{"gene":"PIN1","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2000,"finding":"Pin1 catalyzes prolyl isomerization of specific pSer/Thr-Pro motifs in Cdc25C and tau, facilitating their dephosphorylation by PP2A. PP2A is conformation-specific, effectively dephosphorylating only the trans pSer/Thr-Pro isomer, and Pin1 prolyl isomerase activity is essential for cell division in vivo.","method":"In vitro prolyl isomerization assay, PP2A dephosphorylation assay with cis/trans-specific substrates, genetic epistasis (Pin1/PP2A reciprocal genetic interactions in yeast), active-site mutagenesis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with native substrates, active-site mutagenesis, genetic epistasis, highly cited foundational paper","pmids":["11090625"],"is_preprint":false},{"year":2003,"finding":"Pin1 influences the phosphorylation status of the RNA polymerase II CTD by inhibiting the CTD phosphatase FCP1 and stimulating CTD phosphorylation by cdc2/cyclin B. Pin1 overexpression inhibits ongoing transcription and RNAP II-stimulated pre-mRNA splicing; Pin1 directly associates with a hyper-hyperphosphorylated form of RNAP II in M-phase.","method":"In vitro phosphatase inhibition assay, in vitro kinase assay (cdc2/cyclin B), Co-IP of Pin1 with RNAP II, in vivo transcription assay, pin1-/- cell analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including in vitro assays, Co-IP, and KO cells","pmids":["14600023"],"is_preprint":false},{"year":2007,"finding":"Pin1 has an important function in chromosome condensation during mitosis; its interaction with chromatin is elevated in G2/M phase correlating with presence of mitotic phosphoproteins, especially topoisomerase IIα. Purified Pin1 together with cdc2/cyclin B is sufficient to induce chromosome condensation in vitro, and Pin1 increases TopoIIα phosphorylation by cdc2/cyclin B, promoting formation of a TopoIIα/Pin1/DNA complex.","method":"Pin1 siRNA knockdown, immunodepletion from mitotic extracts, in vitro reconstitution with purified Pin1 and cdc2/cyclin B, in vitro kinase assay, Co-IP","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution with purified components, immunodepletion, siRNA KD, multiple orthogonal methods","pmids":["17466629"],"is_preprint":false},{"year":2007,"finding":"NMR analysis of Pin1 catalytic domain dynamics during catalysis reveals conformational exchange processes in the microsecond timescale at active site residues even in absence of substrate, suggesting the active site is pre-organized ('primed') for catalysis. Substrate binding versus substrate isomerization affect distinct regions of the active site.","method":"15N NMR relaxation dispersion, NOE measurements, substrate concentration-dependent conformational exchange analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — NMR structure/dynamics study with functional validation, rigorous mechanistic dissection","pmids":["17316687"],"is_preprint":false},{"year":2008,"finding":"Pin1 interacts with SMRT corepressor in a WW domain-dependent, phosphorylation-dependent manner and regulates SMRT protein stability. Cdk2-mediated phosphorylation of SMRT is required for Pin1 binding and decreases SMRT stability; mutation of phosphorylation sites abrogates Pin1 binding and stabilizes SMRT. Her2/Neu/ErbB2 functions upstream of both Pin1 and Cdk2 in this cascade.","method":"Co-IP in mammalian cells, in vitro pulldown, site-directed mutagenesis of phosphorylation sites, Cdk2 kinase assay, protein stability assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP, in vitro pulldown, mutagenesis, epistasis, multiple orthogonal methods","pmids":["18838553"],"is_preprint":false},{"year":2008,"finding":"Pin1 has opposite effects on wild-type versus P301L mutant tau stability: Pin1 KO or knockdown increases WT tau protein stability, while Pin1 overexpression suppresses tauopathy in WT tau transgenic mice. Conversely, Pin1 KO decreases P301L tau stability and abolishes its tauopathy phenotype in mice; Pin1 overexpression exacerbates P301L tauopathy.","method":"Pin1 KO mice, Pin1 knockdown (siRNA/shRNA), tau transgenic mouse models (WT and P301L), in vitro stability assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — clean KO and KD with defined phenotype, multiple in vivo and in vitro models, replicated across conditions","pmids":["18431510"],"is_preprint":false},{"year":2010,"finding":"Pin1 is present in dendritic spines and shafts and inhibits glutamatergic signaling-induced protein synthesis, possibly through eIF4E and 4E-BP1/2. Pin1-/- mice show enhanced late LTP (L-LTP). PKMzeta phosphorylates Pin1 at Ser16, inhibiting Pin1 and thereby maintaining dendritic translation.","method":"Live imaging (Pin1 localization in dendrites), Pin1-/- mouse LTP recordings, dendritic translation assay, PKMzeta kinase assay on Pin1 Ser16, Co-IP of PKMzeta with Pin1","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 — direct localization with functional consequence, KO phenotype, kinase assay identifying specific modification site","pmids":["20215645"],"is_preprint":false},{"year":2011,"finding":"Pin1 deficiency causes endothelial dysfunction and hypertension by failing to isomerize phospho-eNOS Ser116-Pro117, preventing dephosphorylation of eNOS Ser116. Pin1 binds eNOS (confirmed by Co-IP), and Pin1 knockdown or inhibition increases eNOS Ser116 phosphorylation, reducing NO production and endothelium-dependent dilation.","method":"Co-IP of Pin1 with eNOS, siRNA knockdown, pharmacological inhibition (juglone), Pin1 KO mice, eNOS phosphorylation measurement, NO production assay, vascular relaxation assay","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, KO mice, KD, multiple orthogonal methods with specific phenotypic readout","pmids":["21810655"],"is_preprint":false},{"year":2012,"finding":"Pin1 directly interacts with the spacer domain of pRb protein at phospho-Ser608/612, promotes hyperphosphorylation of pRb without affecting CDK or PP1/PP2 activity, and mediates interaction between CDK/cyclin complexes and pRb in mid/late G1 to drive cell cycle progression.","method":"Co-IP, GST pulldown, site-directed mutagenesis (pRb Ser608/612), cell cycle analysis, Pin1 overexpression/KD","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, pulldown, mutagenesis of specific binding motif, functional cell cycle readout","pmids":["22322860"],"is_preprint":false},{"year":2013,"finding":"Pin1 interacts with phosphorylated histone H1, promotes its dephosphorylation (sub-stoichiometric Pin1 stimulates H1 dephosphorylation in vitro), modulates C-terminal domain structure of H1, and stabilizes H1 binding to chromatin when Pin1 binding sites on H1 are present. Pin1 depletion destabilizes H1-chromatin binding.","method":"In vitro dephosphorylation assay, Pin1 depletion (siRNA), FRAP (H1 chromatin binding stability), structural analysis of H1 CTD, Co-IP","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution, FRAP with functional consequence, depletion experiments, multiple methods","pmids":["24100296"],"is_preprint":false},{"year":2015,"finding":"Pin1 directly binds phosphorylated ERα Ser118-Pro119 via its isomerase activity and enhances ERα DNA binding affinity in a reconstituted in vitro system with purified components. Pin1 selectively enhances ERα binding to consensus DNA elements, and isomerization is required for this effect.","method":"In vitro DNA binding assay with purified Pin1 and ERα, DNA binding microarray, stable Pin1 overexpression, isomerase-dead mutant controls","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with purified components, mutagenesis (isomerase activity required), unbiased DNA microarray validation","pmids":["25866209"],"is_preprint":false},{"year":2015,"finding":"Aurora A phosphorylates Pin1 at Ser16, suppressing Pin1 enzymatic activity, and cooperates with hBora to modulate G2/M transition.","method":"Kinase assay (Aurora A on Pin1 Ser16), site-directed mutagenesis, cell cycle analysis","journal":"Experimental biology and medicine","confidence":"Medium","confidence_rationale":"Tier 2 — kinase assay with mutant validation, but described in a review context citing original data from this lab","pmids":["25662955"],"is_preprint":false},{"year":2016,"finding":"Pin1 directly binds phosphorylated Thr204 of BRD4 (confirmed by peptide binding and crystallographic studies), catalyzes isomerization of Pro205, induces conformational changes that promote BRD4 interaction with CDK9, increases BRD4 transcriptional activity, and inhibits BRD4 ubiquitination to enhance its stability. BRD4-T204A mutant abolishes Pin1 binding and reduces BRD4 stability and activity.","method":"Peptide binding assay, X-ray crystallography (co-crystal structure), Co-IP, ubiquitination assay, site-directed mutagenesis (T204A), gene expression analysis, tumor formation assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 — crystal structure, mutagenesis, reconstituted biochemistry, multiple orthogonal methods in one study","pmids":["28481868"],"is_preprint":false},{"year":2016,"finding":"NMR and structural studies show that pSer235-Pro (but not pThr231-Pro) of tau is exclusively catalyzed by full-length Pin1 and isolated PPIase domain. The WW domain is not required for turnover at pSer235, and Pin1 catalysis of CDK2/CycA-phosphorylated full-length tau occurs at multiple sites simultaneously with different efficiencies. Pin1 does not increase dephosphorylation rates by PP2A of these tau sites, refuting prior models.","method":"NMR (site-specific catalysis measurements), isothermal calorimetry (ITC), SAXS, CDK2/CycA phosphorylation of full-length tau, domain-deletion mutants of Pin1","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — NMR with site-specific resolution, ITC, SAXS, domain mutagenesis, rigorous mechanistic dissection","pmids":["26996941"],"is_preprint":false},{"year":2016,"finding":"Pin1 does not promote phosphorylated tau-induced microtubule formation in vitro, refuting the previously accepted model that Pin1 binding/catalysis at the AT180 epitope restores phosphorylated tau's ability to promote microtubule polymerization.","method":"Turbidity assay (MT polymerization), time-resolved SAXS, time-resolved negative stain EM, NMR","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal in vitro assays directly testing the mechanistic model","pmids":["26996940"],"is_preprint":false},{"year":2017,"finding":"KPT-6566, a covalent inhibitor, selectively binds to the catalytic site (Cys113) of PIN1 and targets PIN1 for degradation. This interaction releases a quinone-mimicking drug that generates ROS and DNA damage, inducing cell death specifically in cancer cells.","method":"Covalent binding assay (mechanism-based screening), Pin1 degradation assay, ROS measurement, DNA damage assay, in vitro and in vivo tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — mechanism-based inhibitor with defined covalent binding site (Cys113), validated by multiple cellular and in vivo assays","pmids":["28598431"],"is_preprint":false},{"year":2019,"finding":"IRAK1 inhibitors synergize with Pin1 inhibitors in suppressing radiation resistance, demonstrating that Pin1 is essential for IRAK1 activation in response to both pathogens and ionizing radiation. IRAK1 drives radioresistance through a pathway involving IRAK4 and TRAF6, and Pin1 is required for this IRAK1 activation.","method":"Compound screening in zebrafish, genetic epistasis (IRAK1 pathway), IRAK1 inhibitor/Pin1 inhibitor combination studies, tumor models","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — epistasis and pharmacological combination established the PIN1-IRAK1 axis, but mechanistic details are partially indirect","pmids":["30664786"],"is_preprint":false},{"year":2020,"finding":"Activity-induced Kv4.2 phosphorylation at pThr607-Pro triggers Pin1 binding and isomerization of Kv4.2, leading to dissociation of the Kv4.2-DPP6 complex, increased A-type K+ current, and reduced neuronal excitability. Kv4.2-T607A knock-in mice exhibit altered Kv4.2-DPP6 interaction, increased A-type K+ current, and improved reversal learning.","method":"Co-IP, knock-in mouse model (Kv4.2-T607A), electrophysiology, behavioral assays (Morris water maze, lever press)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — knock-in mouse with site-specific mutation abolishing Pin1 binding, Co-IP, electrophysiology, defined behavioral phenotype","pmids":["32218435"],"is_preprint":false},{"year":2021,"finding":"Sulfopin covalently targets Pin1's active site Cys113 with nanomolar potency; validated by two independent chemoproteomics methods, achieving potent cellular and in vivo target engagement. Pin1 inhibition downregulates c-Myc target genes and confers survival benefit in MYCN-driven neuroblastoma and pancreatic cancer models.","method":"Covalent fragment screening targeting Cys113, chemoproteomics (two independent methods), cellular target engagement assay, in vivo zebrafish and murine tumor models, genetic KO comparison","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1-2 — covalent active-site engagement validated by two chemoproteomics methods, phenocopies genetic KO, in vivo validation","pmids":["33972797"],"is_preprint":false},{"year":2021,"finding":"JNK kinases directly bind to and phosphorylate PIN1 at Ser115, which prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation, thereby stabilizing PIN1 and promoting ICC cell proliferation.","method":"In vitro kinase assay (JNK phosphorylating PIN1 Ser115), ubiquitination assay (Lys117 mono-ubiquitination), loss-of-function/gain-of-function studies in vitro and in vivo, Co-IP","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 1-2 — direct kinase assay identifying specific phosphorylation site, ubiquitination assay with specific lysine, in vivo validation","pmids":["34048060"],"is_preprint":false},{"year":2021,"finding":"Pin1 promotes NLRP3 inflammasome activation through the p38 MAPK pathway. Pin1 interacts with p-p38 MAPK (not directly but functionally), affects p38 MAPK phosphorylation, and Pin1 deficiency reduces NLRP3, ASC, Caspase1 expression, gasdermin D cleavage, and IL-1β/IL-18 secretion in macrophages during septic shock.","method":"Pin1-/- mice, Co-IP (Pin1 with p-p38 MAPK), LPS-induced macrophage model, inflammasome component analysis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 — KO mice with defined phenotype, Co-IP showing interaction, but Pin1-p38 interaction is indirect and mechanism not fully reconstituted","pmids":["33717117"],"is_preprint":false},{"year":2022,"finding":"Ligand-specific conformational changes drive interdomain allostery in Pin1: pCDC25c binding to the WW domain doubles the population of extended interdomain states and triggers conformational changes propagating to the catalytic site via the interdomain interface; FFpSPR binding to the PPIase displaces a helix leading to repositioning of the catalytic loop.","method":"NMR (MR-based protocol for intra/interdomain structural sampling), EPR (PELDOR), Pin1 domain dynamics in apo and ligand-bound states","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — NMR and EPR structural/dynamic analysis with multiple ligand states, mechanistically rigorous","pmids":["35927276"],"is_preprint":false},{"year":2023,"finding":"CDK1 directly phosphorylates pVHL at Ser80, which primes pVHL recognition by PIN1. PIN1 then binds phospho-pVHL and facilitates recruitment of E3 ligase WSB1, targeting pVHL for ubiquitination and proteasomal degradation, thereby promoting tumor growth.","method":"In vitro CDK1 kinase assay on pVHL Ser80, Co-IP (PIN1 with pVHL), ubiquitination assay, E3 ligase (WSB1) pulldown, site-directed mutagenesis, in vitro and in vivo tumor assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 — direct kinase assay, specific phosphorylation site identified, ubiquitination mechanism reconstituted, in vivo validation","pmids":["36813923"],"is_preprint":false},{"year":2024,"finding":"USP34 deubiquitinates and stabilizes Pin1 in glioma stem cells; this interaction is facilitated by Plk1-mediated phosphorylation of Pin1. Stabilized Pin1 isomerizes the SUMO E2 enzyme Ubc9 (requiring CDK1-mediated phosphorylation of Ubc9), upregulating Ubc9 thioester formation with SUMO1 and promoting hypersumoylation to support GSC maintenance.","method":"Co-IP (Pin1 with USP34, Pin1 with Ubc9), ubiquitination assay (USP34 deubiquitinating Pin1), Plk1 kinase assay (phosphorylating Pin1), CDK1 phosphorylation of Ubc9, SUMO1 thioester formation assay, shRNA KD, in vivo orthotopic tumor model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — multiple enzymatic assays identifying specific modification sites, Co-IP, reconstituted biochemistry, in vivo validation","pmids":["38167292"],"is_preprint":false},{"year":2012,"finding":"Androgen receptor (AR) Ser81 is involved in the interaction with Pin1, and this interaction is important for the transcriptional activity of AR. Pin1 binds phospho-Ser81 of AR to modulate AR function.","method":"Co-IP, site-directed mutagenesis (AR Ser81), transcriptional reporter assay","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with mutagenesis of binding site, single lab study","pmids":["22894932"],"is_preprint":false},{"year":2014,"finding":"Pin1 interacts with HIF-1α in a p42/p44 MAPK phosphorylation-dependent manner, catalyzes conformational change in HIF-1α (shown by proteolysis studies), and is required for gene-specific HIF-1 transcriptional activity.","method":"Co-IP, GST pulldown, proteolysis (limited proteolysis to detect conformational change), HIF-1 transcriptional reporter assay, Pin1 inhibition/knockdown","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP, proteolysis assay (conformational change), functional transcription assay, but single lab","pmids":["24726894"],"is_preprint":false},{"year":2020,"finding":"Pin1 interacts with METTL3, prevents its ubiquitin-dependent proteasomal and lysosomal degradation, thereby stabilizing METTL3 and increasing m6A modification of TAZ and EGFR mRNA, enhancing their translation. MEK1/2 kinases act upstream of this PIN1-METTL3 axis.","method":"Co-IP (PIN1 with METTL3), ubiquitination assay, polysome profiling (TAZ and EGFR mRNA distribution), METTL3 KO, PIN1 KO, in vivo orthotopic tumor model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, ubiquitination assay, polysome profiling, multiple KO models, in vivo validation","pmids":["36755057"],"is_preprint":false},{"year":2020,"finding":"BJP-06-005-3 covalently targets Cys113 in the Pin1 active site; Pin1 cooperates with mutant KRAS to promote transformation in PDAC, and Pin1 inhibition impairs PDAC cell viability over time.","method":"Rational peptide inhibitor design targeting Cys113, selectivity profiling, genetic KO and chemical-genetic strategies in PDAC cell lines","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1-2 — structure-guided design, covalent active-site targeting confirmed, chemical-genetic epistasis establishing cooperation with mutant KRAS","pmids":["32483379"],"is_preprint":false},{"year":2016,"finding":"Pin1 promotes sustained B cell proliferation upon oncogenic Myc activation through the ARF-p53 pathway, not through altering Ser62 phosphorylation or Myc transcription. Genetic ablation of Pin1 reduces lymphomagenesis in Eμ-myc transgenic mice.","method":"Pin1 genetic ablation, Eμ-myc transgenic mice, ARF-p53 pathway analysis, Myc phosphorylation analysis, B cell proliferation assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined pathway (ARF-p53) and in vivo tumor model, but mechanism of how Pin1 activates ARF-p53 is not fully resolved","pmids":["26943576"],"is_preprint":false},{"year":2011,"finding":"Pin1 isomerizes TR3 orphan nuclear receptor at phospho-Ser95-Pro and phospho-Ser431-Pro motifs; isomerization at Ser95-Pro retards TR3 degradation (enhancing stability), while isomerization at ERK2-phosphorylated Ser431-Pro enhances TR3 transactivation and promotes TR3 targeting to the cyclin D2 promoter and recruitment of p300.","method":"Co-IP, in vitro isomerization assay, site-directed mutagenesis, ERK2 kinase assay, luciferase reporter assay, ChIP, in vivo tumor assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — isomerization assay, kinase identification, mutagenesis of specific sites, ChIP, in vivo validation","pmids":["22002310"],"is_preprint":false},{"year":2020,"finding":"Pin1 binds and stabilizes hepatitis B virus core protein (HBc) at phospho-Thr160-Pro and phospho-Ser162-Pro motifs in a phosphorylation-dependent manner. Pin1 inhibition accelerates HBc degradation via a lysosome-dependent pathway. PDP2 phosphatase dephosphorylates HBc at these Pin1-binding sites, suppressing Pin1-mediated HBc stabilization.","method":"Phos-tag gel electrophoresis, site-directed mutagenesis of HBc phospho-sites, GST pulldown, Co-IP, Pin1 inhibitor/KO, lysosome inhibitor assay, PDP2 dephosphorylation assay","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 — site-specific phosphorylation mapping by Phos-tag, pulldown and Co-IP confirming interaction, enzyme assay identifying writer (CDK) and eraser (PDP2) of binding marks","pmids":["32083080"],"is_preprint":false},{"year":2021,"finding":"Pin1 facilitates ubiquitin-mediated proteasomal degradation of STK3 (MST2) in melanoma cells, leading to reduced LATS1/2 activity, nuclear translocation of TAZ, and increased CTGF expression through TAZ/TEAD complex formation.","method":"Co-IP (PIN1 with STK3), ubiquitination assay, shRNA KD, nuclear fractionation (TAZ localization), reporter assay (CTGF), in vivo melanoma model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP, ubiquitination assay, fractionation showing localization change, single lab study","pmids":["33253791"],"is_preprint":false}],"current_model":"PIN1 is a phosphorylation-dependent peptidyl-prolyl cis/trans isomerase that specifically binds pSer/Thr-Pro motifs (via its WW domain) and catalyzes cis-to-trans isomerization at its active site Cys113, inducing conformational changes in substrates such as Cdc25C, tau, RNAP II CTD, BRD4, pRb, eNOS, Kv4.2, HIF-1α, and many others; these conformational changes regulate substrate dephosphorylation (by enabling access of PP2A to the trans isomer), protein stability (by modulating ubiquitination), protein-protein interactions, enzymatic activity, transcriptional activity, and subcellular localization, with PIN1 itself being regulated by phosphorylation (e.g., Ser16 by PKMzeta/Aurora A, Ser115 by JNK) and deubiquitination (by USP34), collectively positioning PIN1 as a master post-phosphorylation conformational switch controlling cell cycle progression, neuronal function, and oncogenic signaling."},"narrative":{"teleology":[{"year":2000,"claim":"Establishing that PIN1 prolyl isomerase activity controls substrate dephosphorylation answered how phosphorylation-dependent signaling could be regulated at the conformational level — PP2A selectively dephosphorylates the trans pSer/Thr-Pro isomer, and PIN1 catalyzes the cis-to-trans conversion required for this step.","evidence":"In vitro isomerization and PP2A dephosphorylation assays with Cdc25C and tau peptides, active-site mutagenesis, yeast genetic epistasis","pmids":["11090625"],"confidence":"High","gaps":["Whether all PIN1 substrates require PP2A-mediated dephosphorylation or whether this is substrate-specific","Identity of the full substrate repertoire at this time was unknown"]},{"year":2003,"claim":"Demonstrating that PIN1 modulates RNAP II CTD phosphorylation and inhibits transcription and splicing extended PIN1 function beyond cell cycle phosphatases to transcriptional regulation, showing it could alter kinase/phosphatase balance on a major transcriptional machinery component.","evidence":"In vitro FCP1 phosphatase inhibition, cdc2/cyclin B kinase stimulation, Co-IP with hyperphosphorylated RNAP II, transcription/splicing assays in pin1−/− cells","pmids":["14600023"],"confidence":"High","gaps":["Whether PIN1 directly isomerizes CTD repeats or acts indirectly through accessory factors","Structural basis of PIN1–CTD interaction"]},{"year":2007,"claim":"Two concurrent advances resolved PIN1's mitotic chromatin role and its intrinsic catalytic dynamics: PIN1 with cdc2/cyclin B was sufficient to induce chromosome condensation via TopoIIα, while NMR revealed that the PIN1 active site undergoes pre-organized conformational exchange even without substrate, explaining its catalytic efficiency.","evidence":"In vitro chromosome condensation reconstitution with purified PIN1/cdc2/cyclin B; 15N NMR relaxation dispersion measuring microsecond dynamics at active-site residues","pmids":["17466629","17316687"],"confidence":"High","gaps":["How PIN1 coordinates condensin and TopoIIα activities during mitosis","Whether pre-organized active-site dynamics are altered by post-translational modifications of PIN1"]},{"year":2008,"claim":"Studies on SMRT and tau revealed PIN1 as a general regulator of protein stability through phosphorylation-dependent binding: PIN1 destabilizes SMRT downstream of Cdk2/Her2 signaling, and exerts opposite stability effects on wild-type versus P301L mutant tau in vivo, establishing that PIN1's effect on substrate turnover is context-dependent.","evidence":"Co-IP, Cdk2 kinase assay, mutagenesis of SMRT phospho-sites; Pin1 KO crossed with WT and P301L tau transgenic mice","pmids":["18838553","18431510"],"confidence":"High","gaps":["E3 ligase(s) mediating PIN1-dependent SMRT degradation not identified","Structural basis for opposite effects on WT vs. P301L tau stability"]},{"year":2010,"claim":"Identifying PKMζ-mediated Ser16 phosphorylation of PIN1 in dendrites, which inhibits PIN1 to sustain dendritic translation and late LTP, established PIN1 as a regulated signaling node in synaptic plasticity — not merely a constitutive isomerase.","evidence":"Pin1−/− mouse LTP recordings, dendritic translation assays, PKMζ kinase assay on Ser16, live imaging of PIN1 in dendrites","pmids":["20215645"],"confidence":"High","gaps":["Direct substrates mediating PIN1's translational repression (eIF4E/4E-BP involvement only inferred)","Whether other kinases regulate Ser16 in neurons"]},{"year":2011,"claim":"PIN1's vascular and nuclear receptor roles were defined: PIN1 isomerizes eNOS pSer116-Pro to enable its dephosphorylation and NO production, and isomerizes TR3 at two distinct sites with separable functional outcomes (stability vs. transactivation), demonstrating that multi-site isomerization can generate diverse functional outputs on a single substrate.","evidence":"Co-IP, Pin1 KO mice vascular relaxation assays, eNOS phosphorylation measurements; TR3 site-directed mutagenesis, ERK2 kinase assay, ChIP at cyclin D2 promoter","pmids":["21810655","22002310"],"confidence":"High","gaps":["Whether PIN1-eNOS axis is relevant to human cardiovascular disease","Full set of TR3 target genes regulated by PIN1-dependent isomerization"]},{"year":2012,"claim":"PIN1 was shown to bind pRb at phospho-Ser608/612 and promote its hyperphosphorylation to drive G1/S progression, and to bind AR at phospho-Ser81 modulating its transcriptional activity, broadening PIN1's roles in cell cycle and hormone signaling.","evidence":"Co-IP, GST pulldown, mutagenesis of pRb Ser608/612, cell cycle analysis; Co-IP and mutagenesis of AR Ser81 with transcriptional reporter","pmids":["22322860","22894932"],"confidence":"High","gaps":["Whether PIN1-mediated pRb hyperphosphorylation acts by enhancing CDK access or inhibiting phosphatase access","AR Ser81 finding from single lab, awaits independent replication"]},{"year":2013,"claim":"PIN1 was found to bind phosphorylated histone H1, promote its dephosphorylation sub-stoichiometrically, and stabilize H1–chromatin association, extending PIN1's chromatin functions beyond condensation to interphase chromatin architecture.","evidence":"In vitro dephosphorylation assay, FRAP measuring H1 chromatin residence time, PIN1 depletion by siRNA","pmids":["24100296"],"confidence":"High","gaps":["Which phosphatase dephosphorylates H1 after PIN1 isomerization","Genome-wide consequences of PIN1-dependent H1 stabilization"]},{"year":2015,"claim":"PIN1 was shown to enhance ERα DNA binding affinity in a fully reconstituted system requiring isomerase activity, and Aurora A was identified as a second Ser16 kinase suppressing PIN1 at G2/M, refining the regulatory logic of PIN1 activation and inhibition.","evidence":"In vitro DNA binding assay with purified PIN1/ERα, isomerase-dead mutant controls; Aurora A kinase assay on Ser16 with cell cycle analysis","pmids":["25866209","25662955"],"confidence":"High","gaps":["Whether Ser16 phosphorylation by Aurora A vs. PKMζ occurs in distinct subcellular compartments","Genome-wide targets of PIN1-enhanced ERα binding"]},{"year":2016,"claim":"Crystallographic and NMR studies provided atomic-level understanding of PIN1 substrate engagement: a co-crystal structure of PIN1 with BRD4 pThr204 peptide showed how isomerization promotes CDK9 recruitment and BRD4 stabilization, while NMR site-resolution on full-length tau revealed that PIN1 catalyzes multiple sites with different efficiencies and — contradicting prior models — does not enhance PP2A-mediated tau dephosphorylation or restore phospho-tau microtubule assembly.","evidence":"X-ray crystallography (PIN1–BRD4 peptide), ubiquitination assay, mutagenesis (BRD4-T204A); NMR site-specific catalysis on CDK2-phosphorylated full-length tau, ITC, SAXS, turbidity/EM microtubule assays","pmids":["28481868","26996941","26996940"],"confidence":"High","gaps":["Whether revised tau model applies to all tauopathy-relevant phosphorylation patterns","Structural basis for site-selectivity differences on full-length tau"]},{"year":2017,"claim":"The discovery of KPT-6566 as a covalent Cys113-targeting PIN1 inhibitor that induces PIN1 degradation and releases a ROS-generating quinone fragment validated PIN1's catalytic cysteine as a druggable site and provided a tool compound for cancer biology.","evidence":"Mechanism-based covalent screening, PIN1 degradation assay, ROS and DNA damage measurements, in vitro and in vivo tumor models","pmids":["28598431"],"confidence":"High","gaps":["Off-target effects of the released quinone fragment","Whether PIN1 degradation or ROS generation is the primary anti-tumor mechanism"]},{"year":2019,"claim":"PIN1 was placed upstream of IRAK1 activation in innate immune and radiation-resistance signaling, linking its isomerase activity to the IRAK1-IRAK4-TRAF6 axis — a previously unrecognized role in immune signaling.","evidence":"Zebrafish compound screen, IRAK1/PIN1 inhibitor synergy, genetic epistasis in tumor models","pmids":["30664786"],"confidence":"Medium","gaps":["Direct biochemical mechanism of PIN1-mediated IRAK1 activation not defined","Whether PIN1 directly isomerizes IRAK1 or acts through an intermediate"]},{"year":2020,"claim":"Multiple studies expanded PIN1's substrate repertoire to include Kv4.2 (neuronal excitability), HBc (viral protein stability), and METTL3 (m6A epitranscriptomic regulation), and validated BJP-06-005-3 as a second-generation Cys113-targeting covalent inhibitor cooperating with mutant KRAS in PDAC.","evidence":"Kv4.2-T607A knock-in mice with electrophysiology and behavioral assays; Phos-tag mapping and Co-IP for HBc; Co-IP and polysome profiling for METTL3; rational inhibitor design with chemical-genetic epistasis for BJP-06-005-3","pmids":["32218435","32083080","36755057","32483379"],"confidence":"High","gaps":["Whether PIN1-METTL3 interaction is direct or mediated by a scaffold","Full epitranscriptomic consequences of PIN1-stabilized METTL3","Whether Kv4.2 isomerization affects other auxiliary subunit interactions beyond DPP6"]},{"year":2021,"claim":"JNK phosphorylation at Ser115 was identified as a stabilizing modification that blocks PIN1 mono-ubiquitination at Lys117, while Sulfopin was validated as a potent in vivo PIN1 inhibitor phenocopying genetic KO in Myc-driven cancers, and PIN1 was linked to NLRP3 inflammasome activation and Hippo pathway regulation via STK3 degradation.","evidence":"JNK kinase assay, Lys117 ubiquitination assay, ICC proliferation models; Sulfopin chemoproteomics (two methods), MYCN neuroblastoma/PDAC models; Pin1−/− macrophage inflammasome assays; STK3 ubiquitination and TAZ nuclear translocation in melanoma","pmids":["34048060","33972797","33717117","33253791"],"confidence":"High","gaps":["E3 ligase responsible for Lys117 mono-ubiquitination not identified","Whether p38 MAPK is a direct PIN1 substrate in inflammasome signaling","Whether STK3 degradation is direct or requires additional cofactors"]},{"year":2022,"claim":"NMR/EPR-based structural analysis revealed that WW domain substrate binding allosterically remodels the PPIase domain through the interdomain interface, providing a physical mechanism for how substrate recognition is coupled to catalysis in PIN1.","evidence":"NMR interdomain structural sampling protocol, EPR PELDOR distance measurements, comparison of apo, WW-bound, and PPIase-bound states","pmids":["35927276"],"confidence":"High","gaps":["Whether allosteric coupling strength differs for different phospho-substrates","How post-translational modifications of PIN1 affect interdomain dynamics"]},{"year":2023,"claim":"PIN1 was shown to mediate CDK1-primed, WSB1-dependent ubiquitination and degradation of pVHL, directly linking PIN1 isomerase activity to HIF pathway derepression in tumors.","evidence":"CDK1 kinase assay on pVHL Ser80, Co-IP, WSB1 E3 ligase pulldown, ubiquitination assay, in vivo tumor models","pmids":["36813923"],"confidence":"High","gaps":["Whether PIN1-pVHL axis operates under normoxic conditions in non-tumor cells","Whether other E3 ligases besides WSB1 participate"]},{"year":2024,"claim":"A Plk1→USP34→PIN1→Ubc9 signaling cascade was delineated in glioma stem cells, where USP34 deubiquitinates PIN1 and stabilized PIN1 isomerizes CDK1-phosphorylated Ubc9 to enhance SUMO1 conjugation, connecting PIN1 to the SUMOylation machinery for the first time.","evidence":"Co-IP (PIN1–USP34, PIN1–Ubc9), Plk1 kinase assay, CDK1 phosphorylation of Ubc9, SUMO1 thioester assay, orthotopic glioma model","pmids":["38167292"],"confidence":"High","gaps":["Whether PIN1-Ubc9 axis operates in non-GSC contexts","Identity of SUMOylation targets critical for GSC maintenance downstream of this cascade","Whether other DUBs besides USP34 regulate PIN1 stability"]},{"year":null,"claim":"Despite extensive substrate identification, a systematic and quantitative understanding of how PIN1 achieves substrate selectivity among the thousands of pSer/Thr-Pro motifs in the phosphoproteome, and how its multiple regulatory inputs (Ser16, Ser115, Lys117 ubiquitination, USP34) are integrated in space and time, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No proteome-wide quantitative selectivity model for PIN1","How opposing regulatory phosphorylations (Ser16 vs. Ser115) are coordinated in specific cell types","Whether PIN1 acts processively on multi-site substrates or through distributive encounters"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[0,3,10,12,13,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,5,8,22,26]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,9,10]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[2,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,17]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,8,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,10,12,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,20,22,31]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,12,22,23]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,27,28]}],"complexes":[],"partners":["PP2A","BRD4","UBC9","USP34","METTL3","PVHL","ENOS","SMRT"],"other_free_text":[]},"mechanistic_narrative":"PIN1 is a phosphorylation-dependent peptidyl-prolyl cis/trans isomerase that acts as a post-phosphorylation conformational switch, binding pSer/Thr-Pro motifs via its WW domain and catalyzing prolyl isomerization at its active-site Cys113 to regulate substrate dephosphorylation, stability, protein–protein interactions, and transcriptional activity across cell cycle control, chromatin organization, neuronal signaling, and oncogenic pathways. PIN1-catalyzed isomerization renders substrates accessible to conformation-specific phosphatases such as PP2A and modulates ubiquitin-dependent turnover of diverse targets including BRD4, pVHL, SMRT, METTL3, and STK3, thereby controlling downstream signaling outputs including Hippo, HIF-1, and Myc pathways [PMID:11090625, PMID:28481868, PMID:36813923, PMID:36755057, PMID:33253791]. PIN1 itself is regulated by phosphorylation at Ser16 (by PKMζ and Aurora A, inhibiting substrate binding), Ser115 (by JNK, preventing ubiquitination and stabilizing PIN1), and by USP34-mediated deubiquitination downstream of Plk1 [PMID:20215645, PMID:25662955, PMID:34048060, PMID:38167292]. Interdomain allostery between the WW and PPIase domains, revealed by NMR and EPR, couples substrate recognition to catalytic-site rearrangement, with the active site pre-organized for catalysis through intrinsic microsecond-timescale conformational exchange [PMID:17316687, PMID:35927276]."},"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":"11090625","id":"PMC_11090625","title":"Pin1-dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau proteins.","date":"2000","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/11090625","citation_count":474,"is_preprint":false},{"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":295,"is_preprint":false},{"pmid":"17410202","id":"PMC_17410202","title":"PIN1, the cell cycle and cancer.","date":"2007","source":"Nature reviews. 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PP2A is conformation-specific, effectively dephosphorylating only the trans pSer/Thr-Pro isomer, and Pin1 prolyl isomerase activity is essential for cell division in vivo.\",\n      \"method\": \"In vitro prolyl isomerization assay, PP2A dephosphorylation assay with cis/trans-specific substrates, genetic epistasis (Pin1/PP2A reciprocal genetic interactions in yeast), active-site mutagenesis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with native substrates, active-site mutagenesis, genetic epistasis, highly cited foundational paper\",\n      \"pmids\": [\"11090625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Pin1 influences the phosphorylation status of the RNA polymerase II CTD by inhibiting the CTD phosphatase FCP1 and stimulating CTD phosphorylation by cdc2/cyclin B. Pin1 overexpression inhibits ongoing transcription and RNAP II-stimulated pre-mRNA splicing; Pin1 directly associates with a hyper-hyperphosphorylated form of RNAP II in M-phase.\",\n      \"method\": \"In vitro phosphatase inhibition assay, in vitro kinase assay (cdc2/cyclin B), Co-IP of Pin1 with RNAP II, in vivo transcription assay, pin1-/- cell analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including in vitro assays, Co-IP, and KO cells\",\n      \"pmids\": [\"14600023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Pin1 has an important function in chromosome condensation during mitosis; its interaction with chromatin is elevated in G2/M phase correlating with presence of mitotic phosphoproteins, especially topoisomerase IIα. Purified Pin1 together with cdc2/cyclin B is sufficient to induce chromosome condensation in vitro, and Pin1 increases TopoIIα phosphorylation by cdc2/cyclin B, promoting formation of a TopoIIα/Pin1/DNA complex.\",\n      \"method\": \"Pin1 siRNA knockdown, immunodepletion from mitotic extracts, in vitro reconstitution with purified Pin1 and cdc2/cyclin B, in vitro kinase assay, Co-IP\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution with purified components, immunodepletion, siRNA KD, multiple orthogonal methods\",\n      \"pmids\": [\"17466629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NMR analysis of Pin1 catalytic domain dynamics during catalysis reveals conformational exchange processes in the microsecond timescale at active site residues even in absence of substrate, suggesting the active site is pre-organized ('primed') for catalysis. Substrate binding versus substrate isomerization affect distinct regions of the active site.\",\n      \"method\": \"15N NMR relaxation dispersion, NOE measurements, substrate concentration-dependent conformational exchange analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure/dynamics study with functional validation, rigorous mechanistic dissection\",\n      \"pmids\": [\"17316687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Pin1 interacts with SMRT corepressor in a WW domain-dependent, phosphorylation-dependent manner and regulates SMRT protein stability. Cdk2-mediated phosphorylation of SMRT is required for Pin1 binding and decreases SMRT stability; mutation of phosphorylation sites abrogates Pin1 binding and stabilizes SMRT. Her2/Neu/ErbB2 functions upstream of both Pin1 and Cdk2 in this cascade.\",\n      \"method\": \"Co-IP in mammalian cells, in vitro pulldown, site-directed mutagenesis of phosphorylation sites, Cdk2 kinase assay, protein stability assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP, in vitro pulldown, mutagenesis, epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"18838553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Pin1 has opposite effects on wild-type versus P301L mutant tau stability: Pin1 KO or knockdown increases WT tau protein stability, while Pin1 overexpression suppresses tauopathy in WT tau transgenic mice. Conversely, Pin1 KO decreases P301L tau stability and abolishes its tauopathy phenotype in mice; Pin1 overexpression exacerbates P301L tauopathy.\",\n      \"method\": \"Pin1 KO mice, Pin1 knockdown (siRNA/shRNA), tau transgenic mouse models (WT and P301L), in vitro stability assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO and KD with defined phenotype, multiple in vivo and in vitro models, replicated across conditions\",\n      \"pmids\": [\"18431510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Pin1 is present in dendritic spines and shafts and inhibits glutamatergic signaling-induced protein synthesis, possibly through eIF4E and 4E-BP1/2. Pin1-/- mice show enhanced late LTP (L-LTP). PKMzeta phosphorylates Pin1 at Ser16, inhibiting Pin1 and thereby maintaining dendritic translation.\",\n      \"method\": \"Live imaging (Pin1 localization in dendrites), Pin1-/- mouse LTP recordings, dendritic translation assay, PKMzeta kinase assay on Pin1 Ser16, Co-IP of PKMzeta with Pin1\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence, KO phenotype, kinase assay identifying specific modification site\",\n      \"pmids\": [\"20215645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Pin1 deficiency causes endothelial dysfunction and hypertension by failing to isomerize phospho-eNOS Ser116-Pro117, preventing dephosphorylation of eNOS Ser116. Pin1 binds eNOS (confirmed by Co-IP), and Pin1 knockdown or inhibition increases eNOS Ser116 phosphorylation, reducing NO production and endothelium-dependent dilation.\",\n      \"method\": \"Co-IP of Pin1 with eNOS, siRNA knockdown, pharmacological inhibition (juglone), Pin1 KO mice, eNOS phosphorylation measurement, NO production assay, vascular relaxation assay\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, KO mice, KD, multiple orthogonal methods with specific phenotypic readout\",\n      \"pmids\": [\"21810655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Pin1 directly interacts with the spacer domain of pRb protein at phospho-Ser608/612, promotes hyperphosphorylation of pRb without affecting CDK or PP1/PP2 activity, and mediates interaction between CDK/cyclin complexes and pRb in mid/late G1 to drive cell cycle progression.\",\n      \"method\": \"Co-IP, GST pulldown, site-directed mutagenesis (pRb Ser608/612), cell cycle analysis, Pin1 overexpression/KD\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, pulldown, mutagenesis of specific binding motif, functional cell cycle readout\",\n      \"pmids\": [\"22322860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Pin1 interacts with phosphorylated histone H1, promotes its dephosphorylation (sub-stoichiometric Pin1 stimulates H1 dephosphorylation in vitro), modulates C-terminal domain structure of H1, and stabilizes H1 binding to chromatin when Pin1 binding sites on H1 are present. Pin1 depletion destabilizes H1-chromatin binding.\",\n      \"method\": \"In vitro dephosphorylation assay, Pin1 depletion (siRNA), FRAP (H1 chromatin binding stability), structural analysis of H1 CTD, Co-IP\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution, FRAP with functional consequence, depletion experiments, multiple methods\",\n      \"pmids\": [\"24100296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pin1 directly binds phosphorylated ERα Ser118-Pro119 via its isomerase activity and enhances ERα DNA binding affinity in a reconstituted in vitro system with purified components. Pin1 selectively enhances ERα binding to consensus DNA elements, and isomerization is required for this effect.\",\n      \"method\": \"In vitro DNA binding assay with purified Pin1 and ERα, DNA binding microarray, stable Pin1 overexpression, isomerase-dead mutant controls\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with purified components, mutagenesis (isomerase activity required), unbiased DNA microarray validation\",\n      \"pmids\": [\"25866209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Aurora A phosphorylates Pin1 at Ser16, suppressing Pin1 enzymatic activity, and cooperates with hBora to modulate G2/M transition.\",\n      \"method\": \"Kinase assay (Aurora A on Pin1 Ser16), site-directed mutagenesis, cell cycle analysis\",\n      \"journal\": \"Experimental biology and medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — kinase assay with mutant validation, but described in a review context citing original data from this lab\",\n      \"pmids\": [\"25662955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pin1 directly binds phosphorylated Thr204 of BRD4 (confirmed by peptide binding and crystallographic studies), catalyzes isomerization of Pro205, induces conformational changes that promote BRD4 interaction with CDK9, increases BRD4 transcriptional activity, and inhibits BRD4 ubiquitination to enhance its stability. BRD4-T204A mutant abolishes Pin1 binding and reduces BRD4 stability and activity.\",\n      \"method\": \"Peptide binding assay, X-ray crystallography (co-crystal structure), Co-IP, ubiquitination assay, site-directed mutagenesis (T204A), gene expression analysis, tumor formation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure, mutagenesis, reconstituted biochemistry, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28481868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NMR and structural studies show that pSer235-Pro (but not pThr231-Pro) of tau is exclusively catalyzed by full-length Pin1 and isolated PPIase domain. The WW domain is not required for turnover at pSer235, and Pin1 catalysis of CDK2/CycA-phosphorylated full-length tau occurs at multiple sites simultaneously with different efficiencies. Pin1 does not increase dephosphorylation rates by PP2A of these tau sites, refuting prior models.\",\n      \"method\": \"NMR (site-specific catalysis measurements), isothermal calorimetry (ITC), SAXS, CDK2/CycA phosphorylation of full-length tau, domain-deletion mutants of Pin1\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR with site-specific resolution, ITC, SAXS, domain mutagenesis, rigorous mechanistic dissection\",\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, refuting the previously accepted model that Pin1 binding/catalysis at the AT180 epitope restores phosphorylated tau's ability to promote microtubule polymerization.\",\n      \"method\": \"Turbidity assay (MT polymerization), time-resolved SAXS, time-resolved negative stain EM, NMR\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal in vitro assays directly testing the mechanistic model\",\n      \"pmids\": [\"26996940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KPT-6566, a covalent inhibitor, selectively binds to the catalytic site (Cys113) of PIN1 and targets PIN1 for degradation. This interaction releases a quinone-mimicking drug that generates ROS and DNA damage, inducing cell death specifically in cancer cells.\",\n      \"method\": \"Covalent binding assay (mechanism-based screening), Pin1 degradation assay, ROS measurement, DNA damage assay, in vitro and in vivo tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanism-based inhibitor with defined covalent binding site (Cys113), validated by multiple cellular and in vivo assays\",\n      \"pmids\": [\"28598431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IRAK1 inhibitors synergize with Pin1 inhibitors in suppressing radiation resistance, demonstrating that Pin1 is essential for IRAK1 activation in response to both pathogens and ionizing radiation. IRAK1 drives radioresistance through a pathway involving IRAK4 and TRAF6, and Pin1 is required for this IRAK1 activation.\",\n      \"method\": \"Compound screening in zebrafish, genetic epistasis (IRAK1 pathway), IRAK1 inhibitor/Pin1 inhibitor combination studies, tumor models\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — epistasis and pharmacological combination established the PIN1-IRAK1 axis, but mechanistic details are partially indirect\",\n      \"pmids\": [\"30664786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Activity-induced Kv4.2 phosphorylation at pThr607-Pro triggers Pin1 binding and isomerization of Kv4.2, leading to dissociation of the Kv4.2-DPP6 complex, increased A-type K+ current, and reduced neuronal excitability. Kv4.2-T607A knock-in mice exhibit altered Kv4.2-DPP6 interaction, increased A-type K+ current, and improved reversal learning.\",\n      \"method\": \"Co-IP, knock-in mouse model (Kv4.2-T607A), electrophysiology, behavioral assays (Morris water maze, lever press)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knock-in mouse with site-specific mutation abolishing Pin1 binding, Co-IP, electrophysiology, defined behavioral phenotype\",\n      \"pmids\": [\"32218435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sulfopin covalently targets Pin1's active site Cys113 with nanomolar potency; validated by two independent chemoproteomics methods, achieving potent cellular and in vivo target engagement. Pin1 inhibition downregulates c-Myc target genes and confers survival benefit in MYCN-driven neuroblastoma and pancreatic cancer models.\",\n      \"method\": \"Covalent fragment screening targeting Cys113, chemoproteomics (two independent methods), cellular target engagement assay, in vivo zebrafish and murine tumor models, genetic KO comparison\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — covalent active-site engagement validated by two chemoproteomics methods, phenocopies genetic KO, in vivo validation\",\n      \"pmids\": [\"33972797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JNK kinases directly bind to and phosphorylate PIN1 at Ser115, which prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation, thereby stabilizing PIN1 and promoting ICC cell proliferation.\",\n      \"method\": \"In vitro kinase assay (JNK phosphorylating PIN1 Ser115), ubiquitination assay (Lys117 mono-ubiquitination), loss-of-function/gain-of-function studies in vitro and in vivo, Co-IP\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct kinase assay identifying specific phosphorylation site, ubiquitination assay with specific lysine, in vivo validation\",\n      \"pmids\": [\"34048060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pin1 promotes NLRP3 inflammasome activation through the p38 MAPK pathway. Pin1 interacts with p-p38 MAPK (not directly but functionally), affects p38 MAPK phosphorylation, and Pin1 deficiency reduces NLRP3, ASC, Caspase1 expression, gasdermin D cleavage, and IL-1β/IL-18 secretion in macrophages during septic shock.\",\n      \"method\": \"Pin1-/- mice, Co-IP (Pin1 with p-p38 MAPK), LPS-induced macrophage model, inflammasome component analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KO mice with defined phenotype, Co-IP showing interaction, but Pin1-p38 interaction is indirect and mechanism not fully reconstituted\",\n      \"pmids\": [\"33717117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ligand-specific conformational changes drive interdomain allostery in Pin1: pCDC25c binding to the WW domain doubles the population of extended interdomain states and triggers conformational changes propagating to the catalytic site via the interdomain interface; FFpSPR binding to the PPIase displaces a helix leading to repositioning of the catalytic loop.\",\n      \"method\": \"NMR (MR-based protocol for intra/interdomain structural sampling), EPR (PELDOR), Pin1 domain dynamics in apo and ligand-bound states\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR and EPR structural/dynamic analysis with multiple ligand states, mechanistically rigorous\",\n      \"pmids\": [\"35927276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDK1 directly phosphorylates pVHL at Ser80, which primes pVHL recognition by PIN1. PIN1 then binds phospho-pVHL and facilitates recruitment of E3 ligase WSB1, targeting pVHL for ubiquitination and proteasomal degradation, thereby promoting tumor growth.\",\n      \"method\": \"In vitro CDK1 kinase assay on pVHL Ser80, Co-IP (PIN1 with pVHL), ubiquitination assay, E3 ligase (WSB1) pulldown, site-directed mutagenesis, in vitro and in vivo tumor assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct kinase assay, specific phosphorylation site identified, ubiquitination mechanism reconstituted, in vivo validation\",\n      \"pmids\": [\"36813923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP34 deubiquitinates and stabilizes Pin1 in glioma stem cells; this interaction is facilitated by Plk1-mediated phosphorylation of Pin1. Stabilized Pin1 isomerizes the SUMO E2 enzyme Ubc9 (requiring CDK1-mediated phosphorylation of Ubc9), upregulating Ubc9 thioester formation with SUMO1 and promoting hypersumoylation to support GSC maintenance.\",\n      \"method\": \"Co-IP (Pin1 with USP34, Pin1 with Ubc9), ubiquitination assay (USP34 deubiquitinating Pin1), Plk1 kinase assay (phosphorylating Pin1), CDK1 phosphorylation of Ubc9, SUMO1 thioester formation assay, shRNA KD, in vivo orthotopic tumor model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple enzymatic assays identifying specific modification sites, Co-IP, reconstituted biochemistry, in vivo validation\",\n      \"pmids\": [\"38167292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Androgen receptor (AR) Ser81 is involved in the interaction with Pin1, and this interaction is important for the transcriptional activity of AR. Pin1 binds phospho-Ser81 of AR to modulate AR function.\",\n      \"method\": \"Co-IP, site-directed mutagenesis (AR Ser81), transcriptional reporter assay\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with mutagenesis of binding site, single lab study\",\n      \"pmids\": [\"22894932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Pin1 interacts with HIF-1α in a p42/p44 MAPK phosphorylation-dependent manner, catalyzes conformational change in HIF-1α (shown by proteolysis studies), and is required for gene-specific HIF-1 transcriptional activity.\",\n      \"method\": \"Co-IP, GST pulldown, proteolysis (limited proteolysis to detect conformational change), HIF-1 transcriptional reporter assay, Pin1 inhibition/knockdown\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP, proteolysis assay (conformational change), functional transcription assay, but single lab\",\n      \"pmids\": [\"24726894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Pin1 interacts with METTL3, prevents its ubiquitin-dependent proteasomal and lysosomal degradation, thereby stabilizing METTL3 and increasing m6A modification of TAZ and EGFR mRNA, enhancing their translation. MEK1/2 kinases act upstream of this PIN1-METTL3 axis.\",\n      \"method\": \"Co-IP (PIN1 with METTL3), ubiquitination assay, polysome profiling (TAZ and EGFR mRNA distribution), METTL3 KO, PIN1 KO, in vivo orthotopic tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination assay, polysome profiling, multiple KO models, in vivo validation\",\n      \"pmids\": [\"36755057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BJP-06-005-3 covalently targets Cys113 in the Pin1 active site; Pin1 cooperates with mutant KRAS to promote transformation in PDAC, and Pin1 inhibition impairs PDAC cell viability over time.\",\n      \"method\": \"Rational peptide inhibitor design targeting Cys113, selectivity profiling, genetic KO and chemical-genetic strategies in PDAC cell lines\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structure-guided design, covalent active-site targeting confirmed, chemical-genetic epistasis establishing cooperation with mutant KRAS\",\n      \"pmids\": [\"32483379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pin1 promotes sustained B cell proliferation upon oncogenic Myc activation through the ARF-p53 pathway, not through altering Ser62 phosphorylation or Myc transcription. Genetic ablation of Pin1 reduces lymphomagenesis in Eμ-myc transgenic mice.\",\n      \"method\": \"Pin1 genetic ablation, Eμ-myc transgenic mice, ARF-p53 pathway analysis, Myc phosphorylation analysis, B cell proliferation assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined pathway (ARF-p53) and in vivo tumor model, but mechanism of how Pin1 activates ARF-p53 is not fully resolved\",\n      \"pmids\": [\"26943576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Pin1 isomerizes TR3 orphan nuclear receptor at phospho-Ser95-Pro and phospho-Ser431-Pro motifs; isomerization at Ser95-Pro retards TR3 degradation (enhancing stability), while isomerization at ERK2-phosphorylated Ser431-Pro enhances TR3 transactivation and promotes TR3 targeting to the cyclin D2 promoter and recruitment of p300.\",\n      \"method\": \"Co-IP, in vitro isomerization assay, site-directed mutagenesis, ERK2 kinase assay, luciferase reporter assay, ChIP, in vivo tumor assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — isomerization assay, kinase identification, mutagenesis of specific sites, ChIP, in vivo validation\",\n      \"pmids\": [\"22002310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Pin1 binds and stabilizes hepatitis B virus core protein (HBc) at phospho-Thr160-Pro and phospho-Ser162-Pro motifs in a phosphorylation-dependent manner. Pin1 inhibition accelerates HBc degradation via a lysosome-dependent pathway. PDP2 phosphatase dephosphorylates HBc at these Pin1-binding sites, suppressing Pin1-mediated HBc stabilization.\",\n      \"method\": \"Phos-tag gel electrophoresis, site-directed mutagenesis of HBc phospho-sites, GST pulldown, Co-IP, Pin1 inhibitor/KO, lysosome inhibitor assay, PDP2 dephosphorylation assay\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — site-specific phosphorylation mapping by Phos-tag, pulldown and Co-IP confirming interaction, enzyme assay identifying writer (CDK) and eraser (PDP2) of binding marks\",\n      \"pmids\": [\"32083080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pin1 facilitates ubiquitin-mediated proteasomal degradation of STK3 (MST2) in melanoma cells, leading to reduced LATS1/2 activity, nuclear translocation of TAZ, and increased CTGF expression through TAZ/TEAD complex formation.\",\n      \"method\": \"Co-IP (PIN1 with STK3), ubiquitination assay, shRNA KD, nuclear fractionation (TAZ localization), reporter assay (CTGF), in vivo melanoma model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP, ubiquitination assay, fractionation showing localization change, single lab study\",\n      \"pmids\": [\"33253791\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PIN1 is a phosphorylation-dependent peptidyl-prolyl cis/trans isomerase that specifically binds pSer/Thr-Pro motifs (via its WW domain) and catalyzes cis-to-trans isomerization at its active site Cys113, inducing conformational changes in substrates such as Cdc25C, tau, RNAP II CTD, BRD4, pRb, eNOS, Kv4.2, HIF-1α, and many others; these conformational changes regulate substrate dephosphorylation (by enabling access of PP2A to the trans isomer), protein stability (by modulating ubiquitination), protein-protein interactions, enzymatic activity, transcriptional activity, and subcellular localization, with PIN1 itself being regulated by phosphorylation (e.g., Ser16 by PKMzeta/Aurora A, Ser115 by JNK) and deubiquitination (by USP34), collectively positioning PIN1 as a master post-phosphorylation conformational switch controlling cell cycle progression, neuronal function, and oncogenic signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PIN1 is a phosphorylation-dependent peptidyl-prolyl cis/trans isomerase that acts as a post-phosphorylation conformational switch, binding pSer/Thr-Pro motifs via its WW domain and catalyzing prolyl isomerization at its active-site Cys113 to regulate substrate dephosphorylation, stability, protein–protein interactions, and transcriptional activity across cell cycle control, chromatin organization, neuronal signaling, and oncogenic pathways. PIN1-catalyzed isomerization renders substrates accessible to conformation-specific phosphatases such as PP2A and modulates ubiquitin-dependent turnover of diverse targets including BRD4, pVHL, SMRT, METTL3, and STK3, thereby controlling downstream signaling outputs including Hippo, HIF-1, and Myc pathways [PMID:11090625, PMID:28481868, PMID:36813923, PMID:36755057, PMID:33253791]. PIN1 itself is regulated by phosphorylation at Ser16 (by PKMζ and Aurora A, inhibiting substrate binding), Ser115 (by JNK, preventing ubiquitination and stabilizing PIN1), and by USP34-mediated deubiquitination downstream of Plk1 [PMID:20215645, PMID:25662955, PMID:34048060, PMID:38167292]. Interdomain allostery between the WW and PPIase domains, revealed by NMR and EPR, couples substrate recognition to catalytic-site rearrangement, with the active site pre-organized for catalysis through intrinsic microsecond-timescale conformational exchange [PMID:17316687, PMID:35927276].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that PIN1 prolyl isomerase activity controls substrate dephosphorylation answered how phosphorylation-dependent signaling could be regulated at the conformational level — PP2A selectively dephosphorylates the trans pSer/Thr-Pro isomer, and PIN1 catalyzes the cis-to-trans conversion required for this step.\",\n      \"evidence\": \"In vitro isomerization and PP2A dephosphorylation assays with Cdc25C and tau peptides, active-site mutagenesis, yeast genetic epistasis\",\n      \"pmids\": [\"11090625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all PIN1 substrates require PP2A-mediated dephosphorylation or whether this is substrate-specific\", \"Identity of the full substrate repertoire at this time was unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that PIN1 modulates RNAP II CTD phosphorylation and inhibits transcription and splicing extended PIN1 function beyond cell cycle phosphatases to transcriptional regulation, showing it could alter kinase/phosphatase balance on a major transcriptional machinery component.\",\n      \"evidence\": \"In vitro FCP1 phosphatase inhibition, cdc2/cyclin B kinase stimulation, Co-IP with hyperphosphorylated RNAP II, transcription/splicing assays in pin1−/− cells\",\n      \"pmids\": [\"14600023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PIN1 directly isomerizes CTD repeats or acts indirectly through accessory factors\", \"Structural basis of PIN1–CTD interaction\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Two concurrent advances resolved PIN1's mitotic chromatin role and its intrinsic catalytic dynamics: PIN1 with cdc2/cyclin B was sufficient to induce chromosome condensation via TopoIIα, while NMR revealed that the PIN1 active site undergoes pre-organized conformational exchange even without substrate, explaining its catalytic efficiency.\",\n      \"evidence\": \"In vitro chromosome condensation reconstitution with purified PIN1/cdc2/cyclin B; 15N NMR relaxation dispersion measuring microsecond dynamics at active-site residues\",\n      \"pmids\": [\"17466629\", \"17316687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PIN1 coordinates condensin and TopoIIα activities during mitosis\", \"Whether pre-organized active-site dynamics are altered by post-translational modifications of PIN1\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Studies on SMRT and tau revealed PIN1 as a general regulator of protein stability through phosphorylation-dependent binding: PIN1 destabilizes SMRT downstream of Cdk2/Her2 signaling, and exerts opposite stability effects on wild-type versus P301L mutant tau in vivo, establishing that PIN1's effect on substrate turnover is context-dependent.\",\n      \"evidence\": \"Co-IP, Cdk2 kinase assay, mutagenesis of SMRT phospho-sites; Pin1 KO crossed with WT and P301L tau transgenic mice\",\n      \"pmids\": [\"18838553\", \"18431510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase(s) mediating PIN1-dependent SMRT degradation not identified\", \"Structural basis for opposite effects on WT vs. P301L tau stability\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying PKMζ-mediated Ser16 phosphorylation of PIN1 in dendrites, which inhibits PIN1 to sustain dendritic translation and late LTP, established PIN1 as a regulated signaling node in synaptic plasticity — not merely a constitutive isomerase.\",\n      \"evidence\": \"Pin1−/− mouse LTP recordings, dendritic translation assays, PKMζ kinase assay on Ser16, live imaging of PIN1 in dendrites\",\n      \"pmids\": [\"20215645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrates mediating PIN1's translational repression (eIF4E/4E-BP involvement only inferred)\", \"Whether other kinases regulate Ser16 in neurons\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"PIN1's vascular and nuclear receptor roles were defined: PIN1 isomerizes eNOS pSer116-Pro to enable its dephosphorylation and NO production, and isomerizes TR3 at two distinct sites with separable functional outcomes (stability vs. transactivation), demonstrating that multi-site isomerization can generate diverse functional outputs on a single substrate.\",\n      \"evidence\": \"Co-IP, Pin1 KO mice vascular relaxation assays, eNOS phosphorylation measurements; TR3 site-directed mutagenesis, ERK2 kinase assay, ChIP at cyclin D2 promoter\",\n      \"pmids\": [\"21810655\", \"22002310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PIN1-eNOS axis is relevant to human cardiovascular disease\", \"Full set of TR3 target genes regulated by PIN1-dependent isomerization\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"PIN1 was shown to bind pRb at phospho-Ser608/612 and promote its hyperphosphorylation to drive G1/S progression, and to bind AR at phospho-Ser81 modulating its transcriptional activity, broadening PIN1's roles in cell cycle and hormone signaling.\",\n      \"evidence\": \"Co-IP, GST pulldown, mutagenesis of pRb Ser608/612, cell cycle analysis; Co-IP and mutagenesis of AR Ser81 with transcriptional reporter\",\n      \"pmids\": [\"22322860\", \"22894932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PIN1-mediated pRb hyperphosphorylation acts by enhancing CDK access or inhibiting phosphatase access\", \"AR Ser81 finding from single lab, awaits independent replication\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"PIN1 was found to bind phosphorylated histone H1, promote its dephosphorylation sub-stoichiometrically, and stabilize H1–chromatin association, extending PIN1's chromatin functions beyond condensation to interphase chromatin architecture.\",\n      \"evidence\": \"In vitro dephosphorylation assay, FRAP measuring H1 chromatin residence time, PIN1 depletion by siRNA\",\n      \"pmids\": [\"24100296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which phosphatase dephosphorylates H1 after PIN1 isomerization\", \"Genome-wide consequences of PIN1-dependent H1 stabilization\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"PIN1 was shown to enhance ERα DNA binding affinity in a fully reconstituted system requiring isomerase activity, and Aurora A was identified as a second Ser16 kinase suppressing PIN1 at G2/M, refining the regulatory logic of PIN1 activation and inhibition.\",\n      \"evidence\": \"In vitro DNA binding assay with purified PIN1/ERα, isomerase-dead mutant controls; Aurora A kinase assay on Ser16 with cell cycle analysis\",\n      \"pmids\": [\"25866209\", \"25662955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Ser16 phosphorylation by Aurora A vs. PKMζ occurs in distinct subcellular compartments\", \"Genome-wide targets of PIN1-enhanced ERα binding\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Crystallographic and NMR studies provided atomic-level understanding of PIN1 substrate engagement: a co-crystal structure of PIN1 with BRD4 pThr204 peptide showed how isomerization promotes CDK9 recruitment and BRD4 stabilization, while NMR site-resolution on full-length tau revealed that PIN1 catalyzes multiple sites with different efficiencies and — contradicting prior models — does not enhance PP2A-mediated tau dephosphorylation or restore phospho-tau microtubule assembly.\",\n      \"evidence\": \"X-ray crystallography (PIN1–BRD4 peptide), ubiquitination assay, mutagenesis (BRD4-T204A); NMR site-specific catalysis on CDK2-phosphorylated full-length tau, ITC, SAXS, turbidity/EM microtubule assays\",\n      \"pmids\": [\"28481868\", \"26996941\", \"26996940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether revised tau model applies to all tauopathy-relevant phosphorylation patterns\", \"Structural basis for site-selectivity differences on full-length tau\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The discovery of KPT-6566 as a covalent Cys113-targeting PIN1 inhibitor that induces PIN1 degradation and releases a ROS-generating quinone fragment validated PIN1's catalytic cysteine as a druggable site and provided a tool compound for cancer biology.\",\n      \"evidence\": \"Mechanism-based covalent screening, PIN1 degradation assay, ROS and DNA damage measurements, in vitro and in vivo tumor models\",\n      \"pmids\": [\"28598431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Off-target effects of the released quinone fragment\", \"Whether PIN1 degradation or ROS generation is the primary anti-tumor mechanism\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"PIN1 was placed upstream of IRAK1 activation in innate immune and radiation-resistance signaling, linking its isomerase activity to the IRAK1-IRAK4-TRAF6 axis — a previously unrecognized role in immune signaling.\",\n      \"evidence\": \"Zebrafish compound screen, IRAK1/PIN1 inhibitor synergy, genetic epistasis in tumor models\",\n      \"pmids\": [\"30664786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical mechanism of PIN1-mediated IRAK1 activation not defined\", \"Whether PIN1 directly isomerizes IRAK1 or acts through an intermediate\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple studies expanded PIN1's substrate repertoire to include Kv4.2 (neuronal excitability), HBc (viral protein stability), and METTL3 (m6A epitranscriptomic regulation), and validated BJP-06-005-3 as a second-generation Cys113-targeting covalent inhibitor cooperating with mutant KRAS in PDAC.\",\n      \"evidence\": \"Kv4.2-T607A knock-in mice with electrophysiology and behavioral assays; Phos-tag mapping and Co-IP for HBc; Co-IP and polysome profiling for METTL3; rational inhibitor design with chemical-genetic epistasis for BJP-06-005-3\",\n      \"pmids\": [\"32218435\", \"32083080\", \"36755057\", \"32483379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PIN1-METTL3 interaction is direct or mediated by a scaffold\", \"Full epitranscriptomic consequences of PIN1-stabilized METTL3\", \"Whether Kv4.2 isomerization affects other auxiliary subunit interactions beyond DPP6\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"JNK phosphorylation at Ser115 was identified as a stabilizing modification that blocks PIN1 mono-ubiquitination at Lys117, while Sulfopin was validated as a potent in vivo PIN1 inhibitor phenocopying genetic KO in Myc-driven cancers, and PIN1 was linked to NLRP3 inflammasome activation and Hippo pathway regulation via STK3 degradation.\",\n      \"evidence\": \"JNK kinase assay, Lys117 ubiquitination assay, ICC proliferation models; Sulfopin chemoproteomics (two methods), MYCN neuroblastoma/PDAC models; Pin1−/− macrophage inflammasome assays; STK3 ubiquitination and TAZ nuclear translocation in melanoma\",\n      \"pmids\": [\"34048060\", \"33972797\", \"33717117\", \"33253791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase responsible for Lys117 mono-ubiquitination not identified\", \"Whether p38 MAPK is a direct PIN1 substrate in inflammasome signaling\", \"Whether STK3 degradation is direct or requires additional cofactors\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"NMR/EPR-based structural analysis revealed that WW domain substrate binding allosterically remodels the PPIase domain through the interdomain interface, providing a physical mechanism for how substrate recognition is coupled to catalysis in PIN1.\",\n      \"evidence\": \"NMR interdomain structural sampling protocol, EPR PELDOR distance measurements, comparison of apo, WW-bound, and PPIase-bound states\",\n      \"pmids\": [\"35927276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether allosteric coupling strength differs for different phospho-substrates\", \"How post-translational modifications of PIN1 affect interdomain dynamics\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"PIN1 was shown to mediate CDK1-primed, WSB1-dependent ubiquitination and degradation of pVHL, directly linking PIN1 isomerase activity to HIF pathway derepression in tumors.\",\n      \"evidence\": \"CDK1 kinase assay on pVHL Ser80, Co-IP, WSB1 E3 ligase pulldown, ubiquitination assay, in vivo tumor models\",\n      \"pmids\": [\"36813923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PIN1-pVHL axis operates under normoxic conditions in non-tumor cells\", \"Whether other E3 ligases besides WSB1 participate\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A Plk1→USP34→PIN1→Ubc9 signaling cascade was delineated in glioma stem cells, where USP34 deubiquitinates PIN1 and stabilized PIN1 isomerizes CDK1-phosphorylated Ubc9 to enhance SUMO1 conjugation, connecting PIN1 to the SUMOylation machinery for the first time.\",\n      \"evidence\": \"Co-IP (PIN1–USP34, PIN1–Ubc9), Plk1 kinase assay, CDK1 phosphorylation of Ubc9, SUMO1 thioester assay, orthotopic glioma model\",\n      \"pmids\": [\"38167292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PIN1-Ubc9 axis operates in non-GSC contexts\", \"Identity of SUMOylation targets critical for GSC maintenance downstream of this cascade\", \"Whether other DUBs besides USP34 regulate PIN1 stability\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Despite extensive substrate identification, a systematic and quantitative understanding of how PIN1 achieves substrate selectivity among the thousands of pSer/Thr-Pro motifs in the phosphoproteome, and how its multiple regulatory inputs (Ser16, Ser115, Lys117 ubiquitination, USP34) are integrated in space and time, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No proteome-wide quantitative selectivity model for PIN1\", \"How opposing regulatory phosphorylations (Ser16 vs. Ser115) are coordinated in specific cell types\", \"Whether PIN1 acts processively on multi-site substrates or through distributive encounters\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [0, 3, 10, 12, 13, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 5, 8, 22, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 9, 10]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 8, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 10, 12, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 20, 22, 31]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 12, 22, 23]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 27, 28]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PP2A\", \"BRD4\", \"Ubc9\", \"USP34\", \"METTL3\", \"pVHL\", \"eNOS\", \"SMRT\"],\n    \"other_free_text\": []\n  }\n}\n```"}