-1 binding to the WBP2 promoter and activates WBP2 transcription.","method":"Yeast one-hybrid, promoter reporter assay, chromatin immunoprecipitation, tandem mass spectrometry, AKT inhibitor treatment, mutational analysis of E-box","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast one-hybrid, ChIP, and reporter assay from a single lab establishing transcriptional regulation mechanism","pmids":["30183375"],"is_preprint":false},{"year":2018,"finding":"WBP2 is localized to the postacrosomal sheath (PAS) and perforatorium of the sperm perinuclear theca in mice, with highest expression in round spermatids during spermatogenesis. Microinjection of recombinant WBP2 into metaphase II mouse oocytes activates oocytes at comparable rates to WBP2NL (PAWP), identifying WBP2 as a candidate sperm-borne oocyte-activating factor.","method":"Immunoblotting, immunofluorescence, immunohistochemistry, recombinant protein microinjection into MII oocytes","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct microinjection functional assay combined with subcellular localization, from a single lab","pmids":["30010725"],"is_preprint":false},{"year":2020,"finding":"ITCH (E3 ubiquitin ligase) attenuates CD4 T-cell proliferation by promoting WBP2 proteasomal degradation; Itch-deficient CD4 T cells show increased WBP2 protein stability and hyperproliferation. Itch and WBP2 physically interact in CD4 T cells. WBP2 knockdown reduces CD4 T-cell proliferation.","method":"Whole-cell proteomics of primary mouse Itch-KO CD4 T cells, protein stability assay, co-immunoprecipitation, RNAi knockdown, in vitro and in vivo proliferation assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus Co-IP plus functional knockdown, single lab","pmids":["32459862"],"is_preprint":false},{"year":2021,"finding":"WBP2 competitively binds to the WW domain of WWC3 via its PPxY motifs, displacing LATS1 from the WWC3-LATS1 complex, thereby reducing LATS1 phosphorylation, suppressing Hippo pathway activity, and ultimately promoting YAP nuclear translocation and NSCLC progression.","method":"Co-immunoprecipitation, phosphorylation assays, nuclear/cytoplasmic fractionation, gain- and loss-of-function experiments in lung cancer cells, in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and phosphorylation assays establishing competitive binding mechanism, single lab","pmids":["33837178"],"is_preprint":false},{"year":2021,"finding":"WBP2 physically interacts with LATS2 kinase and inhibits LATS2 phosphorylation and activity; WBP2 knockdown increases p-LATS2 with concomitant increase in p-YAP, causing cytoplasmic YAP retention and inhibition of YAP/TEAD target genes (CTGF, CYR61). Loss of LATS2 reverses Hippo pathway activation caused by WBP2 knockdown, establishing LATS2 as the functional effector downstream of WBP2 in this context.","method":"Mass spectrometry-based phosphoproteomics, co-immunoprecipitation, phosphorylation assay, RNAi epistasis (LATS2 rescue), reporter assay, migration assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics, Co-IP, and genetic epistasis from single lab","pmids":["33475198"],"is_preprint":false},{"year":2021,"finding":"WBP2 suppresses microRNA biogenesis by blocking processing of pri-miRNAs to pre-miRNAs; mechanistically, WBP2 physically interacts with components of the microprocessor complex (DGCR8, DDX5, DDX17) and negatively regulates assembly of this complex. WBP2 blocks the tumor-suppressive properties of DGCR8.","method":"Co-immunoprecipitation of microprocessor components, pri-miRNA processing assay, 2D and 3D in vitro proliferation assays, RNAi","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional processing assay, single lab","pmids":["34117091"],"is_preprint":false},{"year":2021,"finding":"WBP2 promotes TNBC cell migration and invasion via TNF-α-stimulated NF-κB activation; mechanistically, WBP2 enhances mRNA stability of BTRC (β-TrCP), the E3 ligase that ubiquitinates IκBα, leading to IκBα degradation and NF-κB nuclear translocation. IκBα overexpression rescues the WBP2-driven invasive phenotype; BTRC loss blocks WBP2-driven migration.","method":"Proteogenomic analysis (TCGA), RNAi knockdown, mRNA stability assay, NF-κB reporter assay, nuclear fractionation, migration/invasion assays, epistasis (IκBα rescue, BTRC knockdown)","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA stability assay, reporter assay, and genetic epistasis from single lab","pmids":["34197030"],"is_preprint":false},{"year":2023,"finding":"WBP2 interacts with GPX4 via its PPXY1 motif and inhibits ferroptosis by competing with HSC70 for binding to KFERQ-like motifs on GPX4, thereby decelerating chaperone-mediated autophagy (CMA) and lysosomal degradation of GPX4. WBP2 downregulation in cisplatin-induced AKI accelerates GPX4 degradation and ferroptosis.","method":"Co-immunoprecipitation (WBP2-GPX4, WBP2-HSC70), competitive binding assay, lysosomal inhibitor experiments, ferroptosis assays, in vivo cisplatin AKI model, bioinformatics","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and competitive binding assay from a single lab establishing CMA-protective mechanism","pmids":["37516014"],"is_preprint":false},{"year":2024,"finding":"Dyrk1b kinase promotes ubiquitylation and proteasomal degradation of Wbp2 in a kinase activity-dependent manner in hepatocytes; restoration of hepatic Wbp2 partially rescues impaired glucose homeostasis caused by Dyrk1b overexpression, placing Wbp2 downstream of Dyrk1b in hepatic glucose regulation.","method":"Quantitative proteomics, in vivo mouse overexpression/knockout, ubiquitylation assay, kinase-dead mutant (Dyrk1b kinase inhibitor AZ191), Wbp2 restoration rescue experiment","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus in vivo genetic rescue from a single lab","pmids":["39296215"],"is_preprint":false},{"year":2024,"finding":"E3 ubiquitin ligase ITCH mediates proteasomal degradation of WBP2 (ligase-dead ITCH C830A mutant loses this activity); WBP2 overexpression drives chemoresistance via activation of the AMOTL2/c-JUN axis; exogenous ITCH suppresses WBP2-mediated chemoresistance and AMOTL2/c-JUN activation in a proteasome-dependent manner.","method":"RNA sequencing, co-immunoprecipitation, proteasome inhibitor (MG132) rescue, ITCH C830A ligase-dead mutagenesis, in vivo xenograft, AMOTL2 knockdown, c-JUN antagonist","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus proteasome-inhibitor rescue and in vivo validation, single lab","pmids":["39709035"],"is_preprint":false},{"year":2026,"finding":"E3 ubiquitin ligase WWP1 interacts with WBP2 in human heart tissue; co-localization and proximity ligation assays confirmed endogenous interaction. Using yeast two-hybrid, the interaction was mapped to WW domains 1 and 3 of WWP1 and PY (PPXY) domains 2 and 3 of WBP2.","method":"Yeast two-hybrid screen (human heart library), immunofluorescence, proximity ligation assay, domain-deletion mapping","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Y2H plus orthogonal proximity ligation assay and co-localization confirming interaction and mapping binding domains, single lab","pmids":["41891541"],"is_preprint":false}],"current_model":"WBP2 is an oncogenic transcriptional co-activator that functions as a scaffold/adaptor connecting multiple signaling pathways: it binds YAP/TAZ (and Drosophila Yorkie) via PPXY motif–WW domain interactions to enhance Hippo-pathway-driven transcription; it is targeted for ubiquitin-mediated proteasomal degradation by E3 ligases ITCH and WWP1, which is counteracted by Wnt/EGFR-mediated tyrosine phosphorylation of WBP2 or by competitive displacement via TAZ/YAP; it directly inactivates the Hippo kinases LATS2 and (via competitive binding to WWC3) LATS1; it interacts with ERα/PGR to regulate steroid-hormone-dependent transcription including MDR1; it stabilizes BTRC mRNA to activate NF-κB/IκBα signaling; it suppresses microRNA biogenesis by physically blocking microprocessor complex assembly; it protects GPX4 from chaperone-mediated lysosomal degradation by competing with HSC70; and in sperm it localizes to the postacrosomal sheath where it can activate oocytes upon injection."},"narrative":{"mechanistic_narrative":"WBP2 is a PPXY-motif adaptor protein that functions principally as a transcriptional co-activator within the Hippo pathway, where its C-terminal PPXY-containing region is recognized by the WW domains of YAP/TAZ to potentiate YAP/TAZ–TEAD-driven oncogenic transcription [PMID:20972459, PMID:21981024]; this role is evolutionarily conserved, as Drosophila Wbp2 binds Yorkie and genetically acts downstream of the Salvador-Warts-Hippo pathway to control tissue growth [PMID:21311569], and in mammalian epidermal stem cells WBP2 serves as a YAP co-factor governing proliferation under adhesion control [PMID:28332498]. WBP2 additionally suppresses Hippo kinase activity directly, binding and inhibiting LATS2 [PMID:33475198] and competitively displacing LATS1 from WWC3 via its PPXY motifs [PMID:33837178], driving YAP nuclear translocation and tumor progression. WBP2 protein levels are tightly governed by PPXY–WW-mediated ubiquitination: the E3 ligases ITCH and WWP1 bind WBP2 and target it for proteasomal degradation [PMID:27578003, PMID:41891541, PMID:32459862, PMID:39709035], a fate counteracted by Wnt/EGFR-driven tyrosine phosphorylation and competitive WW-domain occupancy by TAZ/YAP, with stabilized nuclear WBP2 engaging β-catenin to activate TCF transcription [PMID:27578003]. Beyond Hippo/Wnt, WBP2 acts as a co-activator for the steroid hormone receptors ERα and PGR, controlling MDR1 (ABCB1) transcription and chemoresistance [PMID:29937544, PMID:26881968], stabilizes BTRC mRNA to drive NF-κB signaling and TNBC invasion [PMID:34197030], physically blocks microprocessor (DGCR8/DDX5/DDX17) assembly to suppress microRNA biogenesis [PMID:34117091], and protects GPX4 from chaperone-mediated autophagy by competing with HSC70, thereby restraining ferroptosis [PMID:37516014]. WBP2 also localizes to the sperm postacrosomal sheath and can activate oocytes upon injection [PMID:30010725].","teleology":[{"year":2004,"claim":"Established an early function for WBP-2 as a protein-interaction adaptor by showing it binds a transcription factor outside its canonical WW-ligand context, raising the question of whether it is always a co-activator.","evidence":"GST pulldown and Co-IP of WBP-2 with Pax8, with a negative transcription co-activation result","pmids":["14531730"],"confidence":"Medium","gaps":["Co-activation was explicitly negative in this context","single lab, no in vivo validation","non-WW-domain interaction mode not generalized"]},{"year":2010,"claim":"Defined WBP2 as a required effector of TAZ oncogenicity, answering whether the TAZ WW domain–WBP2 interaction is functionally necessary rather than incidental.","evidence":"Reciprocal Co-IP, WW-domain point mutagenesis, forced-fusion rescue, transformation and reporter assays","pmids":["20972459"],"confidence":"High","gaps":["Mechanism of how WBP2 augments transcription not fully resolved","scope limited to TAZ/ITGB2 readout"]},{"year":2011,"claim":"Placed WBP2 genetically within the Hippo pathway and established evolutionary conservation by showing the fly ortholog enhances Yorkie and modifies warts phenotypes.","evidence":"Co-IP, genetic epistasis with warts loss-of-function, in vivo wing growth and reporter assays in Drosophila","pmids":["21311569"],"confidence":"High","gaps":["Mammalian pathway placement inferred from orthology","molecular step enhanced by Wbp2 not defined"]},{"year":2011,"claim":"Characterized the biophysical determinants of WBP2 recognition, answering which WW domains and PPXY consensus features govern binding.","evidence":"ITC, CD, molecular modeling, and MD simulation of YAP2 WW1/WW2 binding WBP1/WBP2 PPXY motifs","pmids":["21981024"],"confidence":"High","gaps":["Promiscuous binding leaves in-cell selectivity unexplained","no cellular functional readout"]},{"year":2012,"claim":"Extended WBP2 PPXY recognition to the WWOX tumor suppressor and resolved the structural basis of WW1 versus WW2 differential affinity.","evidence":"ITC, CD, modeling, and E66R/Y85W gain-of-function mutagenesis of WWOX WW domains","pmids":["22634283"],"confidence":"High","gaps":["Functional consequence of WWOX-WBP2 binding in cells not addressed","no in vivo validation"]},{"year":2016,"claim":"Defined the regulatory logic controlling WBP2 abundance, showing ITCH degrades WBP2 while Wnt/EGFR phosphorylation and TAZ/YAP competition stabilize it to drive β-catenin/TCF transcription.","evidence":"Reciprocal Co-IP, RNAi, proteasome inhibition, tyrosine phosphorylation analysis, transformation and xenograft assays","pmids":["27578003"],"confidence":"High","gaps":["Phosphosites mediating ITCH dissociation not fully mapped","interplay with Hippo-derived stabilization not quantified"]},{"year":2016,"claim":"Revealed an in vivo physiological role distinct from cancer, linking WBP2 ERα/PGR co-activation to cochlear synapse maintenance and hearing.","evidence":"Wbp2-knockout mice, auditory testing, electron microscopy of inner hair cell synapses","pmids":["26881968"],"confidence":"Medium","gaps":["Molecular link between WBP2/ESR1/PGR and synapse biology not dissected","target genes in cochlea unidentified"]},{"year":2017,"claim":"Demonstrated that WBP2 is a YAP co-factor governing epidermal stem cell proliferation under adhesion control rather than canonical Hippo signaling.","evidence":"Genome-wide RNAi screen, conditional mouse KO, TEAD reporter, reconstituted epidermis","pmids":["28332498"],"confidence":"High","gaps":["Adhesion-to-WBP2/YAP signaling intermediates undefined","context-dependence relative to LATS not resolved"]},{"year":2018,"claim":"Mapped how WBP2 itself is transcriptionally induced, identifying USF-1 and AKT-dependent phosphorylation as upstream drivers.","evidence":"Yeast one-hybrid, promoter reporter, ChIP, MS, AKT inhibition, E-box mutagenesis","pmids":["30183375"],"confidence":"Medium","gaps":["Single-lab transcriptional model","physiological contexts of USF-1-driven induction not surveyed"]},{"year":2018,"claim":"Established WBP2 as a co-activator for ERα at the MDR1 promoter, connecting it directly to chemoresistance.","evidence":"Reciprocal Co-IP, ChIP at MDR1 promoter, RNAi, viability/flow assays, xenograft","pmids":["29937544"],"confidence":"High","gaps":["Generality across ER target genes untested","co-activation mechanism at chromatin not detailed"]},{"year":2018,"claim":"Defined a Wnt-priming circuit in TNBC where WBP2 upregulates GPS1/TNIK to sustain JNK/Jun feedback and AXIN2 expression.","evidence":"RNAi with RNA-Seq and MS, functional rescue, inhibitor and migration/growth assays","pmids":["30442712"],"confidence":"Medium","gaps":["Direct versus indirect regulation of GPS1/TNIK unclear","single-lab pathway model"]},{"year":2018,"claim":"Identified a reproductive role, localizing WBP2 to the sperm postacrosomal sheath and showing it can activate oocytes.","evidence":"Immunoblot/IF/IHC localization and recombinant protein microinjection into MII oocytes","pmids":["30010725"],"confidence":"Medium","gaps":["Physiological requirement during natural fertilization untested","activation mechanism in oocyte unknown"]},{"year":2020,"claim":"Generalized the ITCH–WBP2 degradation axis to immune cells, linking WBP2 stability to CD4 T-cell proliferation.","evidence":"Itch-KO CD4 T-cell proteomics, stability assays, Co-IP, RNAi, in vitro/in vivo proliferation","pmids":["32459862"],"confidence":"Medium","gaps":["Transcriptional effectors of WBP2 in T cells unidentified","single-lab study"]},{"year":2021,"claim":"Showed WBP2 directly suppresses Hippo kinases, both inhibiting LATS2 and displacing LATS1 from WWC3 to promote YAP activation.","evidence":"Phosphoproteomics, Co-IP, phosphorylation/competitive-binding assays, RNAi epistasis, xenografts","pmids":["33475198","33837178"],"confidence":"Medium","gaps":["Whether LATS inhibition is direct enzymatic or steric not fully resolved","relative contribution of LATS1 vs LATS2 axes context-dependent"]},{"year":2021,"claim":"Uncovered non-transcriptional functions: WBP2 stabilizes BTRC mRNA to activate NF-κB and blocks microprocessor assembly to suppress miRNA biogenesis.","evidence":"mRNA stability and pri-miRNA processing assays, Co-IP of microprocessor components, NF-κB reporter, epistasis","pmids":["34197030","34117091"],"confidence":"Medium","gaps":["Mechanism of BTRC mRNA stabilization (RNA-binding direct or indirect) undefined","structural basis of microprocessor blockade unknown"]},{"year":2023,"claim":"Revealed a metabolic/redox role, showing WBP2 protects GPX4 from chaperone-mediated autophagy by competing with HSC70 to suppress ferroptosis.","evidence":"Co-IP, competitive binding assay, lysosomal inhibition, ferroptosis assays, cisplatin AKI model","pmids":["37516014"],"confidence":"Medium","gaps":["Whether WBP2 broadly regulates CMA substrates untested","single-lab mechanism"]},{"year":2024,"claim":"Broadened the ubiquitin-regulator network of WBP2, implicating Dyrk1b-driven degradation in hepatic glucose homeostasis and reaffirming ITCH-driven degradation in chemoresistance via AMOTL2/c-JUN.","evidence":"Quantitative proteomics, in vivo rescue, ubiquitylation assays, ITCH C830A ligase-dead mutant, MG132 rescue, xenografts","pmids":["39296215","39709035"],"confidence":"Medium","gaps":["Whether Dyrk1b directly phosphorylates WBP2 to flag degradation unproven","convergence of multiple E3/kinase inputs on WBP2 not integrated"]},{"year":2026,"claim":"Identified WWP1 as an additional WW-domain E3 ligase partner of WBP2 in cardiac tissue and mapped the interacting domains.","evidence":"Yeast two-hybrid (human heart library), proximity ligation assay, co-localization, domain-deletion mapping","pmids":["41891541"],"confidence":"Medium","gaps":["Functional consequence of WWP1-mediated WBP2 regulation in heart untested","ubiquitination of WBP2 by WWP1 not directly demonstrated"]},{"year":null,"claim":"How the many parallel WBP2 functions (transcriptional co-activation, Hippo kinase inhibition, mRNA stabilization, microprocessor blockade, CMA competition) are coordinated within a cell and which dominate in each tissue context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural or stoichiometric model integrating nuclear and cytoplasmic WBP2 roles","tissue-specific dominance of each function unmapped","post-translational code linking phosphorylation, ubiquitination, and partner choice undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,6,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,7,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13,14,15,17]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,8,13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[14,17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,4,13,14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,6,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,12,18,19,20]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[15,16]}],"complexes":[],"partners":["YAP1","TAZ","ITCH","WWP1","LATS2","WWC3","GPX4","ESR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969T9","full_name":"WW domain-binding protein 2","aliases":[],"length_aa":261,"mass_kda":28.1,"function":"Acts as a transcriptional coactivator of estrogen and progesterone receptors (ESR1 and PGR) upon hormone activation (PubMed:16772533). In presence of estrogen, binds to ESR1-responsive promoters (PubMed:16772533). Synergizes with YAP1 to enhance PGR activity (PubMed:16772533). Modulates expression of post-synaptic scaffolding proteins via regulation of ESR1, ESR2 and PGR (By similarity)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q969T9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WBP2","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000132471","cell_line_id":"CID001009","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":2},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"DYNC1LI1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001009","total_profiled":1310},"omim":[{"mim_id":"617639","title":"DEAFNESS, AUTOSOMAL RECESSIVE 107; DFNB107","url":"https://www.omim.org/entry/617639"},{"mim_id":"610981","title":"WWBP2 N-TERMINAL-LIKE PROTEIN; WBP2NL","url":"https://www.omim.org/entry/610981"},{"mim_id":"606962","title":"WW DOMAIN-BINDING PROTEIN 2; WBP2","url":"https://www.omim.org/entry/606962"},{"mim_id":"606961","title":"WW DOMAIN-BINDING PROTEIN 1; WBP1","url":"https://www.omim.org/entry/606961"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WBP2"},"hgnc":{"alias_symbol":["WBP-2","GRAMD6"],"prev_symbol":[]},"alphafold":{"accession":"Q969T9","domains":[{"cath_id":"2.30.29.30","chopping":"21-134","consensus_level":"high","plddt":95.5352,"start":21,"end":134}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969T9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969T9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969T9-F1-predicted_aligned_error_v6.png","plddt_mean":72.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WBP2","jax_strain_url":"https://www.jax.org/strain/search?query=WBP2"},"sequence":{"accession":"Q969T9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969T9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969T9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969T9"}},"corpus_meta":[{"pmid":"20972459","id":"PMC_20972459","title":"WW domain-mediated interaction with Wbp2 is important for the oncogenic property of TAZ.","date":"2010","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/20972459","citation_count":93,"is_preprint":false},{"pmid":"28332498","id":"PMC_28332498","title":"A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28332498","citation_count":83,"is_preprint":false},{"pmid":"27578003","id":"PMC_27578003","title":"Wnt Signaling Promotes Breast Cancer by Blocking ITCH-Mediated Degradation of YAP/TAZ Transcriptional Coactivator WBP2.","date":"2016","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27578003","citation_count":70,"is_preprint":false},{"pmid":"21311569","id":"PMC_21311569","title":"Wbp2 cooperates with Yorkie to drive tissue growth downstream of the Salvador-Warts-Hippo pathway.","date":"2011","source":"Cell death and 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30442712","citation_count":23,"is_preprint":false},{"pmid":"30010725","id":"PMC_30010725","title":"WBP2 shares a common location in mouse spermatozoa with WBP2NL/PAWP and like its descendent is a candidate mouse oocyte-activating factor.","date":"2018","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/30010725","citation_count":23,"is_preprint":false},{"pmid":"34197030","id":"PMC_34197030","title":"WBP2 promotes BTRC mRNA stability to drive migration and invasion in triple-negative breast cancer via NF-κB activation.","date":"2021","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34197030","citation_count":21,"is_preprint":false},{"pmid":"33837178","id":"PMC_33837178","title":"WBP2 negatively regulates the Hippo pathway by competitively binding to WWC3 with LATS1 to promote non-small cell lung cancer progression.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33837178","citation_count":17,"is_preprint":false},{"pmid":"30183375","id":"PMC_30183375","title":"Phosphorylation of E-box binding USF-1 by PI3K/AKT enhances its transcriptional activation of the WBP2 oncogene in breast cancer cells.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30183375","citation_count":17,"is_preprint":false},{"pmid":"30593516","id":"PMC_30593516","title":"Elevated WBP2 Expression in HER2-positive Breast Cancers Correlates with Sensitivity to Trastuzumab-based Neoadjuvant Therapy: A Retrospective and Multicentric Study.","date":"2018","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/30593516","citation_count":15,"is_preprint":false},{"pmid":"31597592","id":"PMC_31597592","title":"Localisation of phospholipase Cζ1 (PLCZ1) and postacrosomal WW-binding protein (WBP2 N-terminal like) on equine spermatozoa and flow cytometry quantification of PLCZ1 and association with cleavage in vitro.","date":"2019","source":"Reproduction, fertility, and development","url":"https://pubmed.ncbi.nlm.nih.gov/31597592","citation_count":12,"is_preprint":false},{"pmid":"33475198","id":"PMC_33475198","title":"WBP2 promotes gastric cancer cell migration via novel targeting of LATS2 kinase in the Hippo tumor suppressor pathway.","date":"2021","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/33475198","citation_count":11,"is_preprint":false},{"pmid":"36654949","id":"PMC_36654949","title":"WW domain binding protein 2 (WBP2) as an oncogene in breast cancer: mechanisms and therapeutic prospects-a narrative review.","date":"2022","source":"Gland 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alliance","url":"https://pubmed.ncbi.nlm.nih.gov/34117091","citation_count":6,"is_preprint":false},{"pmid":"34831354","id":"PMC_34831354","title":"Reciprocal Regulation of Hippo and WBP2 Signalling-Implications in Cancer Therapy.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34831354","citation_count":5,"is_preprint":false},{"pmid":"39296215","id":"PMC_39296215","title":"Hepatic Dyrk1b impairs systemic glucose homeostasis by modulating Wbp2 expression in a kinase activity-dependent manner.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39296215","citation_count":1,"is_preprint":false},{"pmid":"40958198","id":"PMC_40958198","title":"WBP2 and its network of transcription coregulators in an expanding repertoire of human cancers.","date":"2025","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40958198","citation_count":1,"is_preprint":false},{"pmid":"39486132","id":"PMC_39486132","title":"Evaluating the involvement and mutual interaction of wbp2 and yap in embryogenesis with an emphasis on liver function in zebrafish embryos.","date":"2024","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/39486132","citation_count":0,"is_preprint":false},{"pmid":"41891541","id":"PMC_41891541","title":"Identification and validation of an interaction between the E3 ubiquitin ligase WWP1 and the Transcriptional Co-Activator WBP2 in the human heart.","date":"2026","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/41891541","citation_count":0,"is_preprint":false},{"pmid":"41744824","id":"PMC_41744824","title":"WBP2 Attenuates Metformin Response in HER2-Positive Breast Cancer Cells by Repressing AMPK Activation and Inducing a Lower AMP:ATP Ratio State Through Enhanced ATP Production.","date":"2026","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/41744824","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18707,"output_tokens":5813,"usd":0.071658,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14376,"output_tokens":5338,"usd":0.102665,"stage2_stop_reason":"end_turn"},"total_usd":0.174323,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"The WW domain of TAZ binds WBP2 through interaction with the PPXY-containing C-terminal region of WBP2. Point mutations in the WW domain of TAZ abolished interaction with WBP2 and abolished TAZ-driven transformation and transcriptional activation of ITGB2. Forced fusion of WBP2 (or its TAZ-interacting C-terminal domain) to WW-mutant TAZ rescued transforming and transcription-promoting ability, establishing that WW domain–WBP2 interaction is required for TAZ oncogenic activity.\",\n      \"method\": \"Proteomic interaction screen, co-immunoprecipitation, WW domain point mutagenesis, cell transformation assay, transcription reporter assay, RNAi knockdown, overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, rescue experiment, and multiple functional readouts in a single rigorous study\",\n      \"pmids\": [\"20972459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Drosophila Wbp2 interacts with Yorkie (the fly ortholog of YAP/TAZ) in a WW domain- and PY motif-dependent manner, enhances Yorkie's transcriptional co-activator properties, is required for normal wing growth, and genetically suppresses overgrowth caused by loss of the warts tumor suppressor gene, placing Wbp2 as a downstream component of the Salvador-Warts-Hippo pathway.\",\n      \"method\": \"Co-immunoprecipitation, genetic epistasis (warts loss-of-function suppression), in vivo tissue growth assay, transcription reporter assay in Drosophila\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis, Co-IP, and multiple in vivo functional readouts independently support pathway placement\",\n      \"pmids\": [\"21311569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The WW1 domain of WWOX tumor suppressor binds PPXY motifs within WBP2 in a physiologically relevant manner; the WW2 domain shows no affinity for these motifs due to chemically distinct residues (E66/Y85 vs. R25/W44). Introduction of E66R/Y85W double substitution into WW2 confers gain-of-function binding to WBP2, stronger than wild-type WW1. WW1 is structurally disordered and folds upon ligand binding, while WW2 is pre-structured and acts as a chaperone to stabilize and augment WW1 ligand binding.\",\n      \"method\": \"Isothermal titration calorimetry, circular dichroism, molecular modeling, site-directed mutagenesis (E66R/Y85W gain-of-function)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biophysical methods plus mutagenesis establishing binding mechanism\",\n      \"pmids\": [\"22634283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The WW1 and WW2 domains of YAP2 both recognize PPXY motifs within WBP1 and WBP2 in a promiscuous manner; both WW domains strictly require the consensus PPXY sequence; a PPXYXG motif (glycine one residue C-terminal of the consensus tyrosine) is bound with highest affinity by both domains. Binding interactions are highly dynamic with rapid nanosecond-scale conformational fluctuations.\",\n      \"method\": \"Isothermal titration calorimetry, circular dichroism, molecular modeling, molecular dynamics simulation\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biophysical methods plus computational dynamics characterizing binding determinants\",\n      \"pmids\": [\"21981024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WBP2 protein stability is controlled by the E3 ubiquitin ligase ITCH, which binds WBP2 and targets it for ubiquitin-dependent proteasomal degradation. Wnt3A signaling stabilizes WBP2 by disrupting ITCH–WBP2 interaction via EGFR-mediated tyrosine phosphorylation of WBP2 and competitive binding of TAZ/YAP. Stabilized nuclear WBP2 interacts with β-catenin and activates TCF-mediated transcription. ITCH silencing elevates WBP2 levels; ITCH-mediated WBP2 degradation inhibits TCF/β-catenin transcription, in vitro transformation, and in vivo tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, proteasome inhibitor treatment, in vitro transformation assay, in vivo xenograft, tyrosine phosphorylation analysis, somatic mutation analysis of ITCH\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional rescue, in vivo model, multiple orthogonal methods establishing ITCH-WBP2-β-catenin axis\",\n      \"pmids\": [\"27578003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WBP2 acts as a transcriptional coactivator for estrogen receptor α (ESR1) and progesterone receptor (PGR) in the cochlea; loss of Wbp2 expression in mice leads to progressive high-frequency hearing loss with a primary defect at inner hair cell afferent (glutamatergic) synapses.\",\n      \"method\": \"Mouse knockout (Wbp2-deficient), auditory function testing, electron microscopy of cochlear synapses, histology\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined synaptic phenotype, but molecular mechanism linking WBP2/ESR1/PGR to synapse biology not fully dissected in the abstract\",\n      \"pmids\": [\"26881968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WBP2 functions as a co-factor of YAP that enhances YAP/TEAD-mediated gene transcription in epidermal stem cells. WBP2 deletion in mouse skin reduces proliferation in neonatal and wounded adult epidermis. In reconstituted epidermis, YAP/WBP2 activity is controlled by intercellular adhesion rather than canonical Hippo signaling.\",\n      \"method\": \"Genome-wide pooled RNAi screen, mouse conditional knockout, immunofluorescence, TEAD reporter assay, reconstituted epidermis model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen, mouse KO with defined proliferative phenotype, and mechanistic epistasis placing WBP2 downstream of adhesion/YAP\",\n      \"pmids\": [\"28332498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"WBP-2 binds Pax8 (a thyroid-specific transcription factor) in vitro via pulldown and in vivo via co-immunoprecipitation; the interaction is mediated by a novel protein-interacting domain in the C-terminal portion of Pax8 (not a WW domain). WBP-2 does not act as a transcriptional co-activator of Pax8 but behaves as an adaptor molecule in this context.\",\n      \"method\": \"Immunological/yeast screening, GST pulldown, co-immunoprecipitation, transcription assay (negative result for co-activation)\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pulldown and Co-IP from a single lab; co-activation explicitly shown to be negative\",\n      \"pmids\": [\"14531730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WBP2 interacts with ERα (estrogen receptor α) and directly modulates MDR1 (ABCB1) transcription through binding to ERα; chromatin immunoprecipitation confirmed ERα occupancy at the MDR1 promoter is WBP2-dependent, increasing chemoresistance to doxorubicin.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), RNAi knockdown, overexpression, MTT cell viability, flow cytometry, in vivo xenograft\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ChIP directly demonstrating WBP2-ERα-MDR1 promoter axis, with in vivo validation\",\n      \"pmids\": [\"29937544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WBP2 primes TNBC cells for Wnt responses by upregulating GPS1 and TNIK; GPS1 activates the JNK/Jun pathway, which forms a positive feedback loop with TNIK to mediate Wnt-induced AXIN2 expression. WBP2 is required for expression of core Wnt target genes including AXIN2, which is essential for Wnt/WBP2-driven cancer growth and migration.\",\n      \"method\": \"RNAi coupled with RNA-Seq and mass spectrometry, functional rescue, migration and growth assays, pathway inhibitor studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with RNA-Seq and MS from a single lab; mechanistic pathway placement validated by rescue experiments\",\n      \"pmids\": [\"30442712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USF-1 (upstream stimulatory factor 1) is a key transcription factor that directly drives WBP2 transcription via an E-box motif in the WBP2 minimal promoter; AKT-mediated phosphorylation of USF-1 (stimulated by insulin/PI3K signaling) enhances USF-1 binding to the WBP2 promoter and activates WBP2 transcription.\",\n      \"method\": \"Yeast one-hybrid, promoter reporter assay, chromatin immunoprecipitation, tandem mass spectrometry, AKT inhibitor treatment, mutational analysis of E-box\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast one-hybrid, ChIP, and reporter assay from a single lab establishing transcriptional regulation mechanism\",\n      \"pmids\": [\"30183375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WBP2 is localized to the postacrosomal sheath (PAS) and perforatorium of the sperm perinuclear theca in mice, with highest expression in round spermatids during spermatogenesis. Microinjection of recombinant WBP2 into metaphase II mouse oocytes activates oocytes at comparable rates to WBP2NL (PAWP), identifying WBP2 as a candidate sperm-borne oocyte-activating factor.\",\n      \"method\": \"Immunoblotting, immunofluorescence, immunohistochemistry, recombinant protein microinjection into MII oocytes\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct microinjection functional assay combined with subcellular localization, from a single lab\",\n      \"pmids\": [\"30010725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ITCH (E3 ubiquitin ligase) attenuates CD4 T-cell proliferation by promoting WBP2 proteasomal degradation; Itch-deficient CD4 T cells show increased WBP2 protein stability and hyperproliferation. Itch and WBP2 physically interact in CD4 T cells. WBP2 knockdown reduces CD4 T-cell proliferation.\",\n      \"method\": \"Whole-cell proteomics of primary mouse Itch-KO CD4 T cells, protein stability assay, co-immunoprecipitation, RNAi knockdown, in vitro and in vivo proliferation assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus Co-IP plus functional knockdown, single lab\",\n      \"pmids\": [\"32459862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WBP2 competitively binds to the WW domain of WWC3 via its PPxY motifs, displacing LATS1 from the WWC3-LATS1 complex, thereby reducing LATS1 phosphorylation, suppressing Hippo pathway activity, and ultimately promoting YAP nuclear translocation and NSCLC progression.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, nuclear/cytoplasmic fractionation, gain- and loss-of-function experiments in lung cancer cells, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and phosphorylation assays establishing competitive binding mechanism, single lab\",\n      \"pmids\": [\"33837178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WBP2 physically interacts with LATS2 kinase and inhibits LATS2 phosphorylation and activity; WBP2 knockdown increases p-LATS2 with concomitant increase in p-YAP, causing cytoplasmic YAP retention and inhibition of YAP/TEAD target genes (CTGF, CYR61). Loss of LATS2 reverses Hippo pathway activation caused by WBP2 knockdown, establishing LATS2 as the functional effector downstream of WBP2 in this context.\",\n      \"method\": \"Mass spectrometry-based phosphoproteomics, co-immunoprecipitation, phosphorylation assay, RNAi epistasis (LATS2 rescue), reporter assay, migration assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics, Co-IP, and genetic epistasis from single lab\",\n      \"pmids\": [\"33475198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WBP2 suppresses microRNA biogenesis by blocking processing of pri-miRNAs to pre-miRNAs; mechanistically, WBP2 physically interacts with components of the microprocessor complex (DGCR8, DDX5, DDX17) and negatively regulates assembly of this complex. WBP2 blocks the tumor-suppressive properties of DGCR8.\",\n      \"method\": \"Co-immunoprecipitation of microprocessor components, pri-miRNA processing assay, 2D and 3D in vitro proliferation assays, RNAi\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional processing assay, single lab\",\n      \"pmids\": [\"34117091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WBP2 promotes TNBC cell migration and invasion via TNF-α-stimulated NF-κB activation; mechanistically, WBP2 enhances mRNA stability of BTRC (β-TrCP), the E3 ligase that ubiquitinates IκBα, leading to IκBα degradation and NF-κB nuclear translocation. IκBα overexpression rescues the WBP2-driven invasive phenotype; BTRC loss blocks WBP2-driven migration.\",\n      \"method\": \"Proteogenomic analysis (TCGA), RNAi knockdown, mRNA stability assay, NF-κB reporter assay, nuclear fractionation, migration/invasion assays, epistasis (IκBα rescue, BTRC knockdown)\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA stability assay, reporter assay, and genetic epistasis from single lab\",\n      \"pmids\": [\"34197030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WBP2 interacts with GPX4 via its PPXY1 motif and inhibits ferroptosis by competing with HSC70 for binding to KFERQ-like motifs on GPX4, thereby decelerating chaperone-mediated autophagy (CMA) and lysosomal degradation of GPX4. WBP2 downregulation in cisplatin-induced AKI accelerates GPX4 degradation and ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation (WBP2-GPX4, WBP2-HSC70), competitive binding assay, lysosomal inhibitor experiments, ferroptosis assays, in vivo cisplatin AKI model, bioinformatics\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and competitive binding assay from a single lab establishing CMA-protective mechanism\",\n      \"pmids\": [\"37516014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Dyrk1b kinase promotes ubiquitylation and proteasomal degradation of Wbp2 in a kinase activity-dependent manner in hepatocytes; restoration of hepatic Wbp2 partially rescues impaired glucose homeostasis caused by Dyrk1b overexpression, placing Wbp2 downstream of Dyrk1b in hepatic glucose regulation.\",\n      \"method\": \"Quantitative proteomics, in vivo mouse overexpression/knockout, ubiquitylation assay, kinase-dead mutant (Dyrk1b kinase inhibitor AZ191), Wbp2 restoration rescue experiment\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus in vivo genetic rescue from a single lab\",\n      \"pmids\": [\"39296215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"E3 ubiquitin ligase ITCH mediates proteasomal degradation of WBP2 (ligase-dead ITCH C830A mutant loses this activity); WBP2 overexpression drives chemoresistance via activation of the AMOTL2/c-JUN axis; exogenous ITCH suppresses WBP2-mediated chemoresistance and AMOTL2/c-JUN activation in a proteasome-dependent manner.\",\n      \"method\": \"RNA sequencing, co-immunoprecipitation, proteasome inhibitor (MG132) rescue, ITCH C830A ligase-dead mutagenesis, in vivo xenograft, AMOTL2 knockdown, c-JUN antagonist\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus proteasome-inhibitor rescue and in vivo validation, single lab\",\n      \"pmids\": [\"39709035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"E3 ubiquitin ligase WWP1 interacts with WBP2 in human heart tissue; co-localization and proximity ligation assays confirmed endogenous interaction. Using yeast two-hybrid, the interaction was mapped to WW domains 1 and 3 of WWP1 and PY (PPXY) domains 2 and 3 of WBP2.\",\n      \"method\": \"Yeast two-hybrid screen (human heart library), immunofluorescence, proximity ligation assay, domain-deletion mapping\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Y2H plus orthogonal proximity ligation assay and co-localization confirming interaction and mapping binding domains, single lab\",\n      \"pmids\": [\"41891541\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WBP2 is an oncogenic transcriptional co-activator that functions as a scaffold/adaptor connecting multiple signaling pathways: it binds YAP/TAZ (and Drosophila Yorkie) via PPXY motif–WW domain interactions to enhance Hippo-pathway-driven transcription; it is targeted for ubiquitin-mediated proteasomal degradation by E3 ligases ITCH and WWP1, which is counteracted by Wnt/EGFR-mediated tyrosine phosphorylation of WBP2 or by competitive displacement via TAZ/YAP; it directly inactivates the Hippo kinases LATS2 and (via competitive binding to WWC3) LATS1; it interacts with ERα/PGR to regulate steroid-hormone-dependent transcription including MDR1; it stabilizes BTRC mRNA to activate NF-κB/IκBα signaling; it suppresses microRNA biogenesis by physically blocking microprocessor complex assembly; it protects GPX4 from chaperone-mediated lysosomal degradation by competing with HSC70; and in sperm it localizes to the postacrosomal sheath where it can activate oocytes upon injection.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WBP2 is a PPXY-motif adaptor protein that functions principally as a transcriptional co-activator within the Hippo pathway, where its C-terminal PPXY-containing region is recognized by the WW domains of YAP/TAZ to potentiate YAP/TAZ–TEAD-driven oncogenic transcription [#0, #3]; this role is evolutionarily conserved, as Drosophila Wbp2 binds Yorkie and genetically acts downstream of the Salvador-Warts-Hippo pathway to control tissue growth [#1], and in mammalian epidermal stem cells WBP2 serves as a YAP co-factor governing proliferation under adhesion control [#6]. WBP2 additionally suppresses Hippo kinase activity directly, binding and inhibiting LATS2 [#14] and competitively displacing LATS1 from WWC3 via its PPXY motifs [#13], driving YAP nuclear translocation and tumor progression. WBP2 protein levels are tightly governed by PPXY–WW-mediated ubiquitination: the E3 ligases ITCH and WWP1 bind WBP2 and target it for proteasomal degradation [#4, #20, #12, #19], a fate counteracted by Wnt/EGFR-driven tyrosine phosphorylation and competitive WW-domain occupancy by TAZ/YAP, with stabilized nuclear WBP2 engaging β-catenin to activate TCF transcription [#4]. Beyond Hippo/Wnt, WBP2 acts as a co-activator for the steroid hormone receptors ERα and PGR, controlling MDR1 (ABCB1) transcription and chemoresistance [#8, #5], stabilizes BTRC mRNA to drive NF-κB signaling and TNBC invasion [#16], physically blocks microprocessor (DGCR8/DDX5/DDX17) assembly to suppress microRNA biogenesis [#15], and protects GPX4 from chaperone-mediated autophagy by competing with HSC70, thereby restraining ferroptosis [#17]. WBP2 also localizes to the sperm postacrosomal sheath and can activate oocytes upon injection [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established an early function for WBP-2 as a protein-interaction adaptor by showing it binds a transcription factor outside its canonical WW-ligand context, raising the question of whether it is always a co-activator.\",\n      \"evidence\": \"GST pulldown and Co-IP of WBP-2 with Pax8, with a negative transcription co-activation result\",\n      \"pmids\": [\"14531730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-activation was explicitly negative in this context\", \"single lab, no in vivo validation\", \"non-WW-domain interaction mode not generalized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined WBP2 as a required effector of TAZ oncogenicity, answering whether the TAZ WW domain–WBP2 interaction is functionally necessary rather than incidental.\",\n      \"evidence\": \"Reciprocal Co-IP, WW-domain point mutagenesis, forced-fusion rescue, transformation and reporter assays\",\n      \"pmids\": [\"20972459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of how WBP2 augments transcription not fully resolved\", \"scope limited to TAZ/ITGB2 readout\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed WBP2 genetically within the Hippo pathway and established evolutionary conservation by showing the fly ortholog enhances Yorkie and modifies warts phenotypes.\",\n      \"evidence\": \"Co-IP, genetic epistasis with warts loss-of-function, in vivo wing growth and reporter assays in Drosophila\",\n      \"pmids\": [\"21311569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian pathway placement inferred from orthology\", \"molecular step enhanced by Wbp2 not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Characterized the biophysical determinants of WBP2 recognition, answering which WW domains and PPXY consensus features govern binding.\",\n      \"evidence\": \"ITC, CD, molecular modeling, and MD simulation of YAP2 WW1/WW2 binding WBP1/WBP2 PPXY motifs\",\n      \"pmids\": [\"21981024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Promiscuous binding leaves in-cell selectivity unexplained\", \"no cellular functional readout\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended WBP2 PPXY recognition to the WWOX tumor suppressor and resolved the structural basis of WW1 versus WW2 differential affinity.\",\n      \"evidence\": \"ITC, CD, modeling, and E66R/Y85W gain-of-function mutagenesis of WWOX WW domains\",\n      \"pmids\": [\"22634283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of WWOX-WBP2 binding in cells not addressed\", \"no in vivo validation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the regulatory logic controlling WBP2 abundance, showing ITCH degrades WBP2 while Wnt/EGFR phosphorylation and TAZ/YAP competition stabilize it to drive β-catenin/TCF transcription.\",\n      \"evidence\": \"Reciprocal Co-IP, RNAi, proteasome inhibition, tyrosine phosphorylation analysis, transformation and xenograft assays\",\n      \"pmids\": [\"27578003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosites mediating ITCH dissociation not fully mapped\", \"interplay with Hippo-derived stabilization not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed an in vivo physiological role distinct from cancer, linking WBP2 ERα/PGR co-activation to cochlear synapse maintenance and hearing.\",\n      \"evidence\": \"Wbp2-knockout mice, auditory testing, electron microscopy of inner hair cell synapses\",\n      \"pmids\": [\"26881968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between WBP2/ESR1/PGR and synapse biology not dissected\", \"target genes in cochlea unidentified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that WBP2 is a YAP co-factor governing epidermal stem cell proliferation under adhesion control rather than canonical Hippo signaling.\",\n      \"evidence\": \"Genome-wide RNAi screen, conditional mouse KO, TEAD reporter, reconstituted epidermis\",\n      \"pmids\": [\"28332498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adhesion-to-WBP2/YAP signaling intermediates undefined\", \"context-dependence relative to LATS not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped how WBP2 itself is transcriptionally induced, identifying USF-1 and AKT-dependent phosphorylation as upstream drivers.\",\n      \"evidence\": \"Yeast one-hybrid, promoter reporter, ChIP, MS, AKT inhibition, E-box mutagenesis\",\n      \"pmids\": [\"30183375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab transcriptional model\", \"physiological contexts of USF-1-driven induction not surveyed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established WBP2 as a co-activator for ERα at the MDR1 promoter, connecting it directly to chemoresistance.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP at MDR1 promoter, RNAi, viability/flow assays, xenograft\",\n      \"pmids\": [\"29937544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality across ER target genes untested\", \"co-activation mechanism at chromatin not detailed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a Wnt-priming circuit in TNBC where WBP2 upregulates GPS1/TNIK to sustain JNK/Jun feedback and AXIN2 expression.\",\n      \"evidence\": \"RNAi with RNA-Seq and MS, functional rescue, inhibitor and migration/growth assays\",\n      \"pmids\": [\"30442712\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect regulation of GPS1/TNIK unclear\", \"single-lab pathway model\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a reproductive role, localizing WBP2 to the sperm postacrosomal sheath and showing it can activate oocytes.\",\n      \"evidence\": \"Immunoblot/IF/IHC localization and recombinant protein microinjection into MII oocytes\",\n      \"pmids\": [\"30010725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological requirement during natural fertilization untested\", \"activation mechanism in oocyte unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Generalized the ITCH–WBP2 degradation axis to immune cells, linking WBP2 stability to CD4 T-cell proliferation.\",\n      \"evidence\": \"Itch-KO CD4 T-cell proteomics, stability assays, Co-IP, RNAi, in vitro/in vivo proliferation\",\n      \"pmids\": [\"32459862\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional effectors of WBP2 in T cells unidentified\", \"single-lab study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed WBP2 directly suppresses Hippo kinases, both inhibiting LATS2 and displacing LATS1 from WWC3 to promote YAP activation.\",\n      \"evidence\": \"Phosphoproteomics, Co-IP, phosphorylation/competitive-binding assays, RNAi epistasis, xenografts\",\n      \"pmids\": [\"33475198\", \"33837178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LATS inhibition is direct enzymatic or steric not fully resolved\", \"relative contribution of LATS1 vs LATS2 axes context-dependent\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered non-transcriptional functions: WBP2 stabilizes BTRC mRNA to activate NF-κB and blocks microprocessor assembly to suppress miRNA biogenesis.\",\n      \"evidence\": \"mRNA stability and pri-miRNA processing assays, Co-IP of microprocessor components, NF-κB reporter, epistasis\",\n      \"pmids\": [\"34197030\", \"34117091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of BTRC mRNA stabilization (RNA-binding direct or indirect) undefined\", \"structural basis of microprocessor blockade unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a metabolic/redox role, showing WBP2 protects GPX4 from chaperone-mediated autophagy by competing with HSC70 to suppress ferroptosis.\",\n      \"evidence\": \"Co-IP, competitive binding assay, lysosomal inhibition, ferroptosis assays, cisplatin AKI model\",\n      \"pmids\": [\"37516014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether WBP2 broadly regulates CMA substrates untested\", \"single-lab mechanism\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Broadened the ubiquitin-regulator network of WBP2, implicating Dyrk1b-driven degradation in hepatic glucose homeostasis and reaffirming ITCH-driven degradation in chemoresistance via AMOTL2/c-JUN.\",\n      \"evidence\": \"Quantitative proteomics, in vivo rescue, ubiquitylation assays, ITCH C830A ligase-dead mutant, MG132 rescue, xenografts\",\n      \"pmids\": [\"39296215\", \"39709035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Dyrk1b directly phosphorylates WBP2 to flag degradation unproven\", \"convergence of multiple E3/kinase inputs on WBP2 not integrated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified WWP1 as an additional WW-domain E3 ligase partner of WBP2 in cardiac tissue and mapped the interacting domains.\",\n      \"evidence\": \"Yeast two-hybrid (human heart library), proximity ligation assay, co-localization, domain-deletion mapping\",\n      \"pmids\": [\"41891541\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of WWP1-mediated WBP2 regulation in heart untested\", \"ubiquitination of WBP2 by WWP1 not directly demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many parallel WBP2 functions (transcriptional co-activation, Hippo kinase inhibition, mRNA stabilization, microprocessor blockade, CMA competition) are coordinated within a cell and which dominate in each tissue context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural or stoichiometric model integrating nuclear and cytoplasmic WBP2 roles\", \"tissue-specific dominance of each function unmapped\", \"post-translational code linking phosphorylation, ubiquitination, and partner choice undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 6, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 7, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 14, 15, 17]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 8, 13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [14, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4, 13, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 12, 18, 19, 20]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [15, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"YAP1\", \"TAZ\", \"ITCH\", \"WWP1\", \"LATS2\", \"WWC3\", \"GPX4\", \"ESR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}