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PIN1

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

Length
163 aa
Mass
18.2 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2000 High

    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

    PMID:11090625

    Open questions at the time
    • 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
  2. 2003 High

    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

    PMID:14600023

    Open questions at the time
    • Whether PIN1 directly isomerizes CTD repeats or acts indirectly through accessory factors
    • Structural basis of PIN1–CTD interaction
  3. 2007 High

    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

    PMID:17316687 PMID:17466629

    Open questions at the time
    • How PIN1 coordinates condensin and TopoIIα activities during mitosis
    • Whether pre-organized active-site dynamics are altered by post-translational modifications of PIN1
  4. 2008 High

    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

    PMID:18431510 PMID:18838553

    Open questions at the time
    • E3 ligase(s) mediating PIN1-dependent SMRT degradation not identified
    • Structural basis for opposite effects on WT vs. P301L tau stability
  5. 2010 High

    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

    PMID:20215645

    Open questions at the time
    • Direct substrates mediating PIN1's translational repression (eIF4E/4E-BP involvement only inferred)
    • Whether other kinases regulate Ser16 in neurons
  6. 2011 High

    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

    PMID:21810655 PMID:22002310

    Open questions at the time
    • Whether PIN1-eNOS axis is relevant to human cardiovascular disease
    • Full set of TR3 target genes regulated by PIN1-dependent isomerization
  7. 2012 High

    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

    PMID:22322860 PMID:22894932

    Open questions at the time
    • Whether PIN1-mediated pRb hyperphosphorylation acts by enhancing CDK access or inhibiting phosphatase access
    • AR Ser81 finding from single lab, awaits independent replication
  8. 2013 High

    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

    PMID:24100296

    Open questions at the time
    • Which phosphatase dephosphorylates H1 after PIN1 isomerization
    • Genome-wide consequences of PIN1-dependent H1 stabilization
  9. 2015 High

    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

    PMID:25662955 PMID:25866209

    Open questions at the time
    • Whether Ser16 phosphorylation by Aurora A vs. PKMζ occurs in distinct subcellular compartments
    • Genome-wide targets of PIN1-enhanced ERα binding
  10. 2016 High

    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

    PMID:26996940 PMID:26996941 PMID:28481868

    Open questions at the time
    • Whether revised tau model applies to all tauopathy-relevant phosphorylation patterns
    • Structural basis for site-selectivity differences on full-length tau
  11. 2017 High

    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

    PMID:28598431

    Open questions at the time
    • Off-target effects of the released quinone fragment
    • Whether PIN1 degradation or ROS generation is the primary anti-tumor mechanism
  12. 2019 Medium

    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

    PMID:30664786

    Open questions at the time
    • Direct biochemical mechanism of PIN1-mediated IRAK1 activation not defined
    • Whether PIN1 directly isomerizes IRAK1 or acts through an intermediate
  13. 2020 High

    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

    PMID:32083080 PMID:32218435 PMID:32483379 PMID:36755057

    Open questions at the time
    • 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
  14. 2021 High

    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

    PMID:33253791 PMID:33717117 PMID:33972797 PMID:34048060

    Open questions at the time
    • 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
  15. 2022 High

    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

    PMID:35927276

    Open questions at the time
    • Whether allosteric coupling strength differs for different phospho-substrates
    • How post-translational modifications of PIN1 affect interdomain dynamics
  16. 2023 High

    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

    PMID:36813923

    Open questions at the time
    • Whether PIN1-pVHL axis operates under normoxic conditions in non-tumor cells
    • Whether other E3 ligases besides WSB1 participate
  17. 2024 High

    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

    PMID:38167292

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016853 isomerase activity 6 GO:0098772 molecular function regulator activity 6
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1640170 Cell Cycle 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1643685 Disease 3 R-HSA-112316 Neuronal System 2
Partners
BRD4ENOSMETTL3PP2APVHLSMRTUBC9USP34

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 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. 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 Molecular cell High 11090625
2003 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. 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 Genes & development High 14600023
2007 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. Pin1 siRNA knockdown, immunodepletion from mitotic extracts, in vitro reconstitution with purified Pin1 and cdc2/cyclin B, in vitro kinase assay, Co-IP Molecular cell High 17466629
2007 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. 15N NMR relaxation dispersion, NOE measurements, substrate concentration-dependent conformational exchange analysis Journal of molecular biology High 17316687
2008 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. Co-IP in mammalian cells, in vitro pulldown, site-directed mutagenesis of phosphorylation sites, Cdk2 kinase assay, protein stability assay The Journal of cell biology High 18838553
2008 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. Pin1 KO mice, Pin1 knockdown (siRNA/shRNA), tau transgenic mouse models (WT and P301L), in vitro stability assay The Journal of clinical investigation High 18431510
2010 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. 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 Science signaling High 20215645
2011 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. Co-IP of Pin1 with eNOS, siRNA knockdown, pharmacological inhibition (juglone), Pin1 KO mice, eNOS phosphorylation measurement, NO production assay, vascular relaxation assay Hypertension High 21810655
2012 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. Co-IP, GST pulldown, site-directed mutagenesis (pRb Ser608/612), cell cycle analysis, Pin1 overexpression/KD Cell death and differentiation High 22322860
2013 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. In vitro dephosphorylation assay, Pin1 depletion (siRNA), FRAP (H1 chromatin binding stability), structural analysis of H1 CTD, Co-IP The Journal of cell biology High 24100296
2015 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. In vitro DNA binding assay with purified Pin1 and ERα, DNA binding microarray, stable Pin1 overexpression, isomerase-dead mutant controls The Journal of biological chemistry High 25866209
2015 Aurora A phosphorylates Pin1 at Ser16, suppressing Pin1 enzymatic activity, and cooperates with hBora to modulate G2/M transition. Kinase assay (Aurora A on Pin1 Ser16), site-directed mutagenesis, cell cycle analysis Experimental biology and medicine Medium 25662955
2016 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. Peptide binding assay, X-ray crystallography (co-crystal structure), Co-IP, ubiquitination assay, site-directed mutagenesis (T204A), gene expression analysis, tumor formation assay Oncogene High 28481868
2016 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. NMR (site-specific catalysis measurements), isothermal calorimetry (ITC), SAXS, CDK2/CycA phosphorylation of full-length tau, domain-deletion mutants of Pin1 Journal of molecular biology High 26996941
2016 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. Turbidity assay (MT polymerization), time-resolved SAXS, time-resolved negative stain EM, NMR Journal of molecular biology High 26996940
2017 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. Covalent binding assay (mechanism-based screening), Pin1 degradation assay, ROS measurement, DNA damage assay, in vitro and in vivo tumor models Nature communications High 28598431
2019 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. Compound screening in zebrafish, genetic epistasis (IRAK1 pathway), IRAK1 inhibitor/Pin1 inhibitor combination studies, tumor models Nature cell biology Medium 30664786
2020 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. Co-IP, knock-in mouse model (Kv4.2-T607A), electrophysiology, behavioral assays (Morris water maze, lever press) Nature communications High 32218435
2021 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. Covalent fragment screening targeting Cys113, chemoproteomics (two independent methods), cellular target engagement assay, in vivo zebrafish and murine tumor models, genetic KO comparison Nature chemical biology High 33972797
2021 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. 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 Hepatology High 34048060
2021 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. Pin1-/- mice, Co-IP (Pin1 with p-p38 MAPK), LPS-induced macrophage model, inflammasome component analysis Frontiers in immunology Medium 33717117
2022 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. NMR (MR-based protocol for intra/interdomain structural sampling), EPR (PELDOR), Pin1 domain dynamics in apo and ligand-bound states Nature communications High 35927276
2023 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. 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 Cell death and differentiation High 36813923
2024 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. 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 Nature communications High 38167292
2012 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. Co-IP, site-directed mutagenesis (AR Ser81), transcriptional reporter assay Cell cycle Medium 22894932
2014 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. Co-IP, GST pulldown, proteolysis (limited proteolysis to detect conformational change), HIF-1 transcriptional reporter assay, Pin1 inhibition/knockdown Cellular signalling Medium 24726894
2020 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. Co-IP (PIN1 with METTL3), ubiquitination assay, polysome profiling (TAZ and EGFR mRNA distribution), METTL3 KO, PIN1 KO, in vivo orthotopic tumor model Oncogene High 36755057
2020 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. Rational peptide inhibitor design targeting Cys113, selectivity profiling, genetic KO and chemical-genetic strategies in PDAC cell lines Nature chemical biology High 32483379
2016 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. Pin1 genetic ablation, Eμ-myc transgenic mice, ARF-p53 pathway analysis, Myc phosphorylation analysis, B cell proliferation assay Oncotarget Medium 26943576
2011 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. Co-IP, in vitro isomerization assay, site-directed mutagenesis, ERK2 kinase assay, luciferase reporter assay, ChIP, in vivo tumor assay Oncogene High 22002310
2020 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. Phos-tag gel electrophoresis, site-directed mutagenesis of HBc phospho-sites, GST pulldown, Co-IP, Pin1 inhibitor/KO, lysosome inhibitor assay, PDP2 dephosphorylation assay Frontiers in cell and developmental biology High 32083080
2021 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. Co-IP (PIN1 with STK3), ubiquitination assay, shRNA KD, nuclear fractionation (TAZ localization), reporter assay (CTGF), in vivo melanoma model Cancer letters Medium 33253791

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Pin1-dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau proteins. Molecular cell 474 11090625
2011 Prolyl isomerase Pin1 as a molecular switch to determine the fate of phosphoproteins. Trends in biochemical sciences 295 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
2017 A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action. Nature communications 127 28598431
2021 Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo. Nature chemical biology 112 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 78 25583562
2016 A detailed expression map of the PIN1 auxin transporter in Arabidopsis thaliana root. BMC plant biology 75 26821586
2010 Pin1 and PKMzeta sequentially control dendritic protein synthesis. Science signaling 68 20215645
2010 Pin1: a new genetic link between Alzheimer's disease, cancer and aging. Current aging science 68 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 61 32483379
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
2015 Landscape of Pin1 in the cell cycle. Experimental biology and medicine (Maywood, N.J.) 49 25662955
2002 Substrate-based design of reversible Pin1 inhibitors. Biochemistry 48 12269831
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 45 32258027
2019 An IRAK1-PIN1 signalling axis drives intrinsic tumour resistance to radiation therapy. Nature cell biology 45 30664786
2003 The peptidyl-prolyl isomerase Pin1. Progress in cell cycle research 44 14593743
2021 Cobalt induces neurodegenerative damages through Pin1 inactivation in mice and human neuroglioma cells. Journal of hazardous materials 43 34175703
2015 Investigating Dynamic Interdomain Allostery in Pin1. Biophysical reviews 42 26495045
2017 Prolyl isomerase PIN1 regulates the stability, transcriptional activity and oncogenic potential of BRD4. Oncogene 41 28481868
2016 PIN1 in breast development and cancer: a clinical perspective. Cell death and differentiation 40 27834957
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
2009 Novel role of Pin1 induction in type II collagen-mediated rheumatoid arthritis. Journal of immunology (Baltimore, Md. : 1950) 38 19846884
2006 Interaction of Pin1 with Nek6 and characterization of their expression correlation in Chinese hepatocellular carcinoma patients. Biochemical and biophysical research communications 37 16476580
2020 Activity-dependent isomerization of Kv4.2 by Pin1 regulates cognitive flexibility. Nature communications 36 32218435
2018 Structure and function of the human parvulins Pin1 and Par14/17. Biological chemistry 36 29040060
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
2024 Stabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells. Nature communications 33 38167292
2014 PIN1 inhibition suppresses osteoclast differentiation and inflammatory responses. Journal of dental research 33 25512367
2020 Prolyl Isomerase Pin1 in Human Cancer: Function, Mechanism, and Significance. Frontiers in cell and developmental biology 32 32296699
2019 Oncogenic Hijacking of the PIN1 Signaling Network. Frontiers in oncology 32 30873382
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
2021 Pin1 Promotes NLRP3 Inflammasome Activation by Phosphorylation of p38 MAPK Pathway in Septic Shock. Frontiers in immunology 31 33717117
2018 Gears-In-Motion: The Interplay of WW and PPIase Domains in Pin1. Frontiers in oncology 31 30460195
2020 Protein sumoylation with SUMO1 promoted by Pin1 in glioma stem cells augments glioblastoma malignancy. Neuro-oncology 30 32592588
2016 Pin1 is required for sustained B cell proliferation upon oncogenic activation of Myc. Oncotarget 30 26943576
2016 Inhibition of Pin1 alleviates myocardial fibrosis and dysfunction in STZ-induced diabetic mice. Biochemical and biophysical research communications 30 27634219
2014 Regulation of mitochondrial apoptosis by Pin1 in cancer and neurodegeneration. Mitochondrion 30 25132079
2009 Pin1 overexpression is associated with poor differentiation and survival in oral squamous cell carcinoma. Oncology reports 30 19288014
2006 Pin1 contributes to cervical tumorigenesis by regulating cyclin D1 expression. Oncology reports 30 16865248
2021 Targeting Pin1 for Modulation of Cell Motility and Cancer Therapy. Biomedicines 28 33807199
2013 Pin1 promotes histone H1 dephosphorylation and stabilizes its binding to chromatin. The Journal of cell biology 27 24100296
2019 Secreted parasite Pin1 isomerase stabilizes host PKM2 to reprogram host cell metabolism. Communications biology 25 31044177
2016 Molecular Mechanism of Pin1-Tau Recognition and Catalysis. Journal of molecular biology 25 26996941
2012 Androgen receptor serine 81 mediates Pin1 interaction and activity. Cell cycle (Georgetown, Tex.) 25 22894932
2010 Phosphorylation-specific peptidyl-prolyl isomerization of neuronal cytoskeletal proteins by Pin1: implications for therapeutics in neurodegeneration. Journal of Alzheimer's disease : JAD 25 20110589
2021 Roles of peptidyl-prolyl isomerase Pin1 in disease pathogenesis. Theranostics 24 33537091
2016 Regulation of Microtubule Assembly by Tau and not by Pin1. Journal of molecular biology 24 26996940
2019 Virtual screening identifies a PIN1 inhibitor with possible antiovarian cancer effects. Journal of cellular physiology 23 30697729
2017 The prolyl isomerase Pin1 increases β-cell proliferation and enhances insulin secretion. The Journal of biological chemistry 23 28566287
2016 Synthesis and Pin1 inhibitory activity of thiazole derivatives. Bioorganic & medicinal chemistry 22 27692510
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 Development of Pin1 Inhibitors and their Potential as Therapeutic Agents. Current medicinal chemistry 20 30394205
2016 Understanding the role of PIN1 in hepatocellular carcinoma. World journal of gastroenterology 20 28018099
2014 The prolyl isomerase Pin1 regulates hypoxia-inducible transcription factor (HIF) activity. Cellular signalling 20 24726894
2020 The Peptidyl-prolyl Isomerase Pin1 in Neuronal Signaling: from Neurodevelopment to Neurodegeneration. Molecular neurobiology 19 33083964
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
2023 The regulatory role of Pin1 in neuronal death. Neural regeneration research 18 35799512
2021 Phosphorylation and Stabilization of PIN1 by JNK Promote Intrahepatic Cholangiocarcinoma Growth. Hepatology (Baltimore, Md.) 18 34048060
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
2013 Dissecting Pin1 and phospho-pRb regulation. Journal of cellular physiology 18 22553088
2023 METTL3 stabilization by PIN1 promotes breast tumorigenesis via enhanced m6A-dependent translation. Oncogene 17 36755057
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
2015 Peptidylprolyl Isomerase Pin1 Directly Enhances the DNA Binding Functions of Estrogen Receptor α. The Journal of biological chemistry 17 25866209
2014 p53 negatively regulates Pin1 expression under ER stress. Biochemical and biophysical research communications 17 25451271
2012 Electrochemical investigations of Tau protein phosphorylations and interactions with Pin1. Chemistry & biodiversity 17 22976962
2020 PIN1 facilitates ubiquitin-mediated degradation of serine/threonine kinase 3 and promotes melanoma development via TAZ activation. Cancer letters 15 33253791
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
2022 Hyperglycemia induces gastric carcinoma proliferation and migration via the Pin1/BRD4 pathway. Cell death discovery 14 35461311
2022 Ligand-specific conformational change drives interdomain allostery in Pin1. Nature communications 14 35927276
2017 Down-regulation of Pin1 in Temporal Lobe Epilepsy Patients and Mouse Model. Neurochemical research 14 28239767
2014 Prolyl isomerase Pin1 regulates the osteogenic activity of Osterix. Molecular and cellular endocrinology 14 25463757
2024 Discovery of potent PROTAC degraders of Pin1 for the treatment of acute myeloid leukemia. Chemical science 13 38550694
2023 Small molecules targeting Pin1 as potent anticancer drugs. Frontiers in pharmacology 13 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
2019 Liraglutide Treatment Ameliorates Neurotoxicity Induced by Stable Silencing of Pin1. International journal of molecular sciences 13 31614723
2017 Dual Roles of Pin1 in Cancer Development and Progression. Current pharmaceutical design 13 28671058
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