Affinage

PIN1

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 · UniProt Q13526

Length
163 aa
Mass
18.2 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2002 High

    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

    PMID:11940573

    Open questions at the time
    • Did not resolve isomerization kinetics at the CK2/TopoIIα motif
    • Physiological consequence for chromosome dynamics not addressed here
  2. 2003 High

    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

    PMID:14600023

    Open questions at the time
    • Direct isomerization of CTD prolines not structurally resolved
    • Genome-wide scope of CTD regulation not mapped
  3. 2007 High

    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

    PMID:17316687 PMID:17466629 PMID:18006688

    Open questions at the time
    • In vivo condensation defect not assessed in intact cells across cell types
    • Catalytic conformational exchange not linked to a specific substrate motif
  4. 2008 Medium

    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

    PMID:18838553

    Open questions at the time
    • E3 ligase mediating SMRT turnover not identified
    • Single-lab finding
  5. 2008 High

    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

    PMID:18431510

    Open questions at the time
    • Molecular basis of the WT-versus-mutant divergence not defined
    • Specific tau phospho-motifs catalyzed not pinned down here
  6. 2010 High

    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

    PMID:20215645 PMID:20479004

    Open questions at the time
    • Direct PIN1 substrate in the translation machinery not defined
    • MEK1/2 phospho-motif engaged by PIN1 not mapped
  7. 2011 High

    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

    PMID:21810655 PMID:22002310

    Open questions at the time
    • Phosphatase acting on eNOS Ser116 downstream of PIN1 not identified
    • TR3 isomerization not directly observed structurally
  8. 2012 High

    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

    PMID:22322860 PMID:22613712 PMID:22894932

    Open questions at the time
    • Mechanism by which PIN1 controls Smad6 localization unresolved
    • AR study limited methodologically (single lab)
  9. 2013 High

    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

    PMID:23633483 PMID:24145406 PMID:24309930

    Open questions at the time
    • SUMO E3 ligase for PIN1 not identified
    • p63 finding single-lab
  10. 2015 High

    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

    PMID:25558977 PMID:25866209

    Open questions at the time
    • Structural snapshot of the ERα pSer118-Pro119 isomer not obtained
    • NICD1 study single-lab
  11. 2016 High

    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

    PMID:26996940 PMID:26996941

    Open questions at the time
    • Cellular consequence of site-specific tau isomerization not established
    • Functional output of refuted models replaced only partially
  12. 2017 High

    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

    PMID:28481868 PMID:28566287 PMID:28598431

    Open questions at the time
    • BRD4 isomerization shown for one site; broader BRD4 conformational map not built
    • KPT-6566 mechanistic details partly inferred
  13. 2020 Medium

    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

    PMID:32083080 PMID:32483379 PMID:33253791 PMID:33279499 PMID:36755057

    Open questions at the time
    • Most substrate studies are single-lab
    • Direct isomerization at each substrate motif not biophysically confirmed
  14. 2021 High

    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)

    PMID:33972797 PMID:34048060

    Open questions at the time
    • Full set of in-vivo PIN1 substrates underlying Sulfopin effects not enumerated
    • JNK-PIN1 axis single-lab
  15. 2023 High

    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

    PMID:36813923

    Open questions at the time
    • Conformational change in pVHL driving WSB1 recruitment not structurally resolved
  16. 2024 High

    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

    PMID:38167292

    Open questions at the time
    • Structural basis of Ubc9 isomerization not resolved
    • Generality beyond glioma stem cells untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016853 isomerase activity 4 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 1 GO:0005654 nucleoplasm 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 2
Partners
BRD4ENOSHIPK2METTL3NICD1PVHLSMAD3STK3

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. In vitro phosphatase/kinase assays, in vivo overexpression/knockout cell lines, cell extract transcription/splicing assays, co-immunoprecipitation Genes & development High 14600023
2007 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. Chromatin immunoprecipitation (ChIP) with CTD phospho-specific antibodies, inducible Pin1 overexpression cell lines, in vitro transcription assays with active-site mutant Pin1 Genes & development High 18006688
2007 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. Chromatin fractionation, siRNA knockdown, immunodepletion of mitotic extracts, reconstitution with purified components, in vitro kinase assay Molecular cell High 17466629
2002 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. Co-immunoprecipitation, in vitro phosphorylation assays, domain-deletion and point mutants of Pin1, chimeric CK2 constructs The Journal of biological chemistry High 11940573
2007 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. NMR relaxation dispersion (15N), inter- and intramolecular NOE measurements during catalysis Journal of molecular biology High 17316687
2013 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. Co-immunoprecipitation, site-directed mutagenesis of SUMOylation sites (K6R, K63R), cell transformation assays, centrosome amplification assays Cancer research High 23633483
2012 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. Co-immunoprecipitation, direct binding assays, site-directed mutagenesis, cell proliferation assays, Pin1 knockout cells Cell death and differentiation Medium 22322860
2008 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. Co-immunoprecipitation in vitro and in mammalian cells, domain mutant analysis (WW domain of Pin1), phosphorylation site mutagenesis of SMRT, transcriptional reporter assays The Journal of cell biology Medium 18838553
2010 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. Immunofluorescence localization, genetic knockout (Pin1-/- mice), electrophysiology (LTP recordings), co-immunoprecipitation, site-directed mutagenesis of Pin1 Ser16 Science signaling High 20215645
2008 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. Genetic Pin1 KO and knockdown in mice, Pin1 overexpression in tau transgenic mice, protein stability assays The Journal of clinical investigation High 18431510
2013 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. Co-immunoprecipitation, site-directed mutagenesis (T538A), protein stability assays, cell proliferation/apoptosis assays, tumor xenograft Cell death & disease Medium 24309930
2015 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. Co-immunoprecipitation, Pin1 overexpression/knockdown/knockout, ubiquitination assay, mouse focal stroke model, Pin1 inhibitor treatment Annals of neurology Medium 25558977
2011 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. Co-immunoprecipitation, site-directed mutagenesis of TR3 Pin1-binding sites, chromatin immunoprecipitation, protein stability assays, reporter assays, in vivo tumor growth Oncogene Medium 22002310
2012 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. Genetic knockout (Pin1-/- mice and fibroblasts), siRNA knockdown, subcellular fractionation, reporter assays, in vivo bleomycin fibrosis model The Journal of biological chemistry High 22613712
2013 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. Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis of HIPK2 autophosphorylation sites, in vivo zebrafish DNA damage model, Pin1 KO Proceedings of the National Academy of Sciences of the United States of America High 24145406
2017 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. Peptide binding assay, X-ray crystallography, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (T204A), tumor formation assays Oncogene High 28481868
2017 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. Mechanism-based covalent inhibitor screening, mass spectrometry confirmation of active-site binding, ROS assays, DNA damage assays, in vivo lung metastasis model Nature communications Medium 28598431
2021 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. Covalent fragment screening, chemoproteomics (two independent methods), genetic knockout comparison, in vivo tumor models Nature chemical biology High 33972797
2020 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. Structure-guided inhibitor design, covalent active-site targeting of Cys113, genetic/chemical-genetic strategies in PDAC cell lines Nature chemical biology Medium 32483379
2011 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. Co-immunoprecipitation, siRNA knockdown, Pin1 inhibitor (juglone), Pin1 knockout mice, NO production assay, vascular relaxation assay, blood pressure measurement Hypertension (Dallas, Tex. : 1979) High 21810655
2010 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. Pin1 knockout MEFs, siRNA knockdown, co-immunoprecipitation (Pin1-MEK1/2), promoter activity assays, Western blotting The Journal of biological chemistry Medium 20479004
2015 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. In vitro DNA binding assay with purified components, DNA binding microarray (thousands of permutations), stable Pin1 overexpression, isomerase-dead Pin1 mutant The Journal of biological chemistry High 25866209
2016 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/A Nature communications Low 26791759
2016 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. NMR (site-specific measurements), isothermal calorimetry (ITC), small angle X-ray scattering (SAXS), isolated domain analysis, CDK2/CycA-phosphorylated full-length tau Journal of molecular biology High 26996941
2016 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. Turbidity assays, time-resolved SAXS, time-resolved negative-stain electron microscopy, NMR, in vitro reconstitution with phosphorylated tau Journal of molecular biology High 26996940
2018 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. Co-immunoprecipitation (Pin1-calcineurin), Pin1 knockout neurons, exogenous Pin1 rescue, FK506 treatment, dendritic spine imaging Science signaling High 29559586
2012 Androgen receptor Ser81 mediates interaction with Pin1, and this interaction is important for AR transcriptional activity. Co-immunoprecipitation, site-directed mutagenesis (AR-Ser81), transcriptional activity assays Cell cycle (Georgetown, Tex.) Medium 22894932
2024 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. Co-immunoprecipitation, ubiquitination assay, Phos-tag gel electrophoresis, GST pull-down, genetic KO/KD, pharmacological inhibition, orthotopic tumor model Nature communications High 38167292
2021 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. 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 Hepatology (Baltimore, Md.) Medium 34048060
2020 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. Co-immunoprecipitation, ubiquitination assay, polysome profiling, Pin1 KO, METTL3 KO, in vivo orthotopic tumor model Oncogene Medium 36755057
2020 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. Co-immunoprecipitation, siRNA knockdown, Pin1 overexpression, adipocyte-specific Pin1 KO mice, ubiquitin-proteasome assay, lipolysis assay Metabolism: clinical and experimental Medium 33279499
2023 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. Co-immunoprecipitation, in vitro kinase assay (CDK1 phosphorylation of pVHL), ubiquitination assay, site-directed mutagenesis (Ser80), genetic ablation and pharmacological inhibition, tumor xenograft models Cell death and differentiation High 36813923
2017 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. β-cell-specific Pin1 KO mice, co-immunoprecipitation (Pin1-SIK2), kinase activity assay, intracellular Ca2+ measurement, glucose tolerance test The Journal of biological chemistry Medium 28566287
2020 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. GST pull-down, co-immunoprecipitation, Phos-tag gel electrophoresis, site-directed mutagenesis, Pin1 inhibition (chemical and genetic), lysosome inhibitor assays Frontiers in cell and developmental biology Medium 32083080
2020 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. Co-immunoprecipitation, ubiquitination assay, subcellular fractionation, siRNA/shRNA knockdown, tumor formation assay Cancer letters Medium 33253791

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Prolyl isomerase Pin1 as a molecular switch to determine the fate of phosphoproteins. Trends in biochemical sciences 297 21852138
2007 PIN1, the cell cycle and cancer. Nature reviews. Cancer 224 17410202
2014 Prolyl isomerase Pin1 in cancer. Cell research 168 25124924
2003 Pin1 and Par14 peptidyl prolyl isomerase inhibitors block cell proliferation. Chemistry & biology 155 12573694
2003 Pin1 modulates the structure and function of human RNA polymerase II. Genes & development 144 14600023
2006 Pin1 in Alzheimer's disease. Journal of neurochemistry 136 16945100
2017 A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action. Nature communications 128 28598431
2021 Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo. Nature chemical biology 116 33972797
2008 Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy. The Journal of clinical investigation 105 18431510
2015 Pin1 dysregulation helps to explain the inverse association between cancer and Alzheimer's disease. Biochimica et biophysica acta 80 25583562
2002 Interactions between protein kinase CK2 and Pin1. Evidence for phosphorylation-dependent interactions. The Journal of biological chemistry 80 11940573
2013 SENP1 deSUMOylates and regulates Pin1 protein activity and cellular function. Cancer research 78 23633483
2007 Pin1 in Alzheimer's disease: multiple substrates, one regulatory mechanism? Biochimica et biophysica acta 76 17317113
2007 Pin1 modulates RNA polymerase II activity during the transcription cycle. Genes & development 71 18006688
2010 Pin1 and PKMzeta sequentially control dendritic protein synthesis. Science signaling 69 20215645
2010 Pin1: a new genetic link between Alzheimer's disease, cancer and aging. Current aging science 69 20735350
2012 Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1. Cell death and differentiation 67 22322860
2007 Structure and dynamics of pin1 during catalysis by NMR. Journal of molecular biology 64 17316687
2020 Identification of a potent and selective covalent Pin1 inhibitor. Nature chemical biology 63 32483379
2015 Pin1 promotes neuronal death in stroke by stabilizing Notch intracellular domain. Annals of neurology 59 25558977
2013 Pin1 modulates p63α protein stability in regulation of cell survival, proliferation and tumor formation. Cell death & disease 56 24309930
2008 Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT. The Journal of cell biology 53 18838553
2018 PIN1 in Cell Cycle Control and Cancer. Frontiers in pharmacology 52 30534074
2007 The prolyl isomerase Pin1 functions in mitotic chromosome condensation. Molecular cell 52 17466629
2006 PIN1 expression contributes to hepatic carcinogenesis. The Journal of pathology 52 16841372
2015 Landscape of Pin1 in the cell cycle. Experimental biology and medicine (Maywood, N.J.) 50 25662955
2010 The prolyl isomerase Pin1 induces LC-3 expression and mediates tamoxifen resistance in breast cancer. The Journal of biological chemistry 47 20479004
2006 Targeting carcinogenesis: a role for the prolyl isomerase Pin1? Molecular carcinogenesis 47 16652378
2020 Function of PIN1 in Cancer Development and Its Inhibitors as Cancer Therapeutics. Frontiers in cell and developmental biology 46 32258027
2009 Pin1 as an anticancer drug target. Drug news & perspectives 46 19890497
2013 Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death. Proceedings of the National Academy of Sciences of the United States of America 45 24145406
2003 The peptidyl-prolyl isomerase Pin1. Progress in cell cycle research 44 14593743
2014 Pin1 induction in the fibrotic liver and its roles in TGF-β1 expression and Smad2/3 phosphorylation. Journal of hepatology 43 24530597
2017 Prolyl isomerase PIN1 regulates the stability, transcriptional activity and oncogenic potential of BRD4. Oncogene 42 28481868
2016 PIN1 in breast development and cancer: a clinical perspective. Cell death and differentiation 41 27834957
2015 Pin1 inhibitor Juglone prevents diabetic vascular dysfunction. International journal of cardiology 41 26583846
2016 Pin1At regulates PIN1 polar localization and root gravitropism. Nature communications 39 26791759
2011 Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis. Oncogene 39 22002310
2016 The role of Pin1 in the development and treatment of cancer. Archives of pharmacal research 38 27572155
2007 Pin1 modulates the type 1 immune response. PloS one 38 17311089
2024 Stabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells. Nature communications 37 38167292
2018 Structure and function of the human parvulins Pin1 and Par14/17. Biological chemistry 37 29040060
2012 Pin1 protein regulates Smad protein signaling and pulmonary fibrosis. The Journal of biological chemistry 36 22613712
2020 Prolyl Isomerase Pin1 in Human Cancer: Function, Mechanism, and Significance. Frontiers in cell and developmental biology 34 32296699
2013 PtdIns5P and Pin1 in oxidative stress signaling. Advances in biological regulation 34 23602596
2011 Pin1 deficiency causes endothelial dysfunction and hypertension. Hypertension (Dallas, Tex. : 1979) 34 21810655
2019 Oncogenic Hijacking of the PIN1 Signaling Network. Frontiers in oncology 33 30873382
2014 PIN1 inhibition suppresses osteoclast differentiation and inflammatory responses. Journal of dental research 33 25512367
2019 Prolyl isomerase Pin1 in metabolic reprogramming of cancer cells. Cancer letters 32 31678165
2018 SUV39H1/DNMT3A-dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 29750576
2018 Gears-In-Motion: The Interplay of WW and PPIase Domains in Pin1. Frontiers in oncology 32 30460195
2021 Pin1 Promotes NLRP3 Inflammasome Activation by Phosphorylation of p38 MAPK Pathway in Septic Shock. Frontiers in immunology 31 33717117
2014 Regulation of mitochondrial apoptosis by Pin1 in cancer and neurodegeneration. Mitochondrion 31 25132079
2016 Inhibition of Pin1 alleviates myocardial fibrosis and dysfunction in STZ-induced diabetic mice. Biochemical and biophysical research communications 30 27634219
2021 Targeting Pin1 for Modulation of Cell Motility and Cancer Therapy. Biomedicines 28 33807199
2021 Roles of peptidyl-prolyl isomerase Pin1 in disease pathogenesis. Theranostics 26 33537091
2019 Secreted parasite Pin1 isomerase stabilizes host PKM2 to reprogram host cell metabolism. Communications biology 25 31044177
2018 Pin1 mediates Aβ42-induced dendritic spine loss. Science signaling 25 29559586
2016 Molecular Mechanism of Pin1-Tau Recognition and Catalysis. Journal of molecular biology 25 26996941
2016 Pin1-Targeted Therapy for Systemic Lupus Erythematosus. Arthritis & rheumatology (Hoboken, N.J.) 25 27159270
2012 Androgen receptor serine 81 mediates Pin1 interaction and activity. Cell cycle (Georgetown, Tex.) 25 22894932
2017 The prolyl isomerase Pin1 increases β-cell proliferation and enhances insulin secretion. The Journal of biological chemistry 24 28566287
2016 Regulation of Microtubule Assembly by Tau and not by Pin1. Journal of molecular biology 24 26996940
2016 Synthesis and Pin1 inhibitory activity of thiazole derivatives. Bioorganic & medicinal chemistry 23 27692510
2016 Understanding the role of PIN1 in hepatocellular carcinoma. World journal of gastroenterology 23 28018099
2020 Development of Pin1 Inhibitors and their Potential as Therapeutic Agents. Current medicinal chemistry 21 30394205
2020 Post-translational Modifications of the Peptidyl-Prolyl Isomerase Pin1. Frontiers in cell and developmental biology 21 32195254
2018 Synthesis and biological evaluation of pyrimidine derivatives as novel human Pin1 inhibitors. Bioorganic & medicinal chemistry 21 29576270
2015 Pin1: Intimate involvement with the regulatory protein kinase networks in the global phosphorylation landscape. Biochimica et biophysica acta 21 25766872
2020 The Peptidyl-prolyl Isomerase Pin1 in Neuronal Signaling: from Neurodevelopment to Neurodegeneration. Molecular neurobiology 20 33083964
2009 PIN1 gene variants in Alzheimer's disease. BMC medical genetics 20 19909517
2017 Downregulation of Pin1 in human atherosclerosis and its association with vascular smooth muscle cell senescence. Journal of vascular surgery 19 28986099
2006 Exploring the molecular function of PIN1 by nuclear magnetic resonance. Current protein & peptide science 19 16787258
2005 Tau and GSK3beta dephosphorylations are required for regulating Pin1 phosphorylation. Neurochemical research 19 16258844
2023 The regulatory role of Pin1 in neuronal death. Neural regeneration research 18 35799512
2023 METTL3 stabilization by PIN1 promotes breast tumorigenesis via enhanced m6A-dependent translation. Oncogene 18 36755057
2021 Phosphorylation and Stabilization of PIN1 by JNK Promote Intrahepatic Cholangiocarcinoma Growth. Hepatology (Baltimore, Md.) 18 34048060
2020 Targeting PIN1 as a Therapeutic Approach for Hepatocellular Carcinoma. Frontiers in cell and developmental biology 18 32010690
2019 A Guide to PIN1 Function and Mutations Across Cancers. Frontiers in pharmacology 18 30723410
2017 Dynamic regulation of Pin1 expression and function during zebrafish development. PloS one 18 28426725
2017 Blood-testis barrier integrity depends on Pin1 expression in Sertoli cells. Scientific reports 18 28765625
2015 Peptidylprolyl Isomerase Pin1 Directly Enhances the DNA Binding Functions of Estrogen Receptor α. The Journal of biological chemistry 18 25866209
2013 Dissecting Pin1 and phospho-pRb regulation. Journal of cellular physiology 18 22553088
2006 Pin1 protein associates with neuronal lipofuscin: potential consequences in age-related neurodegeneration. Experimental neurology 18 16480979
2020 Prolyl Isomerase Pin1 Regulates the Stability of Hepatitis B Virus Core Protein. Frontiers in cell and developmental biology 17 32083080
2020 Deficiency of microRNA-628-5p promotes the progression of gastric cancer by upregulating PIN1. Cell death & disease 17 32703934
2014 p53 negatively regulates Pin1 expression under ER stress. Biochemical and biophysical research communications 17 25451271
2022 Hyperglycemia induces gastric carcinoma proliferation and migration via the Pin1/BRD4 pathway. Cell death discovery 16 35461311
2018 PIN1 is a new therapeutic target of craniosynostosis. Human molecular genetics 16 30007339
2020 PIN1 facilitates ubiquitin-mediated degradation of serine/threonine kinase 3 and promotes melanoma development via TAZ activation. Cancer letters 15 33253791
2011 Pin1 inhibition activates cyclin D and produces neurodegenerative pathology. Journal of neurochemistry 15 21443524
2011 Role of Pin1 in UVA-induced cell proliferation and malignant transformation in epidermal cells. Biochemical and biophysical research communications 15 21640077
2023 PIN1 and CDK1 cooperatively govern pVHL stability and suppressive functions. Cell death and differentiation 14 36813923
2023 Small molecules targeting Pin1 as potent anticancer drugs. Frontiers in pharmacology 14 37050909
2022 Computational and Structure-Based Development of High Potent Cell-Active Covalent Inhibitor Targeting the Peptidyl-Prolyl Isomerase NIMA-Interacting-1 (Pin1). Journal of medicinal chemistry 13 35089030
2020 Prolyl isomerase Pin1 interacts with adipose triglyceride lipase and negatively controls both its expression and lipolysis. Metabolism: clinical and experimental 13 33279499
2006 Pin1 flips Alzheimer's switch. ACS chemical biology 13 17163675
2004 A role for Pin1 in mammalian germ cell development and spermatogenesis. Frontiers in bioscience : a journal and virtual library 13 15353353
2023 The metabolic crosstalk between PIN1 and the tumour microenvironment. Seminars in cancer biology 12 36871635
2017 Pin1, the Master Orchestrator of Bone Cell Differentiation. Journal of cellular physiology 12 27225727

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