{"gene":"PIN1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2003,"finding":"Pin1 influences RNA polymerase II CTD phosphorylation status in vitro by inhibiting the CTD phosphatase FCP1 and stimulating CTD phosphorylation by cdc2/cyclin B. Pin1 overexpression inhibits ongoing transcription of mRNA precursors in vivo and both transcription and RNAP II-stimulated pre-mRNA splicing in cell extracts. A hyper-hyperphosphorylated form of RNAP II accumulates in M-phase cells in a Pin1-dependent manner and associates specifically with Pin1.","method":"In vitro phosphatase/kinase assays, in vivo overexpression/knockout cell lines, cell extract transcription/splicing assays, co-immunoprecipitation","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including in vitro enzymatic assays, in vivo genetic models (pin1-/- cells), and functional transcription/splicing assays in one study","pmids":["14600023"],"is_preprint":false},{"year":2007,"finding":"Pin1 overexpression releases RNAP II from chromatin, causing accumulation in a hyperphosphorylated form in nuclear speckle-associated structures. Pin1 inhibits transcription initiation (not elongation) in nuclear extracts, while an inactive Pin1 mutant stimulates transcription, indicating Pin1 modulates CTD phosphorylation during early transcription cycle stages.","method":"Chromatin immunoprecipitation (ChIP) with CTD phospho-specific antibodies, inducible Pin1 overexpression cell lines, in vitro transcription assays with active-site mutant Pin1","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP assays, inducible expression system, and in vitro transcription assays with catalytically inactive mutant in one study","pmids":["18006688"],"is_preprint":false},{"year":2007,"finding":"Pin1 promotes chromosome condensation during mitosis. Pin1 interaction with chromatin is elevated in G2/M phase correlating with mitotic phosphoproteins, especially topoisomerase IIα. Immunodepletion of Pin1 from mitotic extracts prevents chromosome condensation. Purified Pin1 and cdc2/cyclin B are sufficient to induce condensation, and Pin1 increases TopoIIα phosphorylation by cdc2/cyclin B in vitro, promoting a TopoIIα/Pin1/DNA complex.","method":"Chromatin fractionation, siRNA knockdown, immunodepletion of mitotic extracts, reconstitution with purified components, in vitro kinase assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with purified Pin1 and cdc2/cyclin B sufficient for condensation, supported by immunodepletion and in vitro kinase assays","pmids":["17466629"],"is_preprint":false},{"year":2002,"finding":"Pin1 interacts with CK2α in a phosphorylation-dependent manner, requiring the C-terminal domain of CK2α that is phosphorylated by p34(Cdc2) in mitotic cells. CK2α' (which is not phosphorylated in mitosis) does not interact with Pin1, but a chimera bearing the CK2α C-terminus does. Pin1 inhibits CK2-catalyzed phosphorylation of Thr-1342 on topoisomerase IIα. Both the WW domain and isomerase activity of Pin1 are required for CK2 interaction and inhibition of topoisomerase IIα phosphorylation.","method":"Co-immunoprecipitation, in vitro phosphorylation assays, domain-deletion and point mutants of Pin1, chimeric CK2 constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal co-IP, in vitro kinase assay, multiple domain mutants with orthogonal functional readout in one study","pmids":["11940573"],"is_preprint":false},{"year":2007,"finding":"Pin1 catalytic domain undergoes conformational exchange in the microsecond timescale during catalysis as detected by 15N relaxation dispersion NMR. A subset of active-site residues show exchange even without substrate, suggesting the active site is pre-organized for catalysis. NMR NOE data during turnover allowed distinction of residues affected primarily by substrate binding versus substrate isomerization.","method":"NMR relaxation dispersion (15N), inter- and intramolecular NOE measurements during catalysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure and dynamics during catalysis with substrate concentration dependence analysis in one rigorous study","pmids":["17316687"],"is_preprint":false},{"year":2013,"finding":"Pin1 is SUMOylated on Lys6 (WW domain) and Lys63 (PPIase domain), and this SUMOylation inhibits Pin1 protein activity and oncogenic function. SENP1 binds to and deSUMOylates Pin1, and either SENP1 overexpression or disruption of Pin1 SUMOylation promotes centrosome amplification and cell transformation. SENP1 also increases Pin1 protein stability.","method":"Co-immunoprecipitation, site-directed mutagenesis of SUMOylation sites (K6R, K63R), cell transformation assays, centrosome amplification assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, mutagenesis of modification sites, and multiple functional assays (transformation, centrosome amplification) in one study","pmids":["23633483"],"is_preprint":false},{"year":2012,"finding":"Pin1 directly interacts with the spacer domain of pRb and promotes transition from hypo- to hyperphosphorylated pRb without affecting CDK or phosphatase 1/2 activity. Pin1 binding requires phosphorylation of pRb at Ser608/612 and allows CDK/cyclin complexes to interact with pRb in mid/late G1.","method":"Co-immunoprecipitation, direct binding assays, site-directed mutagenesis, cell proliferation assays, Pin1 knockout cells","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, mutagenesis of binding sites, and functional cell proliferation readouts, but single lab","pmids":["22322860"],"is_preprint":false},{"year":2008,"finding":"Pin1 interacts with SMRT corepressor in a phosphorylation- and WW domain-dependent manner. Cdk2-mediated phosphorylation of SMRT at multiple sites is required for Pin1 binding; this decreases SMRT stability and attenuates SMRT-dependent transcriptional repression. Her2/Neu/ErbB2 signaling acts upstream of both Pin1 and Cdk2 in the cascade regulating SMRT stability.","method":"Co-immunoprecipitation in vitro and in mammalian cells, domain mutant analysis (WW domain of Pin1), phosphorylation site mutagenesis of SMRT, transcriptional reporter assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP in vitro and in cells, mutagenesis of phosphorylation/binding sites, transcription reporter assays, single lab","pmids":["18838553"],"is_preprint":false},{"year":2010,"finding":"Pin1 is present in dendritic spines and shafts and inhibits protein synthesis induced by glutamatergic signaling, possibly through eIF4E and 4E-BP1/2. Pin1(-/-) hippocampal slices show enhanced late LTP (L-LTP). PKMζ interacts with and inhibits Pin1 by phosphorylating Ser16, establishing a sequential regulatory mechanism for dendritic translation.","method":"Immunofluorescence localization, genetic knockout (Pin1-/- mice), electrophysiology (LTP recordings), co-immunoprecipitation, site-directed mutagenesis of Pin1 Ser16","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined electrophysiological phenotype, co-IP of Pin1-PKMζ interaction, phosphorylation site mutagenesis, and subcellular localization with functional consequence","pmids":["20215645"],"is_preprint":false},{"year":2008,"finding":"Pin1 has opposite effects on WT and P301L tau stability: Pin1 knockdown or KO increases WT tau protein stability and exacerbates WT tau tauopathy, while Pin1 knockdown or KO decreases P301L tau stability and abolishes its tauopathy phenotype in mice. Pin1 overexpression suppresses WT tau tauopathy but exacerbates P301L tauopathy.","method":"Genetic Pin1 KO and knockdown in mice, Pin1 overexpression in tau transgenic mice, protein stability assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic models (KO, KD, OE) in multiple tau transgenic mouse lines with defined tauopathy phenotypic readouts","pmids":["18431510"],"is_preprint":false},{"year":2013,"finding":"Pin1 directly binds and stabilizes TAp63α and ΔNp63α by inhibiting WWP1-mediated proteasomal degradation. Pin1 interacts specifically with the T538-Pro motif of p63α, disrupting p63α-WWP1 interaction. Pin1 enhances TAp63α-mediated apoptosis and promotes ΔNp63α-induced cell proliferation.","method":"Co-immunoprecipitation, site-directed mutagenesis (T538A), protein stability assays, cell proliferation/apoptosis assays, tumor xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, phosphorylation-site mutagenesis, functional stability assays, and in vivo xenograft rescue experiment; single lab","pmids":["24309930"],"is_preprint":false},{"year":2015,"finding":"Pin1 facilitates NICD1 (Notch1 intracellular domain) stability by inhibiting FBW7-induced polyubiquitination. Pin1 interacts with NICD1 and its overexpression increases NICD1 levels and promotes neuronal death in ischemia; depletion of Pin1 reduces NICD1 levels and confers neuroprotection in a mouse stroke model.","method":"Co-immunoprecipitation, Pin1 overexpression/knockdown/knockout, ubiquitination assay, mouse focal stroke model, Pin1 inhibitor treatment","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, in vivo KO/KD with functional neurological readout; single lab","pmids":["25558977"],"is_preprint":false},{"year":2011,"finding":"Pin1 stabilizes and activates orphan nuclear receptor TR3 by isomerizing phospho-Ser/Thr-Pro motifs. The Ser95-Pro motif is key for Pin1-enhanced TR3 stability (retarding degradation), while the phospho-Ser431-Pro motif (phosphorylated by ERK2) mediates enhanced TR3 transactivation. Pin1 facilitates TR3 targeting to the cyclin D2 promoter and TR3 recruitment of p300.","method":"Co-immunoprecipitation, site-directed mutagenesis of TR3 Pin1-binding sites, chromatin immunoprecipitation, protein stability assays, reporter assays, in vivo tumor growth","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, mutagenesis at phospho-binding sites, functional transcriptional and stability assays; single lab","pmids":["22002310"],"is_preprint":false},{"year":2012,"finding":"Pin1 is required for TGF-β-induced phosphorylation, nuclear translocation, and transcriptional activity of Smad3 in fibroblasts. In Pin1(-/-) cells, inhibitory Smad6 is mislocalized to the cytoplasm. Knockdown of Smad6 in Pin1(-/-) fibroblasts rescues TGF-β-induced Smad3 activation and target gene expression.","method":"Genetic knockout (Pin1-/- mice and fibroblasts), siRNA knockdown, subcellular fractionation, reporter assays, in vivo bleomycin fibrosis model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cellular and in vivo phenotype, epistasis rescue (Smad6 KD in Pin1-/- restores signaling), and multiple functional readouts","pmids":["22613712"],"is_preprint":false},{"year":2013,"finding":"HIPK2 autophosphorylates at Thr880/Ser882 upon DNA damage, creating a binding signal for Pin1. Pin1 binding links HIPK2 activation to its stabilization by inhibiting HIPK2 polyubiquitination and modulating Siah-1-HIPK2 interaction. Pin1 is required for DNA damage-induced HIPK2 stabilization, p53 Ser46 phosphorylation, and apoptosis in cells and in zebrafish.","method":"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis of HIPK2 autophosphorylation sites, in vivo zebrafish DNA damage model, Pin1 KO","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, ubiquitination assay, phosphosite mutagenesis, and in vivo zebrafish validation across multiple methods","pmids":["24145406"],"is_preprint":false},{"year":2017,"finding":"PIN1 directly binds phosphorylated Thr204 of BRD4 (as confirmed by peptide binding and crystallographic studies) and enhances BRD4 stability by inhibiting its ubiquitination. PIN1 catalyzes isomerization of Pro205 of BRD4, inducing a conformational change that promotes BRD4 interaction with CDK9 and increases BRD4 transcriptional activity. BRD4-T204A mutant (PIN1-binding-defective) reduces BRD4 stability and suppresses gastric cancer cell proliferation, migration, and tumor formation.","method":"Peptide binding assay, X-ray crystallography, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (T204A), tumor formation assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of PIN1-BRD4 complex, peptide binding, ubiquitination assay, and mutagenesis with functional rescue experiments in one study","pmids":["28481868"],"is_preprint":false},{"year":2017,"finding":"KPT-6566, a covalent PIN1 inhibitor, binds to the catalytic site of PIN1 (active site covalent modification) and results in release of a quinone-mimicking drug that generates reactive oxygen species and DNA damage, inducing cell death specifically in cancer cells.","method":"Mechanism-based covalent inhibitor screening, mass spectrometry confirmation of active-site binding, ROS assays, DNA damage assays, in vivo lung metastasis model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — covalent active-site binding confirmed by mass spectrometry and cellular assays, but full mechanistic details are partially inferred from the abstract","pmids":["28598431"],"is_preprint":false},{"year":2021,"finding":"Sulfopin covalently targets Pin1's active-site Cys113 (validated by two independent chemoproteomics methods), phenocopies Pin1 genetic knockout, and inhibits c-Myc target genes, reducing tumor progression in murine/zebrafish neuroblastoma and pancreatic cancer models.","method":"Covalent fragment screening, chemoproteomics (two independent methods), genetic knockout comparison, in vivo tumor models","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site Cys113 covalent modification confirmed by two orthogonal chemoproteomics methods, phenocopies genetic KO, validated in vivo","pmids":["33972797"],"is_preprint":false},{"year":2020,"finding":"Rationally designed peptide inhibitors covalently target Cys113 in the Pin1 active site. Pin1 cooperates with mutant KRAS to promote transformation in PDAC, and Pin1 inhibition impairs cell viability over time in PDAC cell lines.","method":"Structure-guided inhibitor design, covalent active-site targeting of Cys113, genetic/chemical-genetic strategies in PDAC cell lines","journal":"Nature chemical biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — active-site covalent modification confirmed by structure-guided design and genetic validation in PDAC; single study","pmids":["32483379"],"is_preprint":false},{"year":2011,"finding":"Pin1 deficiency causes endothelial dysfunction and hypertension. Pin1 binds eNOS (confirmed by co-immunoprecipitation) and enables dephosphorylation of eNOS Ser116, which increases NO production and endothelium-dependent dilation. Pin1 knockdown or inhibition increases eNOS Ser116 phosphorylation and prevents VEGF-induced dephosphorylation of Ser116.","method":"Co-immunoprecipitation, siRNA knockdown, Pin1 inhibitor (juglone), Pin1 knockout mice, NO production assay, vascular relaxation assay, blood pressure measurement","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP of Pin1-eNOS, phosphorylation-specific readout, and in vivo KO mouse validation with defined vascular and blood pressure phenotypes","pmids":["21810655"],"is_preprint":false},{"year":2010,"finding":"Pin1 increases MEK1/2 interaction and phosphorylation, and promotes E2F-4- and Egr-1-driven LC-3 expression in tamoxifen-resistant breast cancer cells. Pin1(-/-) MEFs show lower TPA-induced MEK1/2 phosphorylation than Pin1(+/+) MEFs.","method":"Pin1 knockout MEFs, siRNA knockdown, co-immunoprecipitation (Pin1-MEK1/2), promoter activity assays, Western blotting","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO comparison, co-IP, and promoter activity assays; mechanistic link between Pin1-MEK interaction and LC-3 expression; single lab","pmids":["20479004"],"is_preprint":false},{"year":2015,"finding":"Pin1 directly and selectively enhances ERα DNA binding activity in a manner requiring isomerase activity. Pin1 isomerizes the phosphorylated Ser118-Pro119 bond in the ERα AF1 domain. This is a direct effect confirmed with purified components in solution-based DNA binding assays, with Pin1 selectively enhancing ERα binding to consensus DNA elements.","method":"In vitro DNA binding assay with purified components, DNA binding microarray (thousands of permutations), stable Pin1 overexpression, isomerase-dead Pin1 mutant","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro with purified components plus catalytic mutant validation; direct demonstration of isomerization-dependent DNA binding enhancement","pmids":["25866209"],"is_preprint":false},{"year":2016,"finding":"Pin1 catalyzes isomerization of phosphorylated Ser/Thr-Pro motifs of PIN1 (auxin transporter in plants). Note: this is the plant parvulin Pin1At acting on plant PIN1 protein—this is a symbol collision and should be excluded.","method":"N/A","journal":"Nature communications","confidence":"Low","confidence_rationale":"Excluded — symbol collision (plant Pin1At/PIN1)","pmids":["26791759"],"is_preprint":false},{"year":2016,"finding":"NMR, ITC, and SAXS analysis reveals that phosphorylated Ser235-Pro (but not pThr231-Pro) of tau is exclusively catalyzed by full-length Pin1 and the isolated PPIase domain. The WW domain is dispensable for catalysis at pSer235. Multiple phospho-sites on CDK2/CycA-phosphorylated full-length tau are simultaneously catalyzed by Pin1 with different efficiencies. Pin1 does not increase dephosphorylation rates of tau by PP2A, refuting a previously published model.","method":"NMR (site-specific measurements), isothermal calorimetry (ITC), small angle X-ray scattering (SAXS), isolated domain analysis, CDK2/CycA-phosphorylated full-length tau","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biophysical methods (NMR, ITC, SAXS) on full-length and domain-truncated Pin1 with physiologically phosphorylated tau; refutes prior model with rigorous evidence","pmids":["26996941"],"is_preprint":false},{"year":2016,"finding":"Pin1 does not promote phosphorylated tau-induced microtubule formation in vitro, directly refuting the model that Pin1 binding/catalysis at the AT180 epitope (pThr231/pSer235) restores phospho-tau's function in tubulin assembly. Novel GTP-tubulin ring-shaped species were found in the earliest stage of tau-induced polymerization.","method":"Turbidity assays, time-resolved SAXS, time-resolved negative-stain electron microscopy, NMR, in vitro reconstitution with phosphorylated tau","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biophysical reconstitution methods with rigorous controls; explicitly negative result replicated across methods","pmids":["26996940"],"is_preprint":false},{"year":2018,"finding":"Pin1 interacts with and is dephosphorylated by calcineurin in dendritic spines. Calcineurin-mediated dephosphorylation of Pin1 suppresses its isomerase activity. Knockout of Pin1 or exposure to Aβ42 induces loss of mature dendritic spines; exogenous Pin1 prevents this. FK506 (calcineurin inhibitor) blocks Aβ42-induced spine loss in wild-type but not Pin1-null neurons.","method":"Co-immunoprecipitation (Pin1-calcineurin), Pin1 knockout neurons, exogenous Pin1 rescue, FK506 treatment, dendritic spine imaging","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, genetic KO rescue with exogenous Pin1, pharmacological epistasis (FK506), and defined spine morphology phenotype in multiple conditions","pmids":["29559586"],"is_preprint":false},{"year":2012,"finding":"Androgen receptor Ser81 mediates interaction with Pin1, and this interaction is important for AR transcriptional activity.","method":"Co-immunoprecipitation, site-directed mutagenesis (AR-Ser81), transcriptional activity assays","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and phosphosite mutagenesis with transcriptional readout, but single lab with limited methodological breadth in abstract","pmids":["22894932"],"is_preprint":false},{"year":2024,"finding":"Pin1 is deubiquitinated and stabilized by USP34, which is facilitated by Plk1-mediated phosphorylation of Pin1. Stabilized Pin1 promotes isomerization of the SUMO E2 enzyme Ubc9, requiring CDK1-mediated phosphorylation of Ubc9, leading to increased Ubc9 thioester formation with SUMO1 and hypersumoylation to support glioma stem cell maintenance.","method":"Co-immunoprecipitation, ubiquitination assay, Phos-tag gel electrophoresis, GST pull-down, genetic KO/KD, pharmacological inhibition, orthotopic tumor model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, ubiquitination assay, direct biochemical demonstration of Ubc9 thioester formation, in vivo orthotopic model, multiple orthogonal methods in one study","pmids":["38167292"],"is_preprint":false},{"year":2021,"finding":"JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation, thereby stabilizing PIN1 and promoting ICC cell proliferation.","method":"Loss-of-function and gain-of-function studies in vitro and in vivo, kinase assay (JNK-PIN1), ubiquitination assays, site-specific mutagenesis, xenograft model, ATRA pharmacological inhibition","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct kinase-substrate assay and ubiquitination assay with site-directed mutagenesis in one study; single lab","pmids":["34048060"],"is_preprint":false},{"year":2020,"finding":"Pin1 interacts with METTL3 and prevents its ubiquitin-dependent proteasomal and lysosomal degradation, stabilizing METTL3 and increasing m6A modification of TAZ and EGFR mRNA, resulting in enhanced translation of these oncoproteins.","method":"Co-immunoprecipitation, ubiquitination assay, polysome profiling, Pin1 KO, METTL3 KO, in vivo orthotopic tumor model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, polysome profiling, and in vivo model; single lab with multiple orthogonal methods","pmids":["36755057"],"is_preprint":false},{"year":2020,"finding":"Pin1 directly interacts with adipose triglyceride lipase (ATGL) and enhances its degradation through the ubiquitin-proteasome system. Pin1 overexpression decreases ATGL protein levels without altering mRNA, and Pin1 KO increases lipolysis and ATGL protein expression in adipose tissue.","method":"Co-immunoprecipitation, siRNA knockdown, Pin1 overexpression, adipocyte-specific Pin1 KO mice, ubiquitin-proteasome assay, lipolysis assay","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitin-proteasome assay, tissue-specific KO with functional lipolysis readout; single lab","pmids":["33279499"],"is_preprint":false},{"year":2023,"finding":"CDK1 directly phosphorylates pVHL at Ser80, priming recognition of pVHL by PIN1. PIN1 then binds phosphorylated pVHL and facilitates recruitment of the E3 ligase WSB1, targeting pVHL for ubiquitination and degradation. This CDK1/PIN1 axis promotes tumor growth and chemoresistance in a pVHL-dependent manner.","method":"Co-immunoprecipitation, in vitro kinase assay (CDK1 phosphorylation of pVHL), ubiquitination assay, site-directed mutagenesis (Ser80), genetic ablation and pharmacological inhibition, tumor xenograft models","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay defining the phospho-priming step, co-IP, ubiquitination assay with mutagenesis, and in vivo models in one study","pmids":["36813923"],"is_preprint":false},{"year":2017,"finding":"Pin1 promotes β-cell proliferation and activates insulin secretion by enhancing SIK2 kinase activity. Pin1 binds SIK2 (identified as a Pin1-binding protein) and enhances SIK2 kinase activity, resulting in decreased p35 protein (a negative regulator of Ca2+ influx). β-cell-specific Pin1 KO mice show reduced β-cell mass, impaired Ca2+ influx, and reduced insulin secretion.","method":"β-cell-specific Pin1 KO mice, co-immunoprecipitation (Pin1-SIK2), kinase activity assay, intracellular Ca2+ measurement, glucose tolerance test","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with functional metabolic phenotype, co-IP, kinase activity assay; single lab","pmids":["28566287"],"is_preprint":false},{"year":2020,"finding":"Pin1 binds and stabilizes hepatitis B virus core protein (HBc) in a phosphorylation-dependent manner at Thr160-Pro and Ser162-Pro motifs. Chemical or genetic inhibition of Pin1 accelerates HBc degradation via a lysosome-dependent pathway. PDP2 phosphatase dephosphorylates HBc at Pin1-binding sites, suppressing Pin1-mediated HBc stabilization.","method":"GST pull-down, co-immunoprecipitation, Phos-tag gel electrophoresis, site-directed mutagenesis, Pin1 inhibition (chemical and genetic), lysosome inhibitor assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pulldown, co-IP, phosphosite mutagenesis, degradation pathway assays; single lab","pmids":["32083080"],"is_preprint":false},{"year":2020,"finding":"PIN1 interacts with STK3 (MST2 kinase, upstream Hippo kinase) and induces ubiquitination-dependent proteasomal degradation of STK3, leading to reduced LATS1/2 activity, nuclear translocation of TAZ, and formation of TAZ/TEAD complex increasing CTGF expression in melanoma.","method":"Co-immunoprecipitation, ubiquitination assay, subcellular fractionation, siRNA/shRNA knockdown, tumor formation assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, and functional pathway readout (TAZ nuclear translocation, CTGF expression); single lab","pmids":["33253791"],"is_preprint":false}],"current_model":"PIN1 is a phosphorylation-dependent peptidyl-prolyl cis/trans isomerase that specifically recognizes pSer/Thr-Pro motifs via its WW domain and catalyzes isomerization at its PPIase active site (with catalytic Cys113 as a key residue), thereby inducing conformational changes in substrate proteins that alter their stability (typically by blocking ubiquitin-mediated degradation), activity, protein-protein interactions, and subcellular localization; its substrates include the RNAP II CTD (regulating transcription initiation), topoisomerase IIα (regulating chromosome condensation), pRb (promoting hyperphosphorylation), tau (with complex mutation-dependent effects on stability), BRD4, METTL3, NICD1, Smad3, ATGL, pVHL (targeted for degradation via WSB1 after CDK1-mediated Ser80 phosphorylation), eNOS (enabling Ser116 dephosphorylation to stimulate NO production), and the SUMO E2 enzyme Ubc9; PIN1 itself is regulated post-translationally by phosphorylation (inhibitory at Ser16 by PKMζ/Aurora A, stabilizing at Ser115 by JNK), SUMOylation at Lys6/Lys63 (inhibitory, reversed by SENP1), and deubiquitination by USP34."},"narrative":{"mechanistic_narrative":"PIN1 is a phosphorylation-dependent peptidyl-prolyl cis/trans isomerase that recognizes phosphorylated Ser/Thr-Pro motifs and catalyzes isomerization through a catalytic active site whose key residue is Cys113, acting as a master post-phosphorylation switch that reshapes substrate conformation, stability, activity, and localization across cell-cycle, transcriptional, and signaling programs [PMID:33972797, PMID:25866209, PMID:26996941]. NMR studies of the catalytic domain show an active site pre-organized for catalysis that undergoes microsecond conformational exchange during turnover [PMID:17316687], and biophysical work on tau established that PIN1 catalyzes specific phospho-Ser/Thr-Pro bonds (e.g., pSer235-Pro) with the PPIase domain sufficient for catalysis while the WW domain mediates phospho-dependent substrate engagement [PMID:26996941]. A recurrent mechanistic theme is control of substrate turnover: PIN1 binding to a phosphorylated motif blocks E3-ligase-mediated ubiquitination to stabilize substrates such as BRD4 (isomerizing Pro205 to favor CDK9 interaction) [PMID:28481868], NICD1 (antagonizing FBW7) [PMID:25558977], HIPK2 (modulating Siah-1) [PMID:24145406], TAp63α/ΔNp63α (antagonizing WWP1) [PMID:24309930], TR3 [PMID:22002310], and METTL3 [PMID:36755057]; conversely it can promote degradation of substrates including pVHL (recruiting WSB1 after CDK1-mediated Ser80 priming) [PMID:36813923], ATGL [PMID:33279499], and the Hippo kinase STK3 [PMID:33253791]. PIN1 also directly tunes enzyme and transcription-factor activity, inhibiting the RNAP II CTD phosphatase FCP1 and stimulating CTD phosphorylation to govern transcription initiation [PMID:14600023, PMID:18006688], promoting topoisomerase IIα-dependent mitotic chromosome condensation [PMID:17466629], driving pRb hyperphosphorylation [PMID:22322860], enhancing ERα DNA binding via isomerization of pSer118-Pro119 [PMID:25866209], and enabling eNOS Ser116 dephosphorylation to stimulate NO production [PMID:21810655]. Through these activities PIN1 supports oncogenic programs cooperating with mutant KRAS and c-Myc target gene expression [PMID:33972797, PMID:32483379], and is itself regulated post-translationally—inhibitory phosphorylation at Ser16 by PKMζ [PMID:20215645] and dephosphorylation by calcineurin [PMID:29559586], stabilizing phosphorylation at Ser115 by JNK [PMID:34048060], inhibitory SUMOylation reversed by SENP1 [PMID:23633483], and deubiquitination by USP34 [PMID:38167292]—placing it under tight upstream control in proliferative, neuronal, and metabolic contexts. Covalent active-site inhibitors targeting Cys113 (Sulfopin, KPT-6566, designed peptides) phenocopy PIN1 loss and validate it as a tractable anticancer target [PMID:28598431, PMID:33972797, PMID:32483379].","teleology":[{"year":2002,"claim":"Established that PIN1 engages substrates in a strictly phosphorylation- and WW-domain-dependent manner using mitotic CK2/topoisomerase IIα as a model, defining the recognition logic of the enzyme.","evidence":"Co-IP, in vitro phosphorylation assays, and Pin1 domain/point mutants with chimeric CK2 constructs","pmids":["11940573"],"confidence":"High","gaps":["Did not resolve isomerization kinetics at the CK2/TopoIIα motif","Physiological consequence for chromosome dynamics not addressed here"]},{"year":2003,"claim":"Defined a transcriptional role by showing PIN1 controls RNAP II CTD phosphorylation status, linking proline isomerase activity to the transcription cycle.","evidence":"In vitro phosphatase/kinase assays (FCP1 inhibition, cdc2/cyclin B stimulation), pin1-/- cells, transcription/splicing extract assays, co-IP","pmids":["14600023"],"confidence":"High","gaps":["Direct isomerization of CTD prolines not structurally resolved","Genome-wide scope of CTD regulation not mapped"]},{"year":2007,"claim":"Resolved the stage of transcription PIN1 acts on and demonstrated direct mitotic functions, showing it inhibits initiation and is required for chromosome condensation.","evidence":"ChIP with phospho-CTD antibodies, inducible overexpression and active-site mutants; immunodepletion/reconstitution of mitotic extracts with purified Pin1 and cdc2/cyclin B; NMR relaxation dispersion of the catalytic domain","pmids":["18006688","17466629","17316687"],"confidence":"High","gaps":["In vivo condensation defect not assessed in intact cells across cell types","Catalytic conformational exchange not linked to a specific substrate motif"]},{"year":2008,"claim":"Generalized the stability-control paradigm by showing PIN1 destabilizes the SMRT corepressor downstream of Cdk2/Her2 signaling, connecting the isomerase to nuclear-receptor transcriptional output.","evidence":"Reciprocal co-IP in vitro and in cells, WW-domain and SMRT phosphosite mutagenesis, transcriptional reporter assays","pmids":["18838553"],"confidence":"Medium","gaps":["E3 ligase mediating SMRT turnover not identified","Single-lab finding"]},{"year":2008,"claim":"Revealed mutation-dependent, opposite effects of PIN1 on tau stability in vivo, establishing context-dependent substrate outcomes relevant to tauopathy.","evidence":"Pin1 KO, knockdown, and overexpression across WT and P301L tau transgenic mouse lines with stability and phenotype readouts","pmids":["18431510"],"confidence":"High","gaps":["Molecular basis of the WT-versus-mutant divergence not defined","Specific tau phospho-motifs catalyzed not pinned down here"]},{"year":2010,"claim":"Extended PIN1 to neuronal and signaling contexts, defining a PKMζ→Ser16 inhibitory phospho-switch and a role in dendritic translation, plus MEK1/2 modulation.","evidence":"Pin1-/- mice and LTP electrophysiology, immunofluorescence localization, co-IP, Ser16 mutagenesis; Pin1-/- MEFs, co-IP and promoter assays for MEK1/2","pmids":["20215645","20479004"],"confidence":"High","gaps":["Direct PIN1 substrate in the translation machinery not defined","MEK1/2 phospho-motif engaged by PIN1 not mapped"]},{"year":2011,"claim":"Demonstrated direct enzyme/receptor activity tuning by showing PIN1 enables eNOS Ser116 dephosphorylation to drive NO production and isomerizes TR3 to control its stability and transactivation.","evidence":"Co-IP, Pin1 KO mice, siRNA, inhibitor and phospho-specific readouts for eNOS; co-IP, phosphosite mutagenesis, ChIP and reporter assays for TR3","pmids":["21810655","22002310"],"confidence":"High","gaps":["Phosphatase acting on eNOS Ser116 downstream of PIN1 not identified","TR3 isomerization not directly observed structurally"]},{"year":2012,"claim":"Broadened substrate repertoire to cell-cycle and signaling effectors—pRb hyperphosphorylation, TGF-β/Smad3 activation via Smad6 localization, and androgen receptor activity.","evidence":"Co-IP, direct binding and phosphosite mutagenesis for pRb; Pin1-/- fibroblasts with Smad6-knockdown epistasis rescue and bleomycin fibrosis model; co-IP and AR-Ser81 mutagenesis with transcription assays","pmids":["22322860","22613712","22894932"],"confidence":"High","gaps":["Mechanism by which PIN1 controls Smad6 localization unresolved","AR study limited methodologically (single lab)"]},{"year":2013,"claim":"Defined regulation of PIN1 itself by SUMOylation (Lys6/Lys63, reversed by SENP1) and extended the anti-degradation paradigm to HIPK2 and p63 isoforms in DNA-damage and apoptosis pathways.","evidence":"Co-IP, K6R/K63R mutagenesis, transformation and centrosome assays for SUMO; co-IP, ubiquitination and HIPK2 autophosphosite mutagenesis with zebrafish DNA-damage model; co-IP, T538A mutagenesis and xenograft for p63","pmids":["23633483","24145406","24309930"],"confidence":"High","gaps":["SUMO E3 ligase for PIN1 not identified","p63 finding single-lab"]},{"year":2015,"claim":"Provided direct biochemical proof of isomerization-driven function by reconstituting PIN1-enhanced ERα DNA binding with purified components, and extended substrate stabilization to NICD1 in stroke.","evidence":"In vitro DNA binding assays with purified components and isomerase-dead mutant, DNA-binding microarray; co-IP, ubiquitination assay, Pin1 KO/KD and mouse stroke model for NICD1","pmids":["25866209","25558977"],"confidence":"High","gaps":["Structural snapshot of the ERα pSer118-Pro119 isomer not obtained","NICD1 study single-lab"]},{"year":2016,"claim":"Delivered rigorous biophysical dissection of PIN1 catalysis on tau, defining site-specific catalysis and refuting prior models of PP2A-coupled dephosphorylation and microtubule-assembly restoration.","evidence":"NMR, ITC, SAXS on full-length and isolated PPIase domain with CDK2/CycA-phosphorylated tau; turbidity, time-resolved SAXS/EM reconstitution of tau-induced tubulin polymerization","pmids":["26996941","26996940"],"confidence":"High","gaps":["Cellular consequence of site-specific tau isomerization not established","Functional output of refuted models replaced only partially"]},{"year":2017,"claim":"Captured a substrate complex structurally and validated active-site covalent targeting, cementing the isomerization-then-stabilization mechanism for BRD4 and the druggability of Cys113.","evidence":"Peptide binding, X-ray crystallography of PIN1-BRD4, co-IP, ubiquitination assay, T204A mutagenesis and tumor assays; covalent inhibitor KPT-6566 with mass spectrometry, ROS/DNA-damage and metastasis models; SIK2-dependent β-cell function via tissue-specific KO","pmids":["28481868","28598431","28566287"],"confidence":"High","gaps":["BRD4 isomerization shown for one site; broader BRD4 conformational map not built","KPT-6566 mechanistic details partly inferred"]},{"year":2020,"claim":"Expanded the degradation-and-stabilization network to metabolic, viral, Hippo, and m6A pathways and refined structure-guided covalent Cys113 inhibitors in KRAS-driven cancer.","evidence":"Co-IP, ubiquitin-proteasome and tissue-specific KO assays for ATGL; GST pulldown and lysosome assays for HBV core; co-IP/ubiquitination for STK3; co-IP, ubiquitination and polysome profiling for METTL3; structure-guided peptide inhibitors in PDAC","pmids":["33279499","32083080","33253791","36755057","32483379"],"confidence":"Medium","gaps":["Most substrate studies are single-lab","Direct isomerization at each substrate motif not biophysically confirmed"]},{"year":2021,"claim":"Validated PIN1 as a phenocopyable, in-vivo tractable target via Cys113-directed covalent probes and defined a JNK-Ser115 stabilizing phospho-switch governing PIN1 turnover.","evidence":"Covalent fragment screening and two-method chemoproteomics with genetic-KO comparison and tumor models (Sulfopin); JNK kinase assay, Lys117 ubiquitination and Ser115 mutagenesis with xenograft (ICC)","pmids":["33972797","34048060"],"confidence":"High","gaps":["Full set of in-vivo PIN1 substrates underlying Sulfopin effects not enumerated","JNK-PIN1 axis single-lab"]},{"year":2023,"claim":"Established a phospho-priming module in which CDK1 phosphorylates pVHL Ser80 to license PIN1 binding and WSB1-mediated pVHL degradation, illustrating PIN1-directed positive regulation of substrate turnover.","evidence":"In vitro CDK1 kinase assay, co-IP, ubiquitination assay, Ser80 mutagenesis, genetic/pharmacological ablation and xenografts","pmids":["36813923"],"confidence":"High","gaps":["Conformational change in pVHL driving WSB1 recruitment not structurally resolved"]},{"year":2024,"claim":"Integrated upstream regulation and downstream catalysis by showing USP34/Plk1 stabilize PIN1, which then isomerizes the SUMO E2 Ubc9 to amplify SUMOylation in glioma stem cells.","evidence":"Co-IP, ubiquitination assay, Phos-tag electrophoresis, GST pulldown, Ubc9 thioester assay, genetic KO/KD and orthotopic tumor model","pmids":["38167292"],"confidence":"High","gaps":["Structural basis of Ubc9 isomerization not resolved","Generality beyond glioma stem cells untested"]},{"year":null,"claim":"How PIN1 selects among its many phospho-Ser/Thr-Pro substrates in a given cellular context—and how a single isomerization event is decoded into either stabilization or degradation at the same motif—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying rule for stabilization-versus-degradation outcomes","Limited high-resolution structures of PIN1-substrate isomerization states","Context-specific substrate prioritization not mapped systematically"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[4,21,23,27]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,15,31]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,19,32]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,21]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,6]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,21]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,11,14,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,19,34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,17,18,29]}],"complexes":[],"partners":["BRD4","METTL3","NICD1","HIPK2","ENOS","PVHL","SMAD3","STK3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13526","full_name":"Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1","aliases":["Peptidyl-prolyl cis-trans isomerase Pin1","PPIase Pin1","Rotamase Pin1"],"length_aa":163,"mass_kda":18.2,"function":"Peptidyl-prolyl cis/trans isomerase (PPIase) that binds to and isomerizes specific phosphorylated Ser/Thr-Pro (pSer/Thr-Pro) motifs (PubMed:21497122, PubMed:23623683, PubMed:29686383). By inducing conformational changes in a subset of phosphorylated proteins, acts as a molecular switch in multiple cellular processes (PubMed:21497122, PubMed:22033920, PubMed:23623683). Displays a preference for acidic residues located N-terminally to the proline bond to be isomerized. Regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Down-regulates kinase activity of BTK (PubMed:16644721). Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation (PubMed:15664191). Binds and targets PML and BCL6 for degradation in a phosphorylation-dependent manner (PubMed:17828269). Acts as a regulator of JNK cascade by binding to phosphorylated FBXW7, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation: degradation of FBXW7 leads to subsequent stabilization of JUN (PubMed:22608923). May facilitate the ubiquitination and proteasomal degradation of RBBP8/CtIP through CUL3/KLHL15 E3 ubiquitin-protein ligase complex, hence favors DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR) (PubMed:23623683, PubMed:27561354). Upon IL33-induced lung inflammation, catalyzes cis-trans isomerization of phosphorylated IRAK3/IRAK-M, inducing IRAK3 stabilization, nuclear translocation and expression of pro-inflammatory genes in dendritic cells (PubMed:29686383). Catalyzes cis-trans isomerization of phosphorylated phosphoglycerate kinase PGK1 under hypoxic conditions to promote its binding to the TOM complex and targeting to the mitochondrion (PubMed:26942675). Acts as a negative regulator of adipocyte browning by binding to phosphorylated PRDM16, targeting PRDM16 for degradation (By similarity)","subcellular_location":"Nucleus; Nucleus speckle; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q13526/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIN1","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PIN1","total_profiled":1310},"omim":[{"mim_id":"610697","title":"PDZ DOMAIN-CONTAINING 2; PDZD2","url":"https://www.omim.org/entry/610697"},{"mim_id":"609423","title":"HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609423"},{"mim_id":"608179","title":"CAYTAXIN; ATCAY","url":"https://www.omim.org/entry/608179"},{"mim_id":"605498","title":"KINESIN FAMILY MEMBER 20B; KIF20B","url":"https://www.omim.org/entry/605498"},{"mim_id":"603273","title":"TUMOR PROTEIN p63; TP63","url":"https://www.omim.org/entry/603273"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":256.4}],"url":"https://www.proteinatlas.org/search/PIN1"},"hgnc":{"alias_symbol":["dod"],"prev_symbol":[]},"alphafold":{"accession":"Q13526","domains":[{"cath_id":"3.10.50.40","chopping":"54-160","consensus_level":"high","plddt":98.2168,"start":54,"end":160}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13526","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13526-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13526-F1-predicted_aligned_error_v6.png","plddt_mean":91.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIN1","jax_strain_url":"https://www.jax.org/strain/search?query=PIN1"},"sequence":{"accession":"Q13526","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13526.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13526/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13526"}},"corpus_meta":[{"pmid":"21852138","id":"PMC_21852138","title":"Prolyl isomerase Pin1 as a molecular switch to determine the fate of phosphoproteins.","date":"2011","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/21852138","citation_count":297,"is_preprint":false},{"pmid":"17410202","id":"PMC_17410202","title":"PIN1, the cell cycle and cancer.","date":"2007","source":"Nature reviews. 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Pin1 overexpression inhibits ongoing transcription of mRNA precursors in vivo and both transcription and RNAP II-stimulated pre-mRNA splicing in cell extracts. A hyper-hyperphosphorylated form of RNAP II accumulates in M-phase cells in a Pin1-dependent manner and associates specifically with Pin1.\",\n      \"method\": \"In vitro phosphatase/kinase assays, in vivo overexpression/knockout cell lines, cell extract transcription/splicing assays, co-immunoprecipitation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including in vitro enzymatic assays, in vivo genetic models (pin1-/- cells), and functional transcription/splicing assays in one study\",\n      \"pmids\": [\"14600023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Pin1 overexpression releases RNAP II from chromatin, causing accumulation in a hyperphosphorylated form in nuclear speckle-associated structures. Pin1 inhibits transcription initiation (not elongation) in nuclear extracts, while an inactive Pin1 mutant stimulates transcription, indicating Pin1 modulates CTD phosphorylation during early transcription cycle stages.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) with CTD phospho-specific antibodies, inducible Pin1 overexpression cell lines, in vitro transcription assays with active-site mutant Pin1\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP assays, inducible expression system, and in vitro transcription assays with catalytically inactive mutant in one study\",\n      \"pmids\": [\"18006688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Pin1 promotes chromosome condensation during mitosis. Pin1 interaction with chromatin is elevated in G2/M phase correlating with mitotic phosphoproteins, especially topoisomerase IIα. Immunodepletion of Pin1 from mitotic extracts prevents chromosome condensation. Purified Pin1 and cdc2/cyclin B are sufficient to induce condensation, and Pin1 increases TopoIIα phosphorylation by cdc2/cyclin B in vitro, promoting a TopoIIα/Pin1/DNA complex.\",\n      \"method\": \"Chromatin fractionation, siRNA knockdown, immunodepletion of mitotic extracts, reconstitution with purified components, in vitro kinase assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with purified Pin1 and cdc2/cyclin B sufficient for condensation, supported by immunodepletion and in vitro kinase assays\",\n      \"pmids\": [\"17466629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Pin1 interacts with CK2α in a phosphorylation-dependent manner, requiring the C-terminal domain of CK2α that is phosphorylated by p34(Cdc2) in mitotic cells. CK2α' (which is not phosphorylated in mitosis) does not interact with Pin1, but a chimera bearing the CK2α C-terminus does. Pin1 inhibits CK2-catalyzed phosphorylation of Thr-1342 on topoisomerase IIα. Both the WW domain and isomerase activity of Pin1 are required for CK2 interaction and inhibition of topoisomerase IIα phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphorylation assays, domain-deletion and point mutants of Pin1, chimeric CK2 constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal co-IP, in vitro kinase assay, multiple domain mutants with orthogonal functional readout in one study\",\n      \"pmids\": [\"11940573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Pin1 catalytic domain undergoes conformational exchange in the microsecond timescale during catalysis as detected by 15N relaxation dispersion NMR. A subset of active-site residues show exchange even without substrate, suggesting the active site is pre-organized for catalysis. NMR NOE data during turnover allowed distinction of residues affected primarily by substrate binding versus substrate isomerization.\",\n      \"method\": \"NMR relaxation dispersion (15N), inter- and intramolecular NOE measurements during catalysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure and dynamics during catalysis with substrate concentration dependence analysis in one rigorous study\",\n      \"pmids\": [\"17316687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Pin1 is SUMOylated on Lys6 (WW domain) and Lys63 (PPIase domain), and this SUMOylation inhibits Pin1 protein activity and oncogenic function. SENP1 binds to and deSUMOylates Pin1, and either SENP1 overexpression or disruption of Pin1 SUMOylation promotes centrosome amplification and cell transformation. SENP1 also increases Pin1 protein stability.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of SUMOylation sites (K6R, K63R), cell transformation assays, centrosome amplification assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, mutagenesis of modification sites, and multiple functional assays (transformation, centrosome amplification) in one study\",\n      \"pmids\": [\"23633483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Pin1 directly interacts with the spacer domain of pRb and promotes transition from hypo- to hyperphosphorylated pRb without affecting CDK or phosphatase 1/2 activity. Pin1 binding requires phosphorylation of pRb at Ser608/612 and allows CDK/cyclin complexes to interact with pRb in mid/late G1.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assays, site-directed mutagenesis, cell proliferation assays, Pin1 knockout cells\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, mutagenesis of binding sites, and functional cell proliferation readouts, but single lab\",\n      \"pmids\": [\"22322860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Pin1 interacts with SMRT corepressor in a phosphorylation- and WW domain-dependent manner. Cdk2-mediated phosphorylation of SMRT at multiple sites is required for Pin1 binding; this decreases SMRT stability and attenuates SMRT-dependent transcriptional repression. Her2/Neu/ErbB2 signaling acts upstream of both Pin1 and Cdk2 in the cascade regulating SMRT stability.\",\n      \"method\": \"Co-immunoprecipitation in vitro and in mammalian cells, domain mutant analysis (WW domain of Pin1), phosphorylation site mutagenesis of SMRT, transcriptional reporter assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP in vitro and in cells, mutagenesis of phosphorylation/binding sites, transcription reporter assays, single lab\",\n      \"pmids\": [\"18838553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Pin1 is present in dendritic spines and shafts and inhibits protein synthesis induced by glutamatergic signaling, possibly through eIF4E and 4E-BP1/2. Pin1(-/-) hippocampal slices show enhanced late LTP (L-LTP). PKMζ interacts with and inhibits Pin1 by phosphorylating Ser16, establishing a sequential regulatory mechanism for dendritic translation.\",\n      \"method\": \"Immunofluorescence localization, genetic knockout (Pin1-/- mice), electrophysiology (LTP recordings), co-immunoprecipitation, site-directed mutagenesis of Pin1 Ser16\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined electrophysiological phenotype, co-IP of Pin1-PKMζ interaction, phosphorylation site mutagenesis, and subcellular localization with functional consequence\",\n      \"pmids\": [\"20215645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Pin1 has opposite effects on WT and P301L tau stability: Pin1 knockdown or KO increases WT tau protein stability and exacerbates WT tau tauopathy, while Pin1 knockdown or KO decreases P301L tau stability and abolishes its tauopathy phenotype in mice. Pin1 overexpression suppresses WT tau tauopathy but exacerbates P301L tauopathy.\",\n      \"method\": \"Genetic Pin1 KO and knockdown in mice, Pin1 overexpression in tau transgenic mice, protein stability assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic models (KO, KD, OE) in multiple tau transgenic mouse lines with defined tauopathy phenotypic readouts\",\n      \"pmids\": [\"18431510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Pin1 directly binds and stabilizes TAp63α and ΔNp63α by inhibiting WWP1-mediated proteasomal degradation. Pin1 interacts specifically with the T538-Pro motif of p63α, disrupting p63α-WWP1 interaction. Pin1 enhances TAp63α-mediated apoptosis and promotes ΔNp63α-induced cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (T538A), protein stability assays, cell proliferation/apoptosis assays, tumor xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, phosphorylation-site mutagenesis, functional stability assays, and in vivo xenograft rescue experiment; single lab\",\n      \"pmids\": [\"24309930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pin1 facilitates NICD1 (Notch1 intracellular domain) stability by inhibiting FBW7-induced polyubiquitination. Pin1 interacts with NICD1 and its overexpression increases NICD1 levels and promotes neuronal death in ischemia; depletion of Pin1 reduces NICD1 levels and confers neuroprotection in a mouse stroke model.\",\n      \"method\": \"Co-immunoprecipitation, Pin1 overexpression/knockdown/knockout, ubiquitination assay, mouse focal stroke model, Pin1 inhibitor treatment\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, in vivo KO/KD with functional neurological readout; single lab\",\n      \"pmids\": [\"25558977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Pin1 stabilizes and activates orphan nuclear receptor TR3 by isomerizing phospho-Ser/Thr-Pro motifs. The Ser95-Pro motif is key for Pin1-enhanced TR3 stability (retarding degradation), while the phospho-Ser431-Pro motif (phosphorylated by ERK2) mediates enhanced TR3 transactivation. Pin1 facilitates TR3 targeting to the cyclin D2 promoter and TR3 recruitment of p300.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of TR3 Pin1-binding sites, chromatin immunoprecipitation, protein stability assays, reporter assays, in vivo tumor growth\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, mutagenesis at phospho-binding sites, functional transcriptional and stability assays; single lab\",\n      \"pmids\": [\"22002310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Pin1 is required for TGF-β-induced phosphorylation, nuclear translocation, and transcriptional activity of Smad3 in fibroblasts. In Pin1(-/-) cells, inhibitory Smad6 is mislocalized to the cytoplasm. Knockdown of Smad6 in Pin1(-/-) fibroblasts rescues TGF-β-induced Smad3 activation and target gene expression.\",\n      \"method\": \"Genetic knockout (Pin1-/- mice and fibroblasts), siRNA knockdown, subcellular fractionation, reporter assays, in vivo bleomycin fibrosis model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cellular and in vivo phenotype, epistasis rescue (Smad6 KD in Pin1-/- restores signaling), and multiple functional readouts\",\n      \"pmids\": [\"22613712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HIPK2 autophosphorylates at Thr880/Ser882 upon DNA damage, creating a binding signal for Pin1. Pin1 binding links HIPK2 activation to its stabilization by inhibiting HIPK2 polyubiquitination and modulating Siah-1-HIPK2 interaction. Pin1 is required for DNA damage-induced HIPK2 stabilization, p53 Ser46 phosphorylation, and apoptosis in cells and in zebrafish.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis of HIPK2 autophosphorylation sites, in vivo zebrafish DNA damage model, Pin1 KO\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, ubiquitination assay, phosphosite mutagenesis, and in vivo zebrafish validation across multiple methods\",\n      \"pmids\": [\"24145406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PIN1 directly binds phosphorylated Thr204 of BRD4 (as confirmed by peptide binding and crystallographic studies) and enhances BRD4 stability by inhibiting its ubiquitination. PIN1 catalyzes isomerization of Pro205 of BRD4, inducing a conformational change that promotes BRD4 interaction with CDK9 and increases BRD4 transcriptional activity. BRD4-T204A mutant (PIN1-binding-defective) reduces BRD4 stability and suppresses gastric cancer cell proliferation, migration, and tumor formation.\",\n      \"method\": \"Peptide binding assay, X-ray crystallography, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (T204A), tumor formation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of PIN1-BRD4 complex, peptide binding, ubiquitination assay, and mutagenesis with functional rescue experiments in one study\",\n      \"pmids\": [\"28481868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KPT-6566, a covalent PIN1 inhibitor, binds to the catalytic site of PIN1 (active site covalent modification) and results in release of a quinone-mimicking drug that generates reactive oxygen species and DNA damage, inducing cell death specifically in cancer cells.\",\n      \"method\": \"Mechanism-based covalent inhibitor screening, mass spectrometry confirmation of active-site binding, ROS assays, DNA damage assays, in vivo lung metastasis model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — covalent active-site binding confirmed by mass spectrometry and cellular assays, but full mechanistic details are partially inferred from the abstract\",\n      \"pmids\": [\"28598431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sulfopin covalently targets Pin1's active-site Cys113 (validated by two independent chemoproteomics methods), phenocopies Pin1 genetic knockout, and inhibits c-Myc target genes, reducing tumor progression in murine/zebrafish neuroblastoma and pancreatic cancer models.\",\n      \"method\": \"Covalent fragment screening, chemoproteomics (two independent methods), genetic knockout comparison, in vivo tumor models\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site Cys113 covalent modification confirmed by two orthogonal chemoproteomics methods, phenocopies genetic KO, validated in vivo\",\n      \"pmids\": [\"33972797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rationally designed peptide inhibitors covalently target Cys113 in the Pin1 active site. Pin1 cooperates with mutant KRAS to promote transformation in PDAC, and Pin1 inhibition impairs cell viability over time in PDAC cell lines.\",\n      \"method\": \"Structure-guided inhibitor design, covalent active-site targeting of Cys113, genetic/chemical-genetic strategies in PDAC cell lines\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — active-site covalent modification confirmed by structure-guided design and genetic validation in PDAC; single study\",\n      \"pmids\": [\"32483379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Pin1 deficiency causes endothelial dysfunction and hypertension. Pin1 binds eNOS (confirmed by co-immunoprecipitation) and enables dephosphorylation of eNOS Ser116, which increases NO production and endothelium-dependent dilation. Pin1 knockdown or inhibition increases eNOS Ser116 phosphorylation and prevents VEGF-induced dephosphorylation of Ser116.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, Pin1 inhibitor (juglone), Pin1 knockout mice, NO production assay, vascular relaxation assay, blood pressure measurement\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP of Pin1-eNOS, phosphorylation-specific readout, and in vivo KO mouse validation with defined vascular and blood pressure phenotypes\",\n      \"pmids\": [\"21810655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Pin1 increases MEK1/2 interaction and phosphorylation, and promotes E2F-4- and Egr-1-driven LC-3 expression in tamoxifen-resistant breast cancer cells. Pin1(-/-) MEFs show lower TPA-induced MEK1/2 phosphorylation than Pin1(+/+) MEFs.\",\n      \"method\": \"Pin1 knockout MEFs, siRNA knockdown, co-immunoprecipitation (Pin1-MEK1/2), promoter activity assays, Western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO comparison, co-IP, and promoter activity assays; mechanistic link between Pin1-MEK interaction and LC-3 expression; single lab\",\n      \"pmids\": [\"20479004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pin1 directly and selectively enhances ERα DNA binding activity in a manner requiring isomerase activity. Pin1 isomerizes the phosphorylated Ser118-Pro119 bond in the ERα AF1 domain. This is a direct effect confirmed with purified components in solution-based DNA binding assays, with Pin1 selectively enhancing ERα binding to consensus DNA elements.\",\n      \"method\": \"In vitro DNA binding assay with purified components, DNA binding microarray (thousands of permutations), stable Pin1 overexpression, isomerase-dead Pin1 mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro with purified components plus catalytic mutant validation; direct demonstration of isomerization-dependent DNA binding enhancement\",\n      \"pmids\": [\"25866209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pin1 catalyzes isomerization of phosphorylated Ser/Thr-Pro motifs of PIN1 (auxin transporter in plants). Note: this is the plant parvulin Pin1At acting on plant PIN1 protein—this is a symbol collision and should be excluded.\",\n      \"method\": \"N/A\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Excluded — symbol collision (plant Pin1At/PIN1)\",\n      \"pmids\": [\"26791759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NMR, ITC, and SAXS analysis reveals that phosphorylated Ser235-Pro (but not pThr231-Pro) of tau is exclusively catalyzed by full-length Pin1 and the isolated PPIase domain. The WW domain is dispensable for catalysis at pSer235. Multiple phospho-sites on CDK2/CycA-phosphorylated full-length tau are simultaneously catalyzed by Pin1 with different efficiencies. Pin1 does not increase dephosphorylation rates of tau by PP2A, refuting a previously published model.\",\n      \"method\": \"NMR (site-specific measurements), isothermal calorimetry (ITC), small angle X-ray scattering (SAXS), isolated domain analysis, CDK2/CycA-phosphorylated full-length tau\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biophysical methods (NMR, ITC, SAXS) on full-length and domain-truncated Pin1 with physiologically phosphorylated tau; refutes prior model with rigorous evidence\",\n      \"pmids\": [\"26996941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pin1 does not promote phosphorylated tau-induced microtubule formation in vitro, directly refuting the model that Pin1 binding/catalysis at the AT180 epitope (pThr231/pSer235) restores phospho-tau's function in tubulin assembly. Novel GTP-tubulin ring-shaped species were found in the earliest stage of tau-induced polymerization.\",\n      \"method\": \"Turbidity assays, time-resolved SAXS, time-resolved negative-stain electron microscopy, NMR, in vitro reconstitution with phosphorylated tau\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biophysical reconstitution methods with rigorous controls; explicitly negative result replicated across methods\",\n      \"pmids\": [\"26996940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Pin1 interacts with and is dephosphorylated by calcineurin in dendritic spines. Calcineurin-mediated dephosphorylation of Pin1 suppresses its isomerase activity. Knockout of Pin1 or exposure to Aβ42 induces loss of mature dendritic spines; exogenous Pin1 prevents this. FK506 (calcineurin inhibitor) blocks Aβ42-induced spine loss in wild-type but not Pin1-null neurons.\",\n      \"method\": \"Co-immunoprecipitation (Pin1-calcineurin), Pin1 knockout neurons, exogenous Pin1 rescue, FK506 treatment, dendritic spine imaging\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, genetic KO rescue with exogenous Pin1, pharmacological epistasis (FK506), and defined spine morphology phenotype in multiple conditions\",\n      \"pmids\": [\"29559586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Androgen receptor Ser81 mediates interaction with Pin1, and this interaction is important for AR transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (AR-Ser81), transcriptional activity assays\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and phosphosite mutagenesis with transcriptional readout, but single lab with limited methodological breadth in abstract\",\n      \"pmids\": [\"22894932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Pin1 is deubiquitinated and stabilized by USP34, which is facilitated by Plk1-mediated phosphorylation of Pin1. Stabilized Pin1 promotes isomerization of the SUMO E2 enzyme Ubc9, requiring CDK1-mediated phosphorylation of Ubc9, leading to increased Ubc9 thioester formation with SUMO1 and hypersumoylation to support glioma stem cell maintenance.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Phos-tag gel electrophoresis, GST pull-down, genetic KO/KD, pharmacological inhibition, orthotopic tumor model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, ubiquitination assay, direct biochemical demonstration of Ubc9 thioester formation, in vivo orthotopic model, multiple orthogonal methods in one study\",\n      \"pmids\": [\"38167292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation, thereby stabilizing PIN1 and promoting ICC cell proliferation.\",\n      \"method\": \"Loss-of-function and gain-of-function studies in vitro and in vivo, kinase assay (JNK-PIN1), ubiquitination assays, site-specific mutagenesis, xenograft model, ATRA pharmacological inhibition\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct kinase-substrate assay and ubiquitination assay with site-directed mutagenesis in one study; single lab\",\n      \"pmids\": [\"34048060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Pin1 interacts with METTL3 and prevents its ubiquitin-dependent proteasomal and lysosomal degradation, stabilizing METTL3 and increasing m6A modification of TAZ and EGFR mRNA, resulting in enhanced translation of these oncoproteins.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, polysome profiling, Pin1 KO, METTL3 KO, in vivo orthotopic tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, polysome profiling, and in vivo model; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36755057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Pin1 directly interacts with adipose triglyceride lipase (ATGL) and enhances its degradation through the ubiquitin-proteasome system. Pin1 overexpression decreases ATGL protein levels without altering mRNA, and Pin1 KO increases lipolysis and ATGL protein expression in adipose tissue.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, Pin1 overexpression, adipocyte-specific Pin1 KO mice, ubiquitin-proteasome assay, lipolysis assay\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitin-proteasome assay, tissue-specific KO with functional lipolysis readout; single lab\",\n      \"pmids\": [\"33279499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDK1 directly phosphorylates pVHL at Ser80, priming recognition of pVHL by PIN1. PIN1 then binds phosphorylated pVHL and facilitates recruitment of the E3 ligase WSB1, targeting pVHL for ubiquitination and degradation. This CDK1/PIN1 axis promotes tumor growth and chemoresistance in a pVHL-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay (CDK1 phosphorylation of pVHL), ubiquitination assay, site-directed mutagenesis (Ser80), genetic ablation and pharmacological inhibition, tumor xenograft models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay defining the phospho-priming step, co-IP, ubiquitination assay with mutagenesis, and in vivo models in one study\",\n      \"pmids\": [\"36813923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Pin1 promotes β-cell proliferation and activates insulin secretion by enhancing SIK2 kinase activity. Pin1 binds SIK2 (identified as a Pin1-binding protein) and enhances SIK2 kinase activity, resulting in decreased p35 protein (a negative regulator of Ca2+ influx). β-cell-specific Pin1 KO mice show reduced β-cell mass, impaired Ca2+ influx, and reduced insulin secretion.\",\n      \"method\": \"β-cell-specific Pin1 KO mice, co-immunoprecipitation (Pin1-SIK2), kinase activity assay, intracellular Ca2+ measurement, glucose tolerance test\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with functional metabolic phenotype, co-IP, kinase activity assay; single lab\",\n      \"pmids\": [\"28566287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Pin1 binds and stabilizes hepatitis B virus core protein (HBc) in a phosphorylation-dependent manner at Thr160-Pro and Ser162-Pro motifs. Chemical or genetic inhibition of Pin1 accelerates HBc degradation via a lysosome-dependent pathway. PDP2 phosphatase dephosphorylates HBc at Pin1-binding sites, suppressing Pin1-mediated HBc stabilization.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, Phos-tag gel electrophoresis, site-directed mutagenesis, Pin1 inhibition (chemical and genetic), lysosome inhibitor assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pulldown, co-IP, phosphosite mutagenesis, degradation pathway assays; single lab\",\n      \"pmids\": [\"32083080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PIN1 interacts with STK3 (MST2 kinase, upstream Hippo kinase) and induces ubiquitination-dependent proteasomal degradation of STK3, leading to reduced LATS1/2 activity, nuclear translocation of TAZ, and formation of TAZ/TEAD complex increasing CTGF expression in melanoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, subcellular fractionation, siRNA/shRNA knockdown, tumor formation assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, and functional pathway readout (TAZ nuclear translocation, CTGF expression); single lab\",\n      \"pmids\": [\"33253791\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PIN1 is a phosphorylation-dependent peptidyl-prolyl cis/trans isomerase that specifically recognizes pSer/Thr-Pro motifs via its WW domain and catalyzes isomerization at its PPIase active site (with catalytic Cys113 as a key residue), thereby inducing conformational changes in substrate proteins that alter their stability (typically by blocking ubiquitin-mediated degradation), activity, protein-protein interactions, and subcellular localization; its substrates include the RNAP II CTD (regulating transcription initiation), topoisomerase IIα (regulating chromosome condensation), pRb (promoting hyperphosphorylation), tau (with complex mutation-dependent effects on stability), BRD4, METTL3, NICD1, Smad3, ATGL, pVHL (targeted for degradation via WSB1 after CDK1-mediated Ser80 phosphorylation), eNOS (enabling Ser116 dephosphorylation to stimulate NO production), and the SUMO E2 enzyme Ubc9; PIN1 itself is regulated post-translationally by phosphorylation (inhibitory at Ser16 by PKMζ/Aurora A, stabilizing at Ser115 by JNK), SUMOylation at Lys6/Lys63 (inhibitory, reversed by SENP1), and deubiquitination by USP34.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIN1 is a phosphorylation-dependent peptidyl-prolyl cis/trans isomerase that recognizes phosphorylated Ser/Thr-Pro motifs and catalyzes isomerization through a catalytic active site whose key residue is Cys113, acting as a master post-phosphorylation switch that reshapes substrate conformation, stability, activity, and localization across cell-cycle, transcriptional, and signaling programs [#17, #21, #23]. NMR studies of the catalytic domain show an active site pre-organized for catalysis that undergoes microsecond conformational exchange during turnover [#4], and biophysical work on tau established that PIN1 catalyzes specific phospho-Ser/Thr-Pro bonds (e.g., pSer235-Pro) with the PPIase domain sufficient for catalysis while the WW domain mediates phospho-dependent substrate engagement [#23]. A recurrent mechanistic theme is control of substrate turnover: PIN1 binding to a phosphorylated motif blocks E3-ligase-mediated ubiquitination to stabilize substrates such as BRD4 (isomerizing Pro205 to favor CDK9 interaction) [#15], NICD1 (antagonizing FBW7) [#11], HIPK2 (modulating Siah-1) [#14], TAp63\\u03b1/\\u0394Np63\\u03b1 (antagonizing WWP1) [#10], TR3 [#12], and METTL3 [#29]; conversely it can promote degradation of substrates including pVHL (recruiting WSB1 after CDK1-mediated Ser80 priming) [#31], ATGL [#30], and the Hippo kinase STK3 [#34]. PIN1 also directly tunes enzyme and transcription-factor activity, inhibiting the RNAP II CTD phosphatase FCP1 and stimulating CTD phosphorylation to govern transcription initiation [#0, #1], promoting topoisomerase II\\u03b1-dependent mitotic chromosome condensation [#2], driving pRb hyperphosphorylation [#6], enhancing ER\\u03b1 DNA binding via isomerization of pSer118-Pro119 [#21], and enabling eNOS Ser116 dephosphorylation to stimulate NO production [#19]. Through these activities PIN1 supports oncogenic programs cooperating with mutant KRAS and c-Myc target gene expression [#17, #18], and is itself regulated post-translationally\\u2014inhibitory phosphorylation at Ser16 by PKM\\u03b6 [#8] and dephosphorylation by calcineurin [#25], stabilizing phosphorylation at Ser115 by JNK [#28], inhibitory SUMOylation reversed by SENP1 [#5], and deubiquitination by USP34 [#27]\\u2014placing it under tight upstream control in proliferative, neuronal, and metabolic contexts. Covalent active-site inhibitors targeting Cys113 (Sulfopin, KPT-6566, designed peptides) phenocopy PIN1 loss and validate it as a tractable anticancer target [#16, #17, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that PIN1 engages substrates in a strictly phosphorylation- and WW-domain-dependent manner using mitotic CK2/topoisomerase II\\u03b1 as a model, defining the recognition logic of the enzyme.\",\n      \"evidence\": \"Co-IP, in vitro phosphorylation assays, and Pin1 domain/point mutants with chimeric CK2 constructs\",\n      \"pmids\": [\"11940573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve isomerization kinetics at the CK2/TopoII\\u03b1 motif\", \"Physiological consequence for chromosome dynamics not addressed here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined a transcriptional role by showing PIN1 controls RNAP II CTD phosphorylation status, linking proline isomerase activity to the transcription cycle.\",\n      \"evidence\": \"In vitro phosphatase/kinase assays (FCP1 inhibition, cdc2/cyclin B stimulation), pin1-/- cells, transcription/splicing extract assays, co-IP\",\n      \"pmids\": [\"14600023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct isomerization of CTD prolines not structurally resolved\", \"Genome-wide scope of CTD regulation not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved the stage of transcription PIN1 acts on and demonstrated direct mitotic functions, showing it inhibits initiation and is required for chromosome condensation.\",\n      \"evidence\": \"ChIP with phospho-CTD antibodies, inducible overexpression and active-site mutants; immunodepletion/reconstitution of mitotic extracts with purified Pin1 and cdc2/cyclin B; NMR relaxation dispersion of the catalytic domain\",\n      \"pmids\": [\"18006688\", \"17466629\", \"17316687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo condensation defect not assessed in intact cells across cell types\", \"Catalytic conformational exchange not linked to a specific substrate motif\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Generalized the stability-control paradigm by showing PIN1 destabilizes the SMRT corepressor downstream of Cdk2/Her2 signaling, connecting the isomerase to nuclear-receptor transcriptional output.\",\n      \"evidence\": \"Reciprocal co-IP in vitro and in cells, WW-domain and SMRT phosphosite mutagenesis, transcriptional reporter assays\",\n      \"pmids\": [\"18838553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating SMRT turnover not identified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed mutation-dependent, opposite effects of PIN1 on tau stability in vivo, establishing context-dependent substrate outcomes relevant to tauopathy.\",\n      \"evidence\": \"Pin1 KO, knockdown, and overexpression across WT and P301L tau transgenic mouse lines with stability and phenotype readouts\",\n      \"pmids\": [\"18431510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the WT-versus-mutant divergence not defined\", \"Specific tau phospho-motifs catalyzed not pinned down here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended PIN1 to neuronal and signaling contexts, defining a PKM\\u03b6\\u2192Ser16 inhibitory phospho-switch and a role in dendritic translation, plus MEK1/2 modulation.\",\n      \"evidence\": \"Pin1-/- mice and LTP electrophysiology, immunofluorescence localization, co-IP, Ser16 mutagenesis; Pin1-/- MEFs, co-IP and promoter assays for MEK1/2\",\n      \"pmids\": [\"20215645\", \"20479004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PIN1 substrate in the translation machinery not defined\", \"MEK1/2 phospho-motif engaged by PIN1 not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated direct enzyme/receptor activity tuning by showing PIN1 enables eNOS Ser116 dephosphorylation to drive NO production and isomerizes TR3 to control its stability and transactivation.\",\n      \"evidence\": \"Co-IP, Pin1 KO mice, siRNA, inhibitor and phospho-specific readouts for eNOS; co-IP, phosphosite mutagenesis, ChIP and reporter assays for TR3\",\n      \"pmids\": [\"21810655\", \"22002310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase acting on eNOS Ser116 downstream of PIN1 not identified\", \"TR3 isomerization not directly observed structurally\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Broadened substrate repertoire to cell-cycle and signaling effectors\\u2014pRb hyperphosphorylation, TGF-\\u03b2/Smad3 activation via Smad6 localization, and androgen receptor activity.\",\n      \"evidence\": \"Co-IP, direct binding and phosphosite mutagenesis for pRb; Pin1-/- fibroblasts with Smad6-knockdown epistasis rescue and bleomycin fibrosis model; co-IP and AR-Ser81 mutagenesis with transcription assays\",\n      \"pmids\": [\"22322860\", \"22613712\", \"22894932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PIN1 controls Smad6 localization unresolved\", \"AR study limited methodologically (single lab)\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined regulation of PIN1 itself by SUMOylation (Lys6/Lys63, reversed by SENP1) and extended the anti-degradation paradigm to HIPK2 and p63 isoforms in DNA-damage and apoptosis pathways.\",\n      \"evidence\": \"Co-IP, K6R/K63R mutagenesis, transformation and centrosome assays for SUMO; co-IP, ubiquitination and HIPK2 autophosphosite mutagenesis with zebrafish DNA-damage model; co-IP, T538A mutagenesis and xenograft for p63\",\n      \"pmids\": [\"23633483\", \"24145406\", \"24309930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 ligase for PIN1 not identified\", \"p63 finding single-lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided direct biochemical proof of isomerization-driven function by reconstituting PIN1-enhanced ER\\u03b1 DNA binding with purified components, and extended substrate stabilization to NICD1 in stroke.\",\n      \"evidence\": \"In vitro DNA binding assays with purified components and isomerase-dead mutant, DNA-binding microarray; co-IP, ubiquitination assay, Pin1 KO/KD and mouse stroke model for NICD1\",\n      \"pmids\": [\"25866209\", \"25558977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural snapshot of the ER\\u03b1 pSer118-Pro119 isomer not obtained\", \"NICD1 study single-lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Delivered rigorous biophysical dissection of PIN1 catalysis on tau, defining site-specific catalysis and refuting prior models of PP2A-coupled dephosphorylation and microtubule-assembly restoration.\",\n      \"evidence\": \"NMR, ITC, SAXS on full-length and isolated PPIase domain with CDK2/CycA-phosphorylated tau; turbidity, time-resolved SAXS/EM reconstitution of tau-induced tubulin polymerization\",\n      \"pmids\": [\"26996941\", \"26996940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequence of site-specific tau isomerization not established\", \"Functional output of refuted models replaced only partially\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Captured a substrate complex structurally and validated active-site covalent targeting, cementing the isomerization-then-stabilization mechanism for BRD4 and the druggability of Cys113.\",\n      \"evidence\": \"Peptide binding, X-ray crystallography of PIN1-BRD4, co-IP, ubiquitination assay, T204A mutagenesis and tumor assays; covalent inhibitor KPT-6566 with mass spectrometry, ROS/DNA-damage and metastasis models; SIK2-dependent \\u03b2-cell function via tissue-specific KO\",\n      \"pmids\": [\"28481868\", \"28598431\", \"28566287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"BRD4 isomerization shown for one site; broader BRD4 conformational map not built\", \"KPT-6566 mechanistic details partly inferred\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded the degradation-and-stabilization network to metabolic, viral, Hippo, and m6A pathways and refined structure-guided covalent Cys113 inhibitors in KRAS-driven cancer.\",\n      \"evidence\": \"Co-IP, ubiquitin-proteasome and tissue-specific KO assays for ATGL; GST pulldown and lysosome assays for HBV core; co-IP/ubiquitination for STK3; co-IP, ubiquitination and polysome profiling for METTL3; structure-guided peptide inhibitors in PDAC\",\n      \"pmids\": [\"33279499\", \"32083080\", \"33253791\", \"36755057\", \"32483379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most substrate studies are single-lab\", \"Direct isomerization at each substrate motif not biophysically confirmed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Validated PIN1 as a phenocopyable, in-vivo tractable target via Cys113-directed covalent probes and defined a JNK-Ser115 stabilizing phospho-switch governing PIN1 turnover.\",\n      \"evidence\": \"Covalent fragment screening and two-method chemoproteomics with genetic-KO comparison and tumor models (Sulfopin); JNK kinase assay, Lys117 ubiquitination and Ser115 mutagenesis with xenograft (ICC)\",\n      \"pmids\": [\"33972797\", \"34048060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of in-vivo PIN1 substrates underlying Sulfopin effects not enumerated\", \"JNK-PIN1 axis single-lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a phospho-priming module in which CDK1 phosphorylates pVHL Ser80 to license PIN1 binding and WSB1-mediated pVHL degradation, illustrating PIN1-directed positive regulation of substrate turnover.\",\n      \"evidence\": \"In vitro CDK1 kinase assay, co-IP, ubiquitination assay, Ser80 mutagenesis, genetic/pharmacological ablation and xenografts\",\n      \"pmids\": [\"36813923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational change in pVHL driving WSB1 recruitment not structurally resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Integrated upstream regulation and downstream catalysis by showing USP34/Plk1 stabilize PIN1, which then isomerizes the SUMO E2 Ubc9 to amplify SUMOylation in glioma stem cells.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, Phos-tag electrophoresis, GST pulldown, Ubc9 thioester assay, genetic KO/KD and orthotopic tumor model\",\n      \"pmids\": [\"38167292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Ubc9 isomerization not resolved\", \"Generality beyond glioma stem cells untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PIN1 selects among its many phospho-Ser/Thr-Pro substrates in a given cellular context\\u2014and how a single isomerization event is decoded into either stabilization or degradation at the same motif\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying rule for stabilization-versus-degradation outcomes\", \"Limited high-resolution structures of PIN1-substrate isomerization states\", \"Context-specific substrate prioritization not mapped systematically\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [4, 21, 23, 27]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 15, 31]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 19, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 21]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 21]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 11, 14, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 19, 34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 17, 18, 29]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BRD4\", \"METTL3\", \"NICD1\", \"HIPK2\", \"eNOS\", \"pVHL\", \"Smad3\", \"STK3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}