{"gene":"YAP1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1994,"finding":"YAP65 (YAP1) was identified as a novel protein that binds the SH3 domain of the Yes proto-oncogene product via a proline-rich motif (PVKQPPPLAP). Competition assays with synthetic peptides confirmed the involvement of this proline-rich sequence. YAP65 also bound SH3 domains of Nck, Crk, Src, Abl, and GAP.","method":"Anti-idiotypic antibody screen, co-immunoprecipitation, competition assays with synthetic peptides","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — original biochemical characterization with peptide competition assays confirming binding interface, replicated binding to multiple SH3-domain proteins","pmids":["8035999"],"is_preprint":false},{"year":2001,"finding":"YAP65 functions as a transcriptional coactivator for TEAD/TEF transcription factors: it interacts specifically with the C-terminus of all four TEAD proteins via a novel TEAD-binding domain at its N-terminus, provides the transcriptional activation domain for TEAD-dependent transcription, and accumulates in the cytoplasm as a complex with 14-3-3 when in excess. Both TEAD interaction and DNA binding by TEAD were required for transcriptional activation.","method":"Protein purification, co-immunoprecipitation, transcriptional reporter assays, subcellular fractionation, overexpression/squelching experiments","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical purification, co-IP with all four TEAD paralogs, functional reporter assays with domain mapping, multiple orthogonal methods","pmids":["11358867"],"is_preprint":false},{"year":2002,"finding":"YAP65 interacts with Smad7 (identified by yeast two-hybrid and confirmed by co-IP in COS-7 cells), potentiates Smad7's inhibitory activity against TGF-β/Smad3/4-dependent transcription, and augments the association of Smad7 with activated TGF-β receptor type I. A dominant-negative YAP65(1-301) reduced Smad7-TGFβRI interactions.","method":"Yeast two-hybrid screen, co-immunoprecipitation, transcriptional reporter assays, dominant-negative constructs","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid discovery confirmed by co-IP, functional reporter assays, and domain-mapping with dominant-negative construct; single lab but multiple orthogonal methods","pmids":["12118366"],"is_preprint":false},{"year":2006,"finding":"Homozygous knockout of Yap in mice causes developmental arrest at ~E8.5 with defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation, establishing essential in vivo roles for YAP1 in these developmental processes.","method":"Targeted gene disruption in mice, histology, PECAM1 immunostaining, alpha-globin expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean germline knockout with multiple orthogonal phenotypic readouts; well-controlled developmental study","pmids":["16354681"],"is_preprint":false},{"year":2007,"finding":"RUNX2 associates with YAP65 via a PPPY proline-rich motif in its C-terminal domain. Co-expression of RUNX2 and YAP65 synergistically promotes foci formation and anchorage-independent growth. A RUNX2(P409A) mutant that cannot bind YAP65 fails to cooperate with YAP65 in transformation. YAP65 overexpression prevented RUNX2-dependent downregulation of p21(CIP1).","method":"Co-immunoprecipitation, site-directed mutagenesis (RUNX2 P409A), soft agar/foci formation assays, luciferase reporter assays, DNA precipitation","journal":"Cancer biology & therapy","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — co-IP plus mutagenesis validation plus functional transformation assays; single lab but multiple orthogonal methods","pmids":["17438369"],"is_preprint":false},{"year":2016,"finding":"In liver myofibroblasts, integrin beta-1 signaling activates PAK proteins and YAP-1 as core pro-fibrotic mediators. YAP-1 is capable of perpetuating integrin beta-1 expression (positive feedback loop). Pharmacological inhibition of YAP-1 in vivo attenuates liver fibrosis.","method":"In vitro myofibroblast assays, in vivo pharmacological inhibition, gene knockdown","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacological and in vitro knockdown with defined cellular phenotypes; single lab but multiple model systems","pmids":["27535340"],"is_preprint":false},{"year":2016,"finding":"YAP1 was identified as a direct target of miR-375 in prostate cancer. Knockdown of YAP1 phenocopied miR-375 overexpression (inhibiting invasion and migration), and overexpression of YAP1 rescued anti-invasive effects of miR-375. The ZEB1 transcription factor directly represses miR-375 transcription, placing YAP1 downstream of a ZEB1-miR-375-YAP1 regulatory circuit controlling epithelial plasticity.","method":"miRNA target validation, siRNA knockdown, rescue overexpression, invasion/migration assays, multiple patient cohort analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (rescue experiment), phenotypic readouts with KD/OE; single lab","pmids":["27270433"],"is_preprint":false},{"year":2018,"finding":"YAP1/TEAD1 signaling induces mitochondrial biogenesis in endothelial cells and stimulates angiogenesis through PGC1α. A YAP1-S127A constitutively active mutant increased PGC1α expression and mitochondrial biogenesis; a YAP1-S94A mutant that fails to bind TEAD1 attenuated these effects. PGC1α knockdown inhibited YAP1-S127A-induced EC sprouting and vascular morphogenesis.","method":"Constitutively active and binding-deficient YAP1 mutants, TEAD1 knockdown, PGC1α knockdown, in vitro EC sprouting assays, in vivo fibrin gel vascular morphogenesis","journal":"Microvascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function mutant analysis plus in vivo rescue; single lab with multiple orthogonal approaches","pmids":["29680477"],"is_preprint":false},{"year":2018,"finding":"CDK8/19 kinase coordinates BMP4-induced EMT in a YAP1-dependent manner. Both genetic and pharmacological inhibition of CDK8/19 abrogated BMP-induced EMT, nuclear YAP1 localization, and tumor cell invasion. YAP1 activity was required for SMAD1-driven EMT in a matrix-rigidity-dependent manner.","method":"Genetic inhibition (siRNA), pharmacological inhibition, RNA-seq meta-analysis, in vitro invasion assays, in vivo syngeneic EMT model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple inhibition strategies plus in vivo model; single lab","pmids":["29780169"],"is_preprint":false},{"year":2018,"finding":"YAP1 interacts with TEAD transcription factors (TEADs) and AP-1, and this cooperative interaction on downstream gene transcription is required for osteoclastogenesis. Verteporfin (which inhibits YAP1-TEAD association) suppressed osteoclast formation and bone resorption. RANKL-induced NF-κB signaling was impaired when YAP1 was inhibited.","method":"shRNA-mediated knockdown, verteporfin pharmacological inhibition, co-immunoprecipitation, gene expression analysis, osteoclast differentiation assays","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP plus shRNA KD plus pharmacological inhibition with defined cellular phenotype; single lab","pmids":["29432919"],"is_preprint":false},{"year":2019,"finding":"STUB1 (E3 ubiquitin ligase) ubiquitinates YAP1 at K280 via K48-linked polyubiquitination, leading to YAP1 degradation. This suppresses cancer cell survival and chemoresistance. Low STUB1 expression correlates with increased YAP1 protein in gastric cancer.","method":"Co-immunoprecipitation, ubiquitination assays with site-specific mutants (K280), protein stability assays, cell viability assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay with site identification plus co-IP; single lab, moderate mechanistic depth","pmids":["31393050"],"is_preprint":false},{"year":2019,"finding":"BRCA1 facilitates YAP1 protein stabilization and Hippo pathway inactivation through ubiquitination of NF2. In BRCA1-deficient cells, Hippo pathway is turned on. A YAP1-5SA mutant (alanine substitutions at LATS1 recognition sites) resists degradation and rescues YAP1 transcriptional activity in BRCA1-deficient cells, and promotes EGF-independent proliferation and tumorigenesis.","method":"BRCA1 KO cells, YAP1 phosphorylation site mutagenesis (5SA/6SA mutants), ubiquitination assays, proliferation and tumorigenesis assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BRCA1 KO combined with phospho-site mutagenesis and functional rescue; single lab, multiple orthogonal methods","pmids":["30918126"],"is_preprint":false},{"year":2019,"finding":"FUS-DDIT3 fusion oncoprotein promotes YAP1 expression, nuclear localization, and transcriptional activity in myxoid liposarcoma cells, and physically associates with YAP1 in the nucleus. Pharmacologic inhibition of YAP1 impairs MLS cell growth in vitro and in vivo.","method":"Co-immunoprecipitation (nuclear fractionation), functional genomic screen, pharmacological inhibition, in vivo xenograft","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP showing physical association plus in vivo pharmacological inhibition; single lab","pmids":["30898787"],"is_preprint":false},{"year":2019,"finding":"AMOTL1 (Angiomotin Like 1) interacts with YAP1 in the cytoplasm and protects YAP1 from ubiquitin-mediated degradation. This interaction promotes YAP1 nuclear translocation to activate downstream targets such as CTGF. Knockdown of AMOTL1 impairs its oncogenic properties and reduces YAP1 protein levels.","method":"Co-immunoprecipitation, immunofluorescence, shRNA knockdown, ubiquitination assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal co-IP plus ubiquitination assay plus subcellular localization; single lab","pmids":["32313226"],"is_preprint":false},{"year":2019,"finding":"Angiomotin (Amot) and YAP1 form a complex critical for dendritic morphogenesis in hippocampal and Purkinje cells. Conditional deletion of Amot and Yap1 in neurons decreased Purkinje cell dendritic tree complexity and impaired motor coordination. This function does not rely on TEAD interactions or Hippo-dependent gene expression, but instead involves phosphorylation of S6 kinase and S6 ribosomal protein.","method":"Conditional neuronal knockout mice, in vitro hippocampal cultures, co-immunoprecipitation, phosphorylation assays, behavioral tests","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined cellular phenotype, mechanistic dissection via co-IP and phosphorylation assays showing TEAD-independent mechanism, multiple orthogonal approaches","pmids":["31042703"],"is_preprint":false},{"year":2019,"finding":"YAP1 fusions (YAP1-MAML2 and YAP1-NUTM1) in poromas strongly transactivate a TEAD reporter and promote anchorage-independent growth. Immunohistochemical staining showed nuclear expression of the N-terminal YAP1 portion with loss of the C-terminal portion, consistent with constitutive nuclear YAP1 activity in these fusion proteins.","method":"RNA sequencing, RT-PCR, FISH, immunohistochemistry, TEAD reporter assay, anchorage-independent growth assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional reporter assay plus transformation assay confirming oncogenic activity; replicated in large tumor cohort with FISH validation","pmids":["31145701"],"is_preprint":false},{"year":2019,"finding":"YAP1 interacts with epidermal growth factor receptor and TGF-β signaling pathways to regulate granulosa cell proliferation, differentiation, and survival. Nuclear (active) YAP1 is predominant in proliferative granulosa cells; cytoplasmic (inactive) YAP1 is in luteinized cells. Foxl2 promoter-driven knockout of Yap1 caused increased granulosa cell apoptosis, decreased corpora lutea, reduced ovarian size, and subfertility.","method":"Conditional knockout mice (Foxl2-Cre and Cyp19a1-Cre), in vitro pharmacological inhibition, co-IP, subcellular localization analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined phenotypes; mechanistic pathway interaction suggested by co-IP; single lab","pmids":["31199671"],"is_preprint":false},{"year":2019,"finding":"YAP1 directly represses Sox2 expression in early mouse embryos, preventing premature pluripotency onset prior to the 16-cell stage. This repression is sensitive to LATS kinase activity. TEAD4, YAP1, and WWTR1 together mediate direct transcriptional repression of Sox2.","method":"Yap1/Wwtr1/Tead4 knockout mouse embryos, gene expression analysis, genetic epistasis with LATS kinase inhibition","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined transcriptional phenotype plus epistasis with LATS; single lab","pmids":["31444221"],"is_preprint":false},{"year":2020,"finding":"Telomere dysfunction activates YAP1 via pATM/c-ABL-mediated signaling, upregulating pro-IL-18 expression in intestinal epithelium. Pharmacological inhibition of ATM or YAP1 dramatically reduces IL-18 and intestinal inflammation in mice with telomere dysfunction. This establishes a telomere dysfunction-ATM-YAP1-pro-IL-18 inflammatory pathway.","method":"Mouse telomere dysfunction models, pharmacological inhibition (ATM, YAP1, caspase-1 inhibitors), antibiotics treatment, patient biopsy analysis (γH2AX, YAP1, IL-18)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic and pharmacological interventions in vivo plus human patient tissue validation; multiple orthogonal methods","pmids":["32958778"],"is_preprint":false},{"year":2021,"finding":"Phosphorylation of YAP1 on canonical LATS1 sites enhances its rate of nuclear export (not entry). YAP1 import and export rates correlate within the same cell. YAP1 and TAZ rates of nuclear entry and exit are also correlated with each other.","method":"Optogenetic LOV-domain mitochondria sequestration system with blue-light release, live-cell fluorescence imaging, quantitative nuclear/cytoplasmic flux analysis, lattice light-sheet microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — novel optogenetic reconstitution method with quantitative kinetic measurements; single lab but highly rigorous and direct measurement of shuttling rates","pmids":["34060624"],"is_preprint":false},{"year":2021,"finding":"YAP1-MAML2 fusion primarily functions via TEAD-dependent YAP activity that is resistant to Hippo signaling. Expression of YAP1-MAML2 in mice induces meningioma-like tumors resembling NF2 mutant meningiomas. Constitutively active YAP1(S127/397A) alone is sufficient to induce similar tumors, indicating the YAP component drives oncogenesis. YAP-TEAD inhibitors inhibit viability of YAP1-MAML2-driven tumors ex vivo.","method":"Mouse tumor models, gene expression profiling, YAP-TEAD inhibitor treatment (ex vivo), constitutively active YAP1 expression, epistasis with Hippo signaling","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo tumor induction, constitutively active mutant, pharmacological inhibition; multiple orthogonal approaches","pmids":["36008139"],"is_preprint":false},{"year":2022,"finding":"HPV E7 activates YAP1 nuclear localization in basal epithelial cells by binding and degrading PTPN14 tumor suppressor. YAP1 transcriptional activity is required for E7 to extend primary keratinocyte lifespan. YAP1 activation by E7 causes cells to be retained in the basal compartment of stratified epithelia.","method":"HPV E7 expression, PTPN14 knockout, YAP1 nuclear localization assays, primary keratinocyte lifespan assays, stratified epithelium models","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic PTPN14 KO plus E7 expression with functional rescue; multiple cellular phenotype readouts; mechanistic pathway established","pmids":["35170430"],"is_preprint":false},{"year":2022,"finding":"HPV18 E7 degrades PTPN14, which decreases phosphorylation of LATS1 T1079 (active form) and YAP1 S127 (inhibitory phosphorylation). PTPN14-dependent differentiation requires LATS kinases and PTPN14 PPxY motifs. MST1/2 kinases and PTPN14 phosphatase activity are not required for PTPN14 to promote differentiation, establishing that PTPN14 acts upstream of LATS1 to inhibit YAP1.","method":"PTPN14 knockout, HPV18 E7 expression, LATS1 phosphorylation assays, YAP1 S127 phosphorylation assays, domain mutagenesis (PPxY motifs, phosphatase active site)","journal":"mBio","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — phosphorylation site mapping, domain mutagenesis, genetic KO; multiple orthogonal methods firmly placing PTPN14 upstream of LATS1-YAP1","pmids":["39248565"],"is_preprint":false},{"year":2022,"finding":"YAP1-TEAD complex activates DNMT1 expression, which directs hepatocyte-to-biliary epithelial cell fate switch through repression of hepatocyte-specific genes. DNMT1 re-expression restores ICC development following TEAD repression, establishing DNMT1 as a downstream effector of YAP1/TEAD in hepatocyte reprogramming.","method":"Sleeping beauty/hydrodynamic tail vein injection ICC model, Yap1/Sox9 conditional deletion, TEAD inhibition, chromatin immunoprecipitation sequencing, gain/loss-of-function studies","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq plus multiple genetic loss/gain-of-function experiments plus rescue; multiple orthogonal methods in vivo and in vitro","pmids":["35550144"],"is_preprint":false},{"year":2022,"finding":"YAP1 regulates gastruloid fate patterning by attenuating Nodal signaling. YAP1 knockout gastruloids show reduced ectoderm and enlarged mesoderm/endoderm. YAP1 directly represses chromatin accessibility and transcription of NODAL and FOXH1 genes, preventing hyperactive SMAD2/3 nuclear retention and thereby enabling ectoderm differentiation.","method":"YAP1 knockout hESC gastruloids, epigenome (ATAC-seq) and transcriptome (RNA-seq) analysis, immunostaining for SMAD2/3 localization","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO combined with chromatin accessibility and transcriptome data; mechanistic link established; multiple orthogonal methods","pmids":["35063126"],"is_preprint":false},{"year":2022,"finding":"Small-molecule cyanamide compounds form a covalent bond with a conserved cysteine in the TEAD palmitate-binding cavity, inhibiting YAP1 binding to TEADs with submicromolar IC50 values. Co-crystal structures with TEAD2 enabled structure-activity relationship studies. Inhibition suppressed CTGF mRNA and TEAD1-4 transcriptional activity in mammalian cells.","method":"Covalent inhibitor synthesis, co-crystal structures with TEAD2, time/concentration-dependent kinetics (kinact/KI), cellular reporter assays (CTGF mRNA, TEAD transcriptional activity), YAP1-TEAD binding inhibition assay","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — co-crystal structure plus covalent kinetics plus cellular functional validation; single lab but Tier 1 structural + biochemical evidence","pmids":["36562717"],"is_preprint":false},{"year":2022,"finding":"CIC (Capicua) directly represses YAP1 transcription by binding non-consensus GGAAGGAA DNA-binding motifs in a proximal YAP1 regulatory element in an ERK-regulated manner. Silencing YAP1 in CIC-deficient cells restores MAPK inhibitor sensitivity and suppresses tumor growth.","method":"ChIP, reporter assays with GGAA motif mutations, siRNA knockdown epistasis, tumor growth assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay with motif validation plus functional epistasis; single lab","pmids":["36198276"],"is_preprint":false},{"year":2022,"finding":"YAP1 and PRDM14 individually activate transcription of CALM2 and SLC2A1 (GLUT1) as key downstream targets. PRDM14 can rescue cell proliferation and tumorigenesis upon YAP1 suppression. CALM2 or SLC2A1 expression is required for this rescue, placing them as essential mediators of oncogenic YAP1 signaling.","method":"Genome-scale genetic rescue screen (inducible YAP1 shRNA), xenograft models, colon cancer organoids, transcriptional analysis","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-scale genetic screen with functional rescue validation in multiple model systems; single lab","pmids":["34990589"],"is_preprint":false},{"year":2022,"finding":"YAP1 activity alone (in a Hippo-pathway mutated background) is sufficient to maintain established mesothelioma tumor growth in vivo. Conditional YAP1 downregulation in established xenografts leads to inhibition of YAP1/TEAD-dependent gene transcription and tumor regression, but only in YAP1-activated Hippo-mutant background, not in Hippo-independent cancer cells.","method":"Conditional YAP1 knockdown in xenografts, in vitro apoptosis assays, in vivo tumor regression studies, gene expression analysis","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional in vivo KD with tumor regression phenotype plus isogenic control; single lab","pmids":["35689194"],"is_preprint":false},{"year":2023,"finding":"ATXN3 (deubiquitinase) interacts with the WW domains of YAP1 and protects YAP1 from ubiquitination-mediated degradation, promoting tumor growth. CRISPR-Cas9 deletion of ATXN3 decreases YAP1 protein without altering its mRNA. YAP1 reconstitution rescues the growth inhibition caused by ATXN3 suppression.","method":"CRISPR-Cas9 gene deletion, co-immunoprecipitation, ubiquitination assays, YAP1 rescue overexpression, immunohistology","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO plus co-IP plus ubiquitination assay plus rescue; single lab","pmids":["37818078"],"is_preprint":false},{"year":2023,"finding":"OTUD7B deubiquitinase deubiquitinates and stabilizes YAP1 protein, enhancing YAP1 activity and upregulating NUAK2 (and other YAP1 targets including Snail, Slug, CDK6, CTGF, BIRC5) to accelerate gastric cancer progression.","method":"Co-immunoprecipitation, ubiquitination assays, OTUD7B overexpression/knockdown, in vitro and in vivo tumor assays","journal":"Digestive and liver disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP plus ubiquitination assay plus in vivo xenograft; single lab","pmids":["37429790"],"is_preprint":false},{"year":2023,"finding":"ENO1, acting as an RNA-binding protein, binds CUG-rich elements in YAP1 mRNA to promote its translation. ENO1 and YAP1 cooperatively regulate arachidonic acid metabolism via inverse regulation of PLCB1 and HPGD, with subsequent PGE2 accumulation driving cancer progression.","method":"RNA-binding protein assay, mRNA translation assays, gene knockdown, metabolic profiling, in vivo tumor models","journal":"Nature chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-binding assay plus functional metabolic readouts; single lab but novel mechanism with multiple validation approaches","pmids":["37500770"],"is_preprint":false},{"year":2023,"finding":"YAP1 inhibits progesterone receptor (PGR) expression through upregulation of miR-21-5p. YAP1 binding to the miR-21 promoter region was confirmed by ChIP-PCR; miR-21-5p in turn reduces PGR mRNA via RNA immunoprecipitation-validated interaction. Knockdown of YAP1 or verteporfin treatment reduces miR-21-5p, increases PGR expression, and enhances decidualization.","method":"ChIP-PCR, RNA immunoprecipitation, YAP1 inhibitor (verteporfin), siRNA knockdown, mouse endometriosis model","journal":"Human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-PCR and RNA-IP establishing direct YAP1-miR-21-PGR axis plus in vivo mouse model; single lab","pmids":["37071897"],"is_preprint":false},{"year":2024,"finding":"TRAF6 stabilizes YAP1 protein through K63-linked polyubiquitination, which promotes formation of a YAP1/TFCP2 transcriptional complex that drives PD-L1 transcription in melanoma cells. TRAF6 suppression downregulates PD-L1 membrane expression.","method":"CRISPR interference screening, in vitro and in vivo assays, co-immunoprecipitation, ubiquitination assays (K63-linkage specific)","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP plus K63-specific ubiquitination assay plus functional in vivo assay; single lab","pmids":["38583649"],"is_preprint":false},{"year":2024,"finding":"CBX4 (SUMO E3 ligase) induces SUMO1 modification of YAP1 at K97 and K280, which competitively inhibits YAP1 S127 phosphorylation (inhibitory Hippo phosphorylation), thereby preserving YAP1 stability and promoting its cytoplasm-nuclear transport and anti-senescence activity in gastric cancer.","method":"Co-immunoprecipitation, SUMOylation site mutagenesis (K97, K280), phosphorylation assays (S127), ChIP, high-throughput sequencing","journal":"Drug resistance updates","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SUMOylation site mapping with competition of phosphorylation; multiple biochemical methods; single lab","pmids":["39154499"],"is_preprint":false},{"year":2024,"finding":"NEK1 kinase phosphorylates YAP1 at Y407 via an AR→TLK1B→NEK1→YAP1-Y407 sequential kinase cascade. YAP1-Y407F dominant mutant reprograms the YAP1 transcriptome, reduces TEAD- and p73-regulated gene expression, and mediates sensitivity to MMC. YAP1 overexpression (but not Y407F) transforms LNCaP cells to androgen-independent growth.","method":"Phospho-site mutagenesis (Y407F), transcriptome reprogramming analysis, dominant expression assays, NEK1 haploinsufficient TRAMP mice, immunohistochemistry","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-site mutagenesis with functional readouts plus in vivo mouse model; single lab","pmids":["36979713"],"is_preprint":false},{"year":2024,"finding":"Stromal softness promotes YAP1 degradation via an autophagic-lysosomal pathway (not Hippo/proteasome). In soft extracellular matrix, PTEN is upregulated and promotes lysosomal biogenesis, activating cathepsins that directly degrade YAP1. Purified cathepsin L can directly digest YAP1 under acidic conditions in vitro.","method":"In vitro reconstitution (purified cathepsin L + YAP1), hydrogel stiffness matrices, lysosomal inhibition (chloroquine), PTEN manipulation, in vivo liver fibrosis models","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution of cathepsin L-mediated YAP1 degradation plus cellular and in vivo corroboration; novel non-Hippo degradation mechanism","pmids":["39460766"],"is_preprint":false},{"year":2024,"finding":"DAPAGLIFLOZIN (SGLT2 inhibitor) suppresses gastric cancer by decreasing OTUD5 expression, which increases YAP1 ubiquitination and degradation. Overexpression of OTUD5 in gastric cancer cells partly reverses the anti-tumor effect of dapagliflozin, establishing OTUD5 as a deubiquitinase that stabilizes YAP1.","method":"OTUD5 overexpression rescue, ubiquitination assays, in vitro and in vivo tumor models, drug treatment","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — rescue experiment plus ubiquitination assay; single lab, moderate mechanistic depth","pmids":["39293571"],"is_preprint":false},{"year":2019,"finding":"Endothelial YAP1 regulates Tie2 (angiogenic factor receptor) expression; knockdown of YAP1 in endothelial cells decreases Tie2 expression and inhibits EC sprouting, epithelial cell budding, vascular morphogenesis, and compensatory lung growth after pneumonectomy.","method":"siRNA knockdown in endothelial cells, in vitro sprouting assay, in vivo gel implantation on mouse lung, pneumonectomy model, Tie2 expression analysis","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined molecular (Tie2) and cellular phenotypes in vitro and in vivo; single lab","pmids":["30156429"],"is_preprint":false},{"year":2016,"finding":"MST1 activation by shikonin inhibits GLUT1 and C-MYC expression via the MST1-YAP1-TEAD1 axis in human leukemia cells. RNAi experiments confirmed this regulatory axis. YAP1 positively regulates C-MYC mRNA in complex with TEAD1, while it negatively regulates C-MYC levels in cooperation with MST1. Depletion of TEAD1 inhibits lactate production.","method":"RNAi knockdown of pathway components, pharmacological MST1 activation, TEAD1 ChIP binding site analysis, lactate production assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RNAi epistasis establishing axis, bioinformatic binding site validation; single lab","pmids":["27793648"],"is_preprint":false},{"year":2020,"finding":"METTL14-mediated m6A modification of YAP1 mRNA promotes YTHDF2-mediated transcript decay, reducing YAP1 expression and stemness in TNBC. Loss of METTL14 (driven by LSD1-mediated H3K4 demethylation) blocks m6A on YAP1 mRNA, preventing YTHDF2-dependent decay and sustaining YAP1 protein levels and Hippo-independent YAP1 signaling.","method":"m6A-IP sequencing, RNA-IP, ChIP, luciferase reporter assays, KO/KD experiments, tissue microarray validation","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-IP-seq plus RNA-IP plus ChIP establishing epi-transcriptional mechanism; single lab with multiple orthogonal methods","pmids":["39563370"],"is_preprint":false}],"current_model":"YAP1 is a transcriptional coactivator that primarily functions by binding TEAD transcription factors through its N-terminal TEAD-binding domain to drive target gene expression; its activity is regulated by the Hippo kinase cascade (MST1/2→LATS1/2), which phosphorylates YAP1 at S127 to promote cytoplasmic sequestration by 14-3-3 and at additional sites to enhance nuclear export, while YAP1 protein stability is controlled by multiple ubiquitin E3 ligases (STUB1, via K48-linked ubiquitination at K280) and deubiquitinases (ATXN3, OTUD7B, OTUD5, TRAF6 via K63-linkage), SUMOylation at K97/K280 (by CBX4, competing with S127 phosphorylation), tyrosine phosphorylation at Y407 by NEK1, and lysosomal-cathepsin-mediated degradation triggered by matrix softness; YAP1 also interacts with Smad7 (potentiating TGF-β pathway inhibition), RUNX2, Angiomotin/AMOTL1, FUS-DDIT3, and mTOR, and drives tissue-specific programs including vasculogenesis, dendritic morphogenesis, germ layer specification, and inflammatory responses, while oncogenic YAP1 gene fusions (YAP1-MAML2, YAP1-NUTM1, YAP1-TFE3) function through constitutive TEAD-dependent transcriptional activity resistant to Hippo signaling."},"narrative":{"mechanistic_narrative":"YAP1 is a transcriptional coactivator that converts mechanical, developmental, and growth-factor cues into target-gene programs governing tissue growth, cell fate, and tumorigenesis [PMID:11358867, PMID:16354681]. Its central output is a complex with TEAD/TEF transcription factors: YAP1 supplies the transcriptional activation domain through an N-terminal TEAD-binding domain that engages all four TEAD paralogs, and both TEAD interaction and TEAD DNA binding are required for activation, while excess YAP1 is sequestered in the cytoplasm with 14-3-3 [PMID:11358867]. This TEAD-dependent activity drives diverse programs including endothelial mitochondrial biogenesis and angiogenesis via PGC1α [PMID:29680477], DNMT1-mediated hepatocyte-to-biliary reprogramming [PMID:35550144], and oncogenic outputs such as CALM2/SLC2A1 induction [PMID:34990589] and PD-L1 transcription via a YAP1/TFCP2 complex [PMID:38583649]; YAP1/TEAD can also act repressively, silencing Sox2 to restrain premature pluripotency [PMID:31444221] and attenuating NODAL/FOXH1 to pattern germ layers [PMID:35063126]. YAP1 nuclear access is set by the Hippo cascade: LATS1-site phosphorylation, including the inhibitory S127 mark, increases YAP1 nuclear export and cytoplasmic retention, and constitutively active phospho-site mutants (S127A, 5SA) escape this control [PMID:34060624, PMID:30918126]. Layered onto this, YAP1 abundance is tuned by ubiquitin ligases and deubiquitinases (STUB1-mediated K48 ubiquitination at K280 [PMID:31393050]; stabilization by ATXN3, OTUD7B, OTUD5, and TRAF6-mediated K63 linkage [PMID:37818078, PMID:37429790, PMID:39293571, PMID:38583649]), by CBX4 SUMOylation at K97/K280 that competes with S127 phosphorylation [PMID:39154499], by NEK1 phosphorylation at Y407 [PMID:36979713], and by a Hippo-independent matrix-softness route in which PTEN-driven lysosomal cathepsin L directly digests YAP1 [PMID:39460766], as well as by mRNA-level control through ENO1 translation and METTL14/m6A decay [PMID:37500770, PMID:39563370]. Beyond TEAD, YAP1 engages Smad7 to potentiate TGF-β inhibition [PMID:12118366], RUNX2 to drive transformation [PMID:17438369], and Angiomotin/AMOTL1, the latter supporting a TEAD-independent, S6-kinase-linked role in dendritic morphogenesis [PMID:32313226, PMID:31042703]. Germline knockout establishes essential roles in yolk-sac vasculogenesis, chorioallantoic fusion, and axis elongation [PMID:16354681], and oncogenic YAP1 fusions (YAP1-MAML2, YAP1-NUTM1) act through constitutive, Hippo-resistant TEAD-dependent transcription sufficient to induce tumors [PMID:31145701, PMID:36008139].","teleology":[{"year":1994,"claim":"Established YAP1's first molecular partnership, defining it as an SH3-binding adaptor before any transcriptional role was known.","evidence":"Anti-idiotypic antibody screen and peptide-competition co-IP identifying binding to the Yes SH3 domain via a proline-rich motif","pmids":["8035999"],"confidence":"High","gaps":["Did not reveal a transcriptional or signaling function","Functional consequence of SH3 binding in cells not established"]},{"year":2001,"claim":"Defined YAP1's core function as the transcriptional activation module of TEAD factors, explaining how it drives gene expression.","evidence":"Protein purification, co-IP with all four TEAD paralogs, domain mapping, and reporter assays plus cytoplasmic 14-3-3 sequestration","pmids":["11358867"],"confidence":"High","gaps":["Upstream signals controlling the TEAD/14-3-3 balance not yet defined","Genome-wide TEAD target set not mapped"]},{"year":2002,"claim":"Showed YAP1 cross-talks with TGF-β signaling beyond TEAD, broadening its interactome to Smad regulation.","evidence":"Yeast two-hybrid, co-IP, and reporter assays with dominant-negative YAP1(1-301) potentiating Smad7-TGFβRI association","pmids":["12118366"],"confidence":"High","gaps":["Physiological context of Smad7 potentiation unclear","Relationship to TEAD activity not addressed"]},{"year":2006,"claim":"Established YAP1 as essential in vivo for early development, moving it from biochemistry to organismal requirement.","evidence":"Germline Yap knockout in mice with vasculogenesis, chorioallantoic, and axis-elongation defects at E8.5","pmids":["16354681"],"confidence":"High","gaps":["Did not separate TEAD-dependent from -independent contributions","Cell-autonomous vs non-autonomous roles unresolved"]},{"year":2007,"claim":"Linked YAP1 to oncogenic transformation through a defined partner, identifying RUNX2 as a transformation cofactor.","evidence":"Co-IP, RUNX2 P409A binding mutant, and soft-agar/foci transformation assays","pmids":["17438369"],"confidence":"High","gaps":["Direct target genes of the YAP1-RUNX2 complex not defined","In vivo relevance not tested"]},{"year":2016,"claim":"Connected YAP1 to mechano-fibrotic signaling and metabolic regulation, expanding its physiological roles.","evidence":"Integrin-β1/PAK myofibroblast assays and in vivo YAP1 inhibition (fibrosis); MST1-YAP1-TEAD1 RNAi axis controlling GLUT1/C-MYC; miR-375/ZEB1 circuit","pmids":["27535340","27793648","27270433"],"confidence":"Medium","gaps":["Direct vs indirect transcriptional targets in metabolism not fully resolved","Context-dependence of positive vs negative C-MYC regulation unexplained"]},{"year":2018,"claim":"Mechanistically dissected how nuclear YAP1/TEAD drives angiogenic and EMT programs through specific effectors.","evidence":"YAP1-S127A/S94A mutants and PGC1α knockdown (angiogenesis); CDK8/19 and matrix-rigidity-dependent SMAD1-driven EMT; YAP1-AP-1 cooperation in osteoclastogenesis; Tie2 regulation in endothelium","pmids":["29680477","29780169","29432919","30156429"],"confidence":"Medium","gaps":["Tissue-specific selection of distinct effector genes not explained","Direct vs indirect target status of several effectors not established"]},{"year":2019,"claim":"Revealed YAP1 protein-level control by ubiquitin ligases and stabilizing partners, and TEAD-independent functions.","evidence":"STUB1 K48 ubiquitination at K280; BRCA1-NF2-Hippo axis with YAP1-5SA rescue; AMOTL1 cytoplasmic stabilization; Amot-YAP1 S6-kinase-linked dendritic morphogenesis; fusion oncoprotein associations (FUS-DDIT3, YAP1-MAML2/NUTM1)","pmids":["31393050","30918126","32313226","31042703","30898787","31145701"],"confidence":"High","gaps":["Hierarchy among competing stabilizing/destabilizing inputs unclear","How TEAD-independent (S6K) signaling is selected over canonical output not defined"]},{"year":2019,"claim":"Established YAP1/TEAD as a transcriptional repressor in developmental fate decisions, not only an activator.","evidence":"Yap1/Wwtr1/Tead4 KO embryos with LATS-sensitive direct Sox2 repression; granulosa cell conditional KO phenotypes","pmids":["31444221","31199671"],"confidence":"Medium","gaps":["Molecular basis for switch between activation and repression unresolved","Co-repressor identity not defined"]},{"year":2020,"claim":"Placed YAP1 within a stress-responsive inflammatory pathway, linking DNA-damage signaling to cytokine output.","evidence":"Mouse telomere-dysfunction models with ATM/c-ABL-YAP1-pro-IL-18 axis, pharmacological inhibition, and patient tissue validation","pmids":["32958778"],"confidence":"High","gaps":["Whether IL-18 induction is TEAD-dependent not specified","Direct YAP1 binding at the IL-18 locus not shown"]},{"year":2021,"claim":"Quantified the kinetic basis of Hippo regulation, showing LATS phosphorylation acts on nuclear export rather than import.","evidence":"Optogenetic LOV sequestration with live-cell and lattice light-sheet imaging measuring YAP1 shuttling rates","pmids":["34060624"],"confidence":"High","gaps":["Molecular export machinery engaged by phospho-YAP1 not identified","Generalizability across cell types not tested"]},{"year":2022,"claim":"Demonstrated that YAP1 activity alone is sufficient to drive and maintain tumors, and validated direct TEAD-targeting chemistry.","evidence":"YAP1-MAML2 and constitutively active YAP1(S127/397A) mouse meningioma induction; conditional YAP1 knockdown causing mesothelioma regression; covalent cyanamide TEAD palmitate-pocket inhibitors with TEAD2 co-crystals","pmids":["36008139","35689194","36562717"],"confidence":"High","gaps":["Determinants of Hippo-dependent vs -independent tumor reliance not fully defined","Long-term resistance mechanisms to TEAD inhibitors unaddressed"]},{"year":2022,"claim":"Mapped both upstream transcriptional control of the YAP1 gene and key downstream effector targets driving its programs.","evidence":"CIC repression of YAP1 transcription via GGAA motifs; PTPN14-LATS1 axis (HPV E7) controlling YAP1 nuclear localization; YAP1/TEAD-DNMT1 hepatocyte reprogramming (ChIP-seq); CALM2/SLC2A1 rescue screen; NODAL/FOXH1 repression in gastruloids","pmids":["36198276","35170430","39248565","35550144","34990589","35063126"],"confidence":"High","gaps":["Integration of multiple upstream inputs into a single output not modeled","Tissue specificity of effector selection unresolved"]},{"year":2023,"claim":"Expanded post-transcriptional and post-translational tuning of YAP1 abundance through deubiquitinases and mRNA regulation.","evidence":"ATXN3 (WW-domain binding) and OTUD7B deubiquitination stabilizing YAP1; ENO1 CUG-element binding promoting YAP1 translation; YAP1-miR-21-5p-PGR repressive axis (ChIP-PCR, RNA-IP)","pmids":["37818078","37429790","37500770","37071897"],"confidence":"Medium","gaps":["Relative contribution of each regulator in normal physiology unclear","Single-lab co-IP/ubiquitination findings without reciprocal cross-validation"]},{"year":2024,"claim":"Defined additional non-canonical regulatory inputs to YAP1 stability and activity spanning SUMO, tyrosine phosphorylation, K63 ubiquitination, lysosomal degradation, and m6A decay.","evidence":"CBX4 SUMOylation at K97/K280 competing with S127; NEK1 Y407 phosphorylation cascade; TRAF6 K63 ubiquitination enabling YAP1/TFCP2-PD-L1; PTEN-cathepsin L lysosomal degradation under soft matrix (in vitro reconstitution); METTL14/m6A-YTHDF2 transcript decay; OTUD5 stabilization (dapagliflozin)","pmids":["39154499","36979713","38583649","39460766","39563370","39293571"],"confidence":"Medium","gaps":["How these inputs are integrated and prioritized in a given cell unresolved","Several mechanisms rest on single-lab evidence"]},{"year":null,"claim":"It remains unresolved how the convergent layers of YAP1 control — Hippo phosphorylation, multiple ubiquitin/SUMO and mRNA inputs, and partner choice — are quantitatively integrated to select between activating vs repressive, TEAD-dependent vs -independent outputs in a given cell context.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking regulatory input strength to specific transcriptional output","Determinants of TEAD-dependent vs S6-kinase-linked function not defined","Logic of activation vs repression at target loci unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,23,17,24]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[1,23]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,19,21,16]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,13,16]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,23,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[19,22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,17,24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,20,27]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,29,30,33]}],"complexes":["YAP1-TEAD transcriptional complex","YAP1/TFCP2 complex","Angiomotin/AMOTL1-YAP1 complex"],"partners":["TEAD1","AMOTL1","SMAD7","RUNX2","STUB1","ATXN3","TRAF6","CBX4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P46937","full_name":"Transcriptional coactivator YAP1","aliases":["Protein yorkie homolog","Yes-associated protein YAP65 homolog"],"length_aa":504,"mass_kda":54.5,"function":"Transcriptional regulator with dual roles as a coactivator and corepressor. Critical downstream regulatory target in the Hippo signaling pathway, crucial for organ size control and tumor suppression by restricting proliferation and promoting apoptosis (PubMed:17974916, PubMed:18280240, PubMed:18579750, PubMed:21364637, PubMed:30447097). The Hippo signaling pathway core involves a kinase cascade featuring STK3/MST2 and STK4/MST1, along with its regulatory partner SAV1, which phosphorylates and activates LATS1/2 in complex with their regulatory protein, MOB1. This activation leads to the phosphorylation and inactivation of the YAP1 oncoprotein and WWTR1/TAZ (PubMed:18158288). Phosphorylation of YAP1 by LATS1/2 prevents its nuclear translocation, thereby regulating the expression of its target genes (PubMed:18158288, PubMed:26598551, PubMed:34404733). The transcriptional regulation of gene expression requires TEAD transcription factors and modulates cell growth, anchorage-independent growth, and induction of epithelial-mesenchymal transition (EMT) (PubMed:18579750). Plays a key role in tissue tension and 3D tissue shape by regulating the cortical actomyosin network, acting via ARHGAP18, a Rho GTPase activating protein that suppresses F-actin polymerization (PubMed:25778702). It also suppresses ciliogenesis by acting as a transcriptional corepressor of TEAD4 target genes AURKA and PLK1 (PubMed:25849865). In conjunction with WWTR1, regulates TGFB1-dependent SMAD2 and SMAD3 nuclear accumulation (By similarity). Synergizes with WBP2 to enhance PGR activity (PubMed:16772533) Activates the C-terminal fragment (CTF) of ERBB4 (isoform 3) Activates the C-terminal fragment (CTF) of ERBB4 (isoform 3)","subcellular_location":"Cytoplasm; Nucleus; Cell junction, tight junction; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P46937/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YAP1","classification":"Not Classified","n_dependent_lines":370,"n_total_lines":1208,"dependency_fraction":0.30629139072847683},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"YWHAG","stoichiometry":4.0},{"gene":"CALM3","stoichiometry":0.2},{"gene":"COPB2","stoichiometry":0.2},{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"POLR1C","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/YAP1","total_profiled":1310},"omim":[{"mim_id":"621541","title":"OLFACTOMEDIN-LIKE 1; OLFML1","url":"https://www.omim.org/entry/621541"},{"mim_id":"620929","title":"MOB KINASE ACTIVATOR 3A; MOB3A","url":"https://www.omim.org/entry/620929"},{"mim_id":"620845","title":"TRANSMEMBRANE 4 L6 FAMILY, MEMBER 19; TM4SF19","url":"https://www.omim.org/entry/620845"},{"mim_id":"620479","title":"CENTRIOLAR SATELLITE-ASSOCIATED TUBULIN POLYGLUTAMYLASE COMPLEX REGULATOR 1; CSTPP1","url":"https://www.omim.org/entry/620479"},{"mim_id":"620110","title":"WW AND C2 DOMAINS-CONTAINING PROTEIN 2; WWC2","url":"https://www.omim.org/entry/620110"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YAP1"},"hgnc":{"alias_symbol":["YAP65","YAP-1"],"prev_symbol":[]},"alphafold":{"accession":"P46937","domains":[{"cath_id":"2.20.70.10","chopping":"176-208_233-267","consensus_level":"medium","plddt":82.426,"start":176,"end":267}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P46937","model_url":"https://alphafold.ebi.ac.uk/files/AF-P46937-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P46937-F1-predicted_aligned_error_v6.png","plddt_mean":57.41},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YAP1","jax_strain_url":"https://www.jax.org/strain/search?query=YAP1"},"sequence":{"accession":"P46937","fasta_url":"https://rest.uniprot.org/uniprotkb/P46937.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P46937/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P46937"}},"corpus_meta":[{"pmid":"11358867","id":"PMC_11358867","title":"TEAD/TEF 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Competition assays with synthetic peptides confirmed the involvement of this proline-rich sequence. YAP65 also bound SH3 domains of Nck, Crk, Src, Abl, and GAP.\",\n      \"method\": \"Anti-idiotypic antibody screen, co-immunoprecipitation, competition assays with synthetic peptides\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — original biochemical characterization with peptide competition assays confirming binding interface, replicated binding to multiple SH3-domain proteins\",\n      \"pmids\": [\"8035999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"YAP65 functions as a transcriptional coactivator for TEAD/TEF transcription factors: it interacts specifically with the C-terminus of all four TEAD proteins via a novel TEAD-binding domain at its N-terminus, provides the transcriptional activation domain for TEAD-dependent transcription, and accumulates in the cytoplasm as a complex with 14-3-3 when in excess. Both TEAD interaction and DNA binding by TEAD were required for transcriptional activation.\",\n      \"method\": \"Protein purification, co-immunoprecipitation, transcriptional reporter assays, subcellular fractionation, overexpression/squelching experiments\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical purification, co-IP with all four TEAD paralogs, functional reporter assays with domain mapping, multiple orthogonal methods\",\n      \"pmids\": [\"11358867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"YAP65 interacts with Smad7 (identified by yeast two-hybrid and confirmed by co-IP in COS-7 cells), potentiates Smad7's inhibitory activity against TGF-β/Smad3/4-dependent transcription, and augments the association of Smad7 with activated TGF-β receptor type I. A dominant-negative YAP65(1-301) reduced Smad7-TGFβRI interactions.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, transcriptional reporter assays, dominant-negative constructs\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid discovery confirmed by co-IP, functional reporter assays, and domain-mapping with dominant-negative construct; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12118366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Homozygous knockout of Yap in mice causes developmental arrest at ~E8.5 with defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation, establishing essential in vivo roles for YAP1 in these developmental processes.\",\n      \"method\": \"Targeted gene disruption in mice, histology, PECAM1 immunostaining, alpha-globin expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean germline knockout with multiple orthogonal phenotypic readouts; well-controlled developmental study\",\n      \"pmids\": [\"16354681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RUNX2 associates with YAP65 via a PPPY proline-rich motif in its C-terminal domain. Co-expression of RUNX2 and YAP65 synergistically promotes foci formation and anchorage-independent growth. A RUNX2(P409A) mutant that cannot bind YAP65 fails to cooperate with YAP65 in transformation. YAP65 overexpression prevented RUNX2-dependent downregulation of p21(CIP1).\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (RUNX2 P409A), soft agar/foci formation assays, luciferase reporter assays, DNA precipitation\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — co-IP plus mutagenesis validation plus functional transformation assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17438369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In liver myofibroblasts, integrin beta-1 signaling activates PAK proteins and YAP-1 as core pro-fibrotic mediators. YAP-1 is capable of perpetuating integrin beta-1 expression (positive feedback loop). Pharmacological inhibition of YAP-1 in vivo attenuates liver fibrosis.\",\n      \"method\": \"In vitro myofibroblast assays, in vivo pharmacological inhibition, gene knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacological and in vitro knockdown with defined cellular phenotypes; single lab but multiple model systems\",\n      \"pmids\": [\"27535340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"YAP1 was identified as a direct target of miR-375 in prostate cancer. Knockdown of YAP1 phenocopied miR-375 overexpression (inhibiting invasion and migration), and overexpression of YAP1 rescued anti-invasive effects of miR-375. The ZEB1 transcription factor directly represses miR-375 transcription, placing YAP1 downstream of a ZEB1-miR-375-YAP1 regulatory circuit controlling epithelial plasticity.\",\n      \"method\": \"miRNA target validation, siRNA knockdown, rescue overexpression, invasion/migration assays, multiple patient cohort analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (rescue experiment), phenotypic readouts with KD/OE; single lab\",\n      \"pmids\": [\"27270433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"YAP1/TEAD1 signaling induces mitochondrial biogenesis in endothelial cells and stimulates angiogenesis through PGC1α. A YAP1-S127A constitutively active mutant increased PGC1α expression and mitochondrial biogenesis; a YAP1-S94A mutant that fails to bind TEAD1 attenuated these effects. PGC1α knockdown inhibited YAP1-S127A-induced EC sprouting and vascular morphogenesis.\",\n      \"method\": \"Constitutively active and binding-deficient YAP1 mutants, TEAD1 knockdown, PGC1α knockdown, in vitro EC sprouting assays, in vivo fibrin gel vascular morphogenesis\",\n      \"journal\": \"Microvascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function mutant analysis plus in vivo rescue; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"29680477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDK8/19 kinase coordinates BMP4-induced EMT in a YAP1-dependent manner. Both genetic and pharmacological inhibition of CDK8/19 abrogated BMP-induced EMT, nuclear YAP1 localization, and tumor cell invasion. YAP1 activity was required for SMAD1-driven EMT in a matrix-rigidity-dependent manner.\",\n      \"method\": \"Genetic inhibition (siRNA), pharmacological inhibition, RNA-seq meta-analysis, in vitro invasion assays, in vivo syngeneic EMT model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple inhibition strategies plus in vivo model; single lab\",\n      \"pmids\": [\"29780169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"YAP1 interacts with TEAD transcription factors (TEADs) and AP-1, and this cooperative interaction on downstream gene transcription is required for osteoclastogenesis. Verteporfin (which inhibits YAP1-TEAD association) suppressed osteoclast formation and bone resorption. RANKL-induced NF-κB signaling was impaired when YAP1 was inhibited.\",\n      \"method\": \"shRNA-mediated knockdown, verteporfin pharmacological inhibition, co-immunoprecipitation, gene expression analysis, osteoclast differentiation assays\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP plus shRNA KD plus pharmacological inhibition with defined cellular phenotype; single lab\",\n      \"pmids\": [\"29432919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STUB1 (E3 ubiquitin ligase) ubiquitinates YAP1 at K280 via K48-linked polyubiquitination, leading to YAP1 degradation. This suppresses cancer cell survival and chemoresistance. Low STUB1 expression correlates with increased YAP1 protein in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays with site-specific mutants (K280), protein stability assays, cell viability assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay with site identification plus co-IP; single lab, moderate mechanistic depth\",\n      \"pmids\": [\"31393050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BRCA1 facilitates YAP1 protein stabilization and Hippo pathway inactivation through ubiquitination of NF2. In BRCA1-deficient cells, Hippo pathway is turned on. A YAP1-5SA mutant (alanine substitutions at LATS1 recognition sites) resists degradation and rescues YAP1 transcriptional activity in BRCA1-deficient cells, and promotes EGF-independent proliferation and tumorigenesis.\",\n      \"method\": \"BRCA1 KO cells, YAP1 phosphorylation site mutagenesis (5SA/6SA mutants), ubiquitination assays, proliferation and tumorigenesis assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BRCA1 KO combined with phospho-site mutagenesis and functional rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30918126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FUS-DDIT3 fusion oncoprotein promotes YAP1 expression, nuclear localization, and transcriptional activity in myxoid liposarcoma cells, and physically associates with YAP1 in the nucleus. Pharmacologic inhibition of YAP1 impairs MLS cell growth in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation (nuclear fractionation), functional genomic screen, pharmacological inhibition, in vivo xenograft\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP showing physical association plus in vivo pharmacological inhibition; single lab\",\n      \"pmids\": [\"30898787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AMOTL1 (Angiomotin Like 1) interacts with YAP1 in the cytoplasm and protects YAP1 from ubiquitin-mediated degradation. This interaction promotes YAP1 nuclear translocation to activate downstream targets such as CTGF. Knockdown of AMOTL1 impairs its oncogenic properties and reduces YAP1 protein levels.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, shRNA knockdown, ubiquitination assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal co-IP plus ubiquitination assay plus subcellular localization; single lab\",\n      \"pmids\": [\"32313226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Angiomotin (Amot) and YAP1 form a complex critical for dendritic morphogenesis in hippocampal and Purkinje cells. Conditional deletion of Amot and Yap1 in neurons decreased Purkinje cell dendritic tree complexity and impaired motor coordination. This function does not rely on TEAD interactions or Hippo-dependent gene expression, but instead involves phosphorylation of S6 kinase and S6 ribosomal protein.\",\n      \"method\": \"Conditional neuronal knockout mice, in vitro hippocampal cultures, co-immunoprecipitation, phosphorylation assays, behavioral tests\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined cellular phenotype, mechanistic dissection via co-IP and phosphorylation assays showing TEAD-independent mechanism, multiple orthogonal approaches\",\n      \"pmids\": [\"31042703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YAP1 fusions (YAP1-MAML2 and YAP1-NUTM1) in poromas strongly transactivate a TEAD reporter and promote anchorage-independent growth. Immunohistochemical staining showed nuclear expression of the N-terminal YAP1 portion with loss of the C-terminal portion, consistent with constitutive nuclear YAP1 activity in these fusion proteins.\",\n      \"method\": \"RNA sequencing, RT-PCR, FISH, immunohistochemistry, TEAD reporter assay, anchorage-independent growth assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional reporter assay plus transformation assay confirming oncogenic activity; replicated in large tumor cohort with FISH validation\",\n      \"pmids\": [\"31145701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YAP1 interacts with epidermal growth factor receptor and TGF-β signaling pathways to regulate granulosa cell proliferation, differentiation, and survival. Nuclear (active) YAP1 is predominant in proliferative granulosa cells; cytoplasmic (inactive) YAP1 is in luteinized cells. Foxl2 promoter-driven knockout of Yap1 caused increased granulosa cell apoptosis, decreased corpora lutea, reduced ovarian size, and subfertility.\",\n      \"method\": \"Conditional knockout mice (Foxl2-Cre and Cyp19a1-Cre), in vitro pharmacological inhibition, co-IP, subcellular localization analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined phenotypes; mechanistic pathway interaction suggested by co-IP; single lab\",\n      \"pmids\": [\"31199671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YAP1 directly represses Sox2 expression in early mouse embryos, preventing premature pluripotency onset prior to the 16-cell stage. This repression is sensitive to LATS kinase activity. TEAD4, YAP1, and WWTR1 together mediate direct transcriptional repression of Sox2.\",\n      \"method\": \"Yap1/Wwtr1/Tead4 knockout mouse embryos, gene expression analysis, genetic epistasis with LATS kinase inhibition\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined transcriptional phenotype plus epistasis with LATS; single lab\",\n      \"pmids\": [\"31444221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Telomere dysfunction activates YAP1 via pATM/c-ABL-mediated signaling, upregulating pro-IL-18 expression in intestinal epithelium. Pharmacological inhibition of ATM or YAP1 dramatically reduces IL-18 and intestinal inflammation in mice with telomere dysfunction. This establishes a telomere dysfunction-ATM-YAP1-pro-IL-18 inflammatory pathway.\",\n      \"method\": \"Mouse telomere dysfunction models, pharmacological inhibition (ATM, YAP1, caspase-1 inhibitors), antibiotics treatment, patient biopsy analysis (γH2AX, YAP1, IL-18)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic and pharmacological interventions in vivo plus human patient tissue validation; multiple orthogonal methods\",\n      \"pmids\": [\"32958778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Phosphorylation of YAP1 on canonical LATS1 sites enhances its rate of nuclear export (not entry). YAP1 import and export rates correlate within the same cell. YAP1 and TAZ rates of nuclear entry and exit are also correlated with each other.\",\n      \"method\": \"Optogenetic LOV-domain mitochondria sequestration system with blue-light release, live-cell fluorescence imaging, quantitative nuclear/cytoplasmic flux analysis, lattice light-sheet microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — novel optogenetic reconstitution method with quantitative kinetic measurements; single lab but highly rigorous and direct measurement of shuttling rates\",\n      \"pmids\": [\"34060624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YAP1-MAML2 fusion primarily functions via TEAD-dependent YAP activity that is resistant to Hippo signaling. Expression of YAP1-MAML2 in mice induces meningioma-like tumors resembling NF2 mutant meningiomas. Constitutively active YAP1(S127/397A) alone is sufficient to induce similar tumors, indicating the YAP component drives oncogenesis. YAP-TEAD inhibitors inhibit viability of YAP1-MAML2-driven tumors ex vivo.\",\n      \"method\": \"Mouse tumor models, gene expression profiling, YAP-TEAD inhibitor treatment (ex vivo), constitutively active YAP1 expression, epistasis with Hippo signaling\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo tumor induction, constitutively active mutant, pharmacological inhibition; multiple orthogonal approaches\",\n      \"pmids\": [\"36008139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HPV E7 activates YAP1 nuclear localization in basal epithelial cells by binding and degrading PTPN14 tumor suppressor. YAP1 transcriptional activity is required for E7 to extend primary keratinocyte lifespan. YAP1 activation by E7 causes cells to be retained in the basal compartment of stratified epithelia.\",\n      \"method\": \"HPV E7 expression, PTPN14 knockout, YAP1 nuclear localization assays, primary keratinocyte lifespan assays, stratified epithelium models\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic PTPN14 KO plus E7 expression with functional rescue; multiple cellular phenotype readouts; mechanistic pathway established\",\n      \"pmids\": [\"35170430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HPV18 E7 degrades PTPN14, which decreases phosphorylation of LATS1 T1079 (active form) and YAP1 S127 (inhibitory phosphorylation). PTPN14-dependent differentiation requires LATS kinases and PTPN14 PPxY motifs. MST1/2 kinases and PTPN14 phosphatase activity are not required for PTPN14 to promote differentiation, establishing that PTPN14 acts upstream of LATS1 to inhibit YAP1.\",\n      \"method\": \"PTPN14 knockout, HPV18 E7 expression, LATS1 phosphorylation assays, YAP1 S127 phosphorylation assays, domain mutagenesis (PPxY motifs, phosphatase active site)\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — phosphorylation site mapping, domain mutagenesis, genetic KO; multiple orthogonal methods firmly placing PTPN14 upstream of LATS1-YAP1\",\n      \"pmids\": [\"39248565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YAP1-TEAD complex activates DNMT1 expression, which directs hepatocyte-to-biliary epithelial cell fate switch through repression of hepatocyte-specific genes. DNMT1 re-expression restores ICC development following TEAD repression, establishing DNMT1 as a downstream effector of YAP1/TEAD in hepatocyte reprogramming.\",\n      \"method\": \"Sleeping beauty/hydrodynamic tail vein injection ICC model, Yap1/Sox9 conditional deletion, TEAD inhibition, chromatin immunoprecipitation sequencing, gain/loss-of-function studies\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq plus multiple genetic loss/gain-of-function experiments plus rescue; multiple orthogonal methods in vivo and in vitro\",\n      \"pmids\": [\"35550144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YAP1 regulates gastruloid fate patterning by attenuating Nodal signaling. YAP1 knockout gastruloids show reduced ectoderm and enlarged mesoderm/endoderm. YAP1 directly represses chromatin accessibility and transcription of NODAL and FOXH1 genes, preventing hyperactive SMAD2/3 nuclear retention and thereby enabling ectoderm differentiation.\",\n      \"method\": \"YAP1 knockout hESC gastruloids, epigenome (ATAC-seq) and transcriptome (RNA-seq) analysis, immunostaining for SMAD2/3 localization\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO combined with chromatin accessibility and transcriptome data; mechanistic link established; multiple orthogonal methods\",\n      \"pmids\": [\"35063126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Small-molecule cyanamide compounds form a covalent bond with a conserved cysteine in the TEAD palmitate-binding cavity, inhibiting YAP1 binding to TEADs with submicromolar IC50 values. Co-crystal structures with TEAD2 enabled structure-activity relationship studies. Inhibition suppressed CTGF mRNA and TEAD1-4 transcriptional activity in mammalian cells.\",\n      \"method\": \"Covalent inhibitor synthesis, co-crystal structures with TEAD2, time/concentration-dependent kinetics (kinact/KI), cellular reporter assays (CTGF mRNA, TEAD transcriptional activity), YAP1-TEAD binding inhibition assay\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — co-crystal structure plus covalent kinetics plus cellular functional validation; single lab but Tier 1 structural + biochemical evidence\",\n      \"pmids\": [\"36562717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CIC (Capicua) directly represses YAP1 transcription by binding non-consensus GGAAGGAA DNA-binding motifs in a proximal YAP1 regulatory element in an ERK-regulated manner. Silencing YAP1 in CIC-deficient cells restores MAPK inhibitor sensitivity and suppresses tumor growth.\",\n      \"method\": \"ChIP, reporter assays with GGAA motif mutations, siRNA knockdown epistasis, tumor growth assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay with motif validation plus functional epistasis; single lab\",\n      \"pmids\": [\"36198276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YAP1 and PRDM14 individually activate transcription of CALM2 and SLC2A1 (GLUT1) as key downstream targets. PRDM14 can rescue cell proliferation and tumorigenesis upon YAP1 suppression. CALM2 or SLC2A1 expression is required for this rescue, placing them as essential mediators of oncogenic YAP1 signaling.\",\n      \"method\": \"Genome-scale genetic rescue screen (inducible YAP1 shRNA), xenograft models, colon cancer organoids, transcriptional analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-scale genetic screen with functional rescue validation in multiple model systems; single lab\",\n      \"pmids\": [\"34990589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YAP1 activity alone (in a Hippo-pathway mutated background) is sufficient to maintain established mesothelioma tumor growth in vivo. Conditional YAP1 downregulation in established xenografts leads to inhibition of YAP1/TEAD-dependent gene transcription and tumor regression, but only in YAP1-activated Hippo-mutant background, not in Hippo-independent cancer cells.\",\n      \"method\": \"Conditional YAP1 knockdown in xenografts, in vitro apoptosis assays, in vivo tumor regression studies, gene expression analysis\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional in vivo KD with tumor regression phenotype plus isogenic control; single lab\",\n      \"pmids\": [\"35689194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATXN3 (deubiquitinase) interacts with the WW domains of YAP1 and protects YAP1 from ubiquitination-mediated degradation, promoting tumor growth. CRISPR-Cas9 deletion of ATXN3 decreases YAP1 protein without altering its mRNA. YAP1 reconstitution rescues the growth inhibition caused by ATXN3 suppression.\",\n      \"method\": \"CRISPR-Cas9 gene deletion, co-immunoprecipitation, ubiquitination assays, YAP1 rescue overexpression, immunohistology\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO plus co-IP plus ubiquitination assay plus rescue; single lab\",\n      \"pmids\": [\"37818078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OTUD7B deubiquitinase deubiquitinates and stabilizes YAP1 protein, enhancing YAP1 activity and upregulating NUAK2 (and other YAP1 targets including Snail, Slug, CDK6, CTGF, BIRC5) to accelerate gastric cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, OTUD7B overexpression/knockdown, in vitro and in vivo tumor assays\",\n      \"journal\": \"Digestive and liver disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP plus ubiquitination assay plus in vivo xenograft; single lab\",\n      \"pmids\": [\"37429790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ENO1, acting as an RNA-binding protein, binds CUG-rich elements in YAP1 mRNA to promote its translation. ENO1 and YAP1 cooperatively regulate arachidonic acid metabolism via inverse regulation of PLCB1 and HPGD, with subsequent PGE2 accumulation driving cancer progression.\",\n      \"method\": \"RNA-binding protein assay, mRNA translation assays, gene knockdown, metabolic profiling, in vivo tumor models\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-binding assay plus functional metabolic readouts; single lab but novel mechanism with multiple validation approaches\",\n      \"pmids\": [\"37500770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YAP1 inhibits progesterone receptor (PGR) expression through upregulation of miR-21-5p. YAP1 binding to the miR-21 promoter region was confirmed by ChIP-PCR; miR-21-5p in turn reduces PGR mRNA via RNA immunoprecipitation-validated interaction. Knockdown of YAP1 or verteporfin treatment reduces miR-21-5p, increases PGR expression, and enhances decidualization.\",\n      \"method\": \"ChIP-PCR, RNA immunoprecipitation, YAP1 inhibitor (verteporfin), siRNA knockdown, mouse endometriosis model\",\n      \"journal\": \"Human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-PCR and RNA-IP establishing direct YAP1-miR-21-PGR axis plus in vivo mouse model; single lab\",\n      \"pmids\": [\"37071897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRAF6 stabilizes YAP1 protein through K63-linked polyubiquitination, which promotes formation of a YAP1/TFCP2 transcriptional complex that drives PD-L1 transcription in melanoma cells. TRAF6 suppression downregulates PD-L1 membrane expression.\",\n      \"method\": \"CRISPR interference screening, in vitro and in vivo assays, co-immunoprecipitation, ubiquitination assays (K63-linkage specific)\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP plus K63-specific ubiquitination assay plus functional in vivo assay; single lab\",\n      \"pmids\": [\"38583649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CBX4 (SUMO E3 ligase) induces SUMO1 modification of YAP1 at K97 and K280, which competitively inhibits YAP1 S127 phosphorylation (inhibitory Hippo phosphorylation), thereby preserving YAP1 stability and promoting its cytoplasm-nuclear transport and anti-senescence activity in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation, SUMOylation site mutagenesis (K97, K280), phosphorylation assays (S127), ChIP, high-throughput sequencing\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SUMOylation site mapping with competition of phosphorylation; multiple biochemical methods; single lab\",\n      \"pmids\": [\"39154499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NEK1 kinase phosphorylates YAP1 at Y407 via an AR→TLK1B→NEK1→YAP1-Y407 sequential kinase cascade. YAP1-Y407F dominant mutant reprograms the YAP1 transcriptome, reduces TEAD- and p73-regulated gene expression, and mediates sensitivity to MMC. YAP1 overexpression (but not Y407F) transforms LNCaP cells to androgen-independent growth.\",\n      \"method\": \"Phospho-site mutagenesis (Y407F), transcriptome reprogramming analysis, dominant expression assays, NEK1 haploinsufficient TRAMP mice, immunohistochemistry\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-site mutagenesis with functional readouts plus in vivo mouse model; single lab\",\n      \"pmids\": [\"36979713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Stromal softness promotes YAP1 degradation via an autophagic-lysosomal pathway (not Hippo/proteasome). In soft extracellular matrix, PTEN is upregulated and promotes lysosomal biogenesis, activating cathepsins that directly degrade YAP1. Purified cathepsin L can directly digest YAP1 under acidic conditions in vitro.\",\n      \"method\": \"In vitro reconstitution (purified cathepsin L + YAP1), hydrogel stiffness matrices, lysosomal inhibition (chloroquine), PTEN manipulation, in vivo liver fibrosis models\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution of cathepsin L-mediated YAP1 degradation plus cellular and in vivo corroboration; novel non-Hippo degradation mechanism\",\n      \"pmids\": [\"39460766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DAPAGLIFLOZIN (SGLT2 inhibitor) suppresses gastric cancer by decreasing OTUD5 expression, which increases YAP1 ubiquitination and degradation. Overexpression of OTUD5 in gastric cancer cells partly reverses the anti-tumor effect of dapagliflozin, establishing OTUD5 as a deubiquitinase that stabilizes YAP1.\",\n      \"method\": \"OTUD5 overexpression rescue, ubiquitination assays, in vitro and in vivo tumor models, drug treatment\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — rescue experiment plus ubiquitination assay; single lab, moderate mechanistic depth\",\n      \"pmids\": [\"39293571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Endothelial YAP1 regulates Tie2 (angiogenic factor receptor) expression; knockdown of YAP1 in endothelial cells decreases Tie2 expression and inhibits EC sprouting, epithelial cell budding, vascular morphogenesis, and compensatory lung growth after pneumonectomy.\",\n      \"method\": \"siRNA knockdown in endothelial cells, in vitro sprouting assay, in vivo gel implantation on mouse lung, pneumonectomy model, Tie2 expression analysis\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined molecular (Tie2) and cellular phenotypes in vitro and in vivo; single lab\",\n      \"pmids\": [\"30156429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MST1 activation by shikonin inhibits GLUT1 and C-MYC expression via the MST1-YAP1-TEAD1 axis in human leukemia cells. RNAi experiments confirmed this regulatory axis. YAP1 positively regulates C-MYC mRNA in complex with TEAD1, while it negatively regulates C-MYC levels in cooperation with MST1. Depletion of TEAD1 inhibits lactate production.\",\n      \"method\": \"RNAi knockdown of pathway components, pharmacological MST1 activation, TEAD1 ChIP binding site analysis, lactate production assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RNAi epistasis establishing axis, bioinformatic binding site validation; single lab\",\n      \"pmids\": [\"27793648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"METTL14-mediated m6A modification of YAP1 mRNA promotes YTHDF2-mediated transcript decay, reducing YAP1 expression and stemness in TNBC. Loss of METTL14 (driven by LSD1-mediated H3K4 demethylation) blocks m6A on YAP1 mRNA, preventing YTHDF2-dependent decay and sustaining YAP1 protein levels and Hippo-independent YAP1 signaling.\",\n      \"method\": \"m6A-IP sequencing, RNA-IP, ChIP, luciferase reporter assays, KO/KD experiments, tissue microarray validation\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-IP-seq plus RNA-IP plus ChIP establishing epi-transcriptional mechanism; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39563370\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YAP1 is a transcriptional coactivator that primarily functions by binding TEAD transcription factors through its N-terminal TEAD-binding domain to drive target gene expression; its activity is regulated by the Hippo kinase cascade (MST1/2→LATS1/2), which phosphorylates YAP1 at S127 to promote cytoplasmic sequestration by 14-3-3 and at additional sites to enhance nuclear export, while YAP1 protein stability is controlled by multiple ubiquitin E3 ligases (STUB1, via K48-linked ubiquitination at K280) and deubiquitinases (ATXN3, OTUD7B, OTUD5, TRAF6 via K63-linkage), SUMOylation at K97/K280 (by CBX4, competing with S127 phosphorylation), tyrosine phosphorylation at Y407 by NEK1, and lysosomal-cathepsin-mediated degradation triggered by matrix softness; YAP1 also interacts with Smad7 (potentiating TGF-β pathway inhibition), RUNX2, Angiomotin/AMOTL1, FUS-DDIT3, and mTOR, and drives tissue-specific programs including vasculogenesis, dendritic morphogenesis, germ layer specification, and inflammatory responses, while oncogenic YAP1 gene fusions (YAP1-MAML2, YAP1-NUTM1, YAP1-TFE3) function through constitutive TEAD-dependent transcriptional activity resistant to Hippo signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YAP1 is a transcriptional coactivator that converts mechanical, developmental, and growth-factor cues into target-gene programs governing tissue growth, cell fate, and tumorigenesis [#1, #3]. Its central output is a complex with TEAD/TEF transcription factors: YAP1 supplies the transcriptional activation domain through an N-terminal TEAD-binding domain that engages all four TEAD paralogs, and both TEAD interaction and TEAD DNA binding are required for activation, while excess YAP1 is sequestered in the cytoplasm with 14-3-3 [#1]. This TEAD-dependent activity drives diverse programs including endothelial mitochondrial biogenesis and angiogenesis via PGC1\\u03b1 [#7], DNMT1-mediated hepatocyte-to-biliary reprogramming [#23], and oncogenic outputs such as CALM2/SLC2A1 induction [#27] and PD-L1 transcription via a YAP1/TFCP2 complex [#33]; YAP1/TEAD can also act repressively, silencing Sox2 to restrain premature pluripotency [#17] and attenuating NODAL/FOXH1 to pattern germ layers [#24]. YAP1 nuclear access is set by the Hippo cascade: LATS1-site phosphorylation, including the inhibitory S127 mark, increases YAP1 nuclear export and cytoplasmic retention, and constitutively active phospho-site mutants (S127A, 5SA) escape this control [#19, #11]. Layered onto this, YAP1 abundance is tuned by ubiquitin ligases and deubiquitinases (STUB1-mediated K48 ubiquitination at K280 [#10]; stabilization by ATXN3, OTUD7B, OTUD5, and TRAF6-mediated K63 linkage [#29, #30, #37, #33]), by CBX4 SUMOylation at K97/K280 that competes with S127 phosphorylation [#34], by NEK1 phosphorylation at Y407 [#35], and by a Hippo-independent matrix-softness route in which PTEN-driven lysosomal cathepsin L directly digests YAP1 [#36], as well as by mRNA-level control through ENO1 translation and METTL14/m6A decay [#31, #40]. Beyond TEAD, YAP1 engages Smad7 to potentiate TGF-\\u03b2 inhibition [#2], RUNX2 to drive transformation [#4], and Angiomotin/AMOTL1, the latter supporting a TEAD-independent, S6-kinase-linked role in dendritic morphogenesis [#13, #14]. Germline knockout establishes essential roles in yolk-sac vasculogenesis, chorioallantoic fusion, and axis elongation [#3], and oncogenic YAP1 fusions (YAP1-MAML2, YAP1-NUTM1) act through constitutive, Hippo-resistant TEAD-dependent transcription sufficient to induce tumors [#15, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established YAP1's first molecular partnership, defining it as an SH3-binding adaptor before any transcriptional role was known.\",\n      \"evidence\": \"Anti-idiotypic antibody screen and peptide-competition co-IP identifying binding to the Yes SH3 domain via a proline-rich motif\",\n      \"pmids\": [\"8035999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reveal a transcriptional or signaling function\", \"Functional consequence of SH3 binding in cells not established\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined YAP1's core function as the transcriptional activation module of TEAD factors, explaining how it drives gene expression.\",\n      \"evidence\": \"Protein purification, co-IP with all four TEAD paralogs, domain mapping, and reporter assays plus cytoplasmic 14-3-3 sequestration\",\n      \"pmids\": [\"11358867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling the TEAD/14-3-3 balance not yet defined\", \"Genome-wide TEAD target set not mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed YAP1 cross-talks with TGF-\\u03b2 signaling beyond TEAD, broadening its interactome to Smad regulation.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and reporter assays with dominant-negative YAP1(1-301) potentiating Smad7-TGF\\u03b2RI association\",\n      \"pmids\": [\"12118366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological context of Smad7 potentiation unclear\", \"Relationship to TEAD activity not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established YAP1 as essential in vivo for early development, moving it from biochemistry to organismal requirement.\",\n      \"evidence\": \"Germline Yap knockout in mice with vasculogenesis, chorioallantoic, and axis-elongation defects at E8.5\",\n      \"pmids\": [\"16354681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate TEAD-dependent from -independent contributions\", \"Cell-autonomous vs non-autonomous roles unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked YAP1 to oncogenic transformation through a defined partner, identifying RUNX2 as a transformation cofactor.\",\n      \"evidence\": \"Co-IP, RUNX2 P409A binding mutant, and soft-agar/foci transformation assays\",\n      \"pmids\": [\"17438369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes of the YAP1-RUNX2 complex not defined\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected YAP1 to mechano-fibrotic signaling and metabolic regulation, expanding its physiological roles.\",\n      \"evidence\": \"Integrin-\\u03b21/PAK myofibroblast assays and in vivo YAP1 inhibition (fibrosis); MST1-YAP1-TEAD1 RNAi axis controlling GLUT1/C-MYC; miR-375/ZEB1 circuit\",\n      \"pmids\": [\"27535340\", \"27793648\", \"27270433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect transcriptional targets in metabolism not fully resolved\", \"Context-dependence of positive vs negative C-MYC regulation unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mechanistically dissected how nuclear YAP1/TEAD drives angiogenic and EMT programs through specific effectors.\",\n      \"evidence\": \"YAP1-S127A/S94A mutants and PGC1\\u03b1 knockdown (angiogenesis); CDK8/19 and matrix-rigidity-dependent SMAD1-driven EMT; YAP1-AP-1 cooperation in osteoclastogenesis; Tie2 regulation in endothelium\",\n      \"pmids\": [\"29680477\", \"29780169\", \"29432919\", \"30156429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific selection of distinct effector genes not explained\", \"Direct vs indirect target status of several effectors not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed YAP1 protein-level control by ubiquitin ligases and stabilizing partners, and TEAD-independent functions.\",\n      \"evidence\": \"STUB1 K48 ubiquitination at K280; BRCA1-NF2-Hippo axis with YAP1-5SA rescue; AMOTL1 cytoplasmic stabilization; Amot-YAP1 S6-kinase-linked dendritic morphogenesis; fusion oncoprotein associations (FUS-DDIT3, YAP1-MAML2/NUTM1)\",\n      \"pmids\": [\"31393050\", \"30918126\", \"32313226\", \"31042703\", \"30898787\", \"31145701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among competing stabilizing/destabilizing inputs unclear\", \"How TEAD-independent (S6K) signaling is selected over canonical output not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established YAP1/TEAD as a transcriptional repressor in developmental fate decisions, not only an activator.\",\n      \"evidence\": \"Yap1/Wwtr1/Tead4 KO embryos with LATS-sensitive direct Sox2 repression; granulosa cell conditional KO phenotypes\",\n      \"pmids\": [\"31444221\", \"31199671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis for switch between activation and repression unresolved\", \"Co-repressor identity not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed YAP1 within a stress-responsive inflammatory pathway, linking DNA-damage signaling to cytokine output.\",\n      \"evidence\": \"Mouse telomere-dysfunction models with ATM/c-ABL-YAP1-pro-IL-18 axis, pharmacological inhibition, and patient tissue validation\",\n      \"pmids\": [\"32958778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL-18 induction is TEAD-dependent not specified\", \"Direct YAP1 binding at the IL-18 locus not shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Quantified the kinetic basis of Hippo regulation, showing LATS phosphorylation acts on nuclear export rather than import.\",\n      \"evidence\": \"Optogenetic LOV sequestration with live-cell and lattice light-sheet imaging measuring YAP1 shuttling rates\",\n      \"pmids\": [\"34060624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular export machinery engaged by phospho-YAP1 not identified\", \"Generalizability across cell types not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that YAP1 activity alone is sufficient to drive and maintain tumors, and validated direct TEAD-targeting chemistry.\",\n      \"evidence\": \"YAP1-MAML2 and constitutively active YAP1(S127/397A) mouse meningioma induction; conditional YAP1 knockdown causing mesothelioma regression; covalent cyanamide TEAD palmitate-pocket inhibitors with TEAD2 co-crystals\",\n      \"pmids\": [\"36008139\", \"35689194\", \"36562717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of Hippo-dependent vs -independent tumor reliance not fully defined\", \"Long-term resistance mechanisms to TEAD inhibitors unaddressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped both upstream transcriptional control of the YAP1 gene and key downstream effector targets driving its programs.\",\n      \"evidence\": \"CIC repression of YAP1 transcription via GGAA motifs; PTPN14-LATS1 axis (HPV E7) controlling YAP1 nuclear localization; YAP1/TEAD-DNMT1 hepatocyte reprogramming (ChIP-seq); CALM2/SLC2A1 rescue screen; NODAL/FOXH1 repression in gastruloids\",\n      \"pmids\": [\"36198276\", \"35170430\", \"39248565\", \"35550144\", \"34990589\", \"35063126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of multiple upstream inputs into a single output not modeled\", \"Tissue specificity of effector selection unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded post-transcriptional and post-translational tuning of YAP1 abundance through deubiquitinases and mRNA regulation.\",\n      \"evidence\": \"ATXN3 (WW-domain binding) and OTUD7B deubiquitination stabilizing YAP1; ENO1 CUG-element binding promoting YAP1 translation; YAP1-miR-21-5p-PGR repressive axis (ChIP-PCR, RNA-IP)\",\n      \"pmids\": [\"37818078\", \"37429790\", \"37500770\", \"37071897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each regulator in normal physiology unclear\", \"Single-lab co-IP/ubiquitination findings without reciprocal cross-validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined additional non-canonical regulatory inputs to YAP1 stability and activity spanning SUMO, tyrosine phosphorylation, K63 ubiquitination, lysosomal degradation, and m6A decay.\",\n      \"evidence\": \"CBX4 SUMOylation at K97/K280 competing with S127; NEK1 Y407 phosphorylation cascade; TRAF6 K63 ubiquitination enabling YAP1/TFCP2-PD-L1; PTEN-cathepsin L lysosomal degradation under soft matrix (in vitro reconstitution); METTL14/m6A-YTHDF2 transcript decay; OTUD5 stabilization (dapagliflozin)\",\n      \"pmids\": [\"39154499\", \"36979713\", \"38583649\", \"39460766\", \"39563370\", \"39293571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How these inputs are integrated and prioritized in a given cell unresolved\", \"Several mechanisms rest on single-lab evidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the convergent layers of YAP1 control \\u2014 Hippo phosphorylation, multiple ubiquitin/SUMO and mRNA inputs, and partner choice \\u2014 are quantitatively integrated to select between activating vs repressive, TEAD-dependent vs -independent outputs in a given cell context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking regulatory input strength to specific transcriptional output\", \"Determinants of TEAD-dependent vs S6-kinase-linked function not defined\", \"Logic of activation vs repression at target loci unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 23, 17, 24]},\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [1, 23]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 19, 21, 16]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 13, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 23, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [19, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 17, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 20, 27]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 29, 30, 33]}\n    ],\n    \"complexes\": [\n      \"YAP1-TEAD transcriptional complex\",\n      \"YAP1/TFCP2 complex\",\n      \"Angiomotin/AMOTL1-YAP1 complex\"\n    ],\n    \"partners\": [\n      \"TEAD1\",\n      \"AMOTL1\",\n      \"SMAD7\",\n      \"RUNX2\",\n      \"STUB1\",\n      \"ATXN3\",\n      \"TRAF6\",\n      \"CBX4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}