Affinage

PIN4

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 · UniProt Q9Y237

Length
131 aa
Mass
13.8 kDa
Annotated
2026-06-10
20 papers in source corpus 12 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIN4 encodes parvulin-type peptidyl-prolyl cis/trans isomerases (Par14 and the Hominidae-specific longer isoform Par17) whose PPIase activity supports cell proliferation, with chemical inhibition of this activity blocking cancer cell growth (PMID:12573694). Par14 is a non-histone chromatin-associated DNA-binding protein, associating with chromatin in vivo and released by DNase I treatment, and its expression rises during S and G2/M phases (PMID:25645591). In the nucleolus it associates with pre-ribosomal ribonucleoprotein complexes and is required for processing of pre-rRNA into mature 18S and 28S rRNAs, with only its unphosphorylated form engaging pre-40S and pre-60S complexes (PMID:19369196). Beyond ribosome biogenesis, Par14 acts as a phosphorylation-promoting cofactor for nuclear steroid receptors: it binds the androgen receptor via its DNA-binding domain to augment AR transcriptional activity (PMID:36583514) and interacts with estrogen receptor α to drive Ser167 phosphorylation and SRC-3 coactivator recruitment, sustaining proliferation of ERα-positive breast cancer cells (PMID:40796046). In the cytoplasm it potentiates insulin signaling by directly associating with IRS-1 through its N-terminal basic domain, enhancing IRS-1 phosphorylation, PI3K recruitment, and Akt activation, an effect confirmed in vivo where Par14 overexpression improved hyperglycemia in ob/ob mice (PMID:23720771). The Par17 isoform carries an N-terminal extension that targets it to the mitochondrial matrix in a membrane-potential-dependent manner (PMID:17875217) and, through an intramolecular allosteric mechanism, confers distinct substrate selectivity by engaging β-actin and initiating PPIase-dependent actin polymerization, such that Par17 knockdown impairs cell motility (PMID:32142471, PMID:40071814).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2003 Medium

    Established that the PIN4 product Par14 is a catalytically active PPIase whose enzymatic activity is functionally linked to cancer cell proliferation, providing the first druggable handle on the protein.

    Evidence In vitro PPIase activity assay with small-molecule inhibitors and cell proliferation assays

    PMID:12573694

    Open questions at the time
    • Inhibitor data secondary to a Pin1-focused study from a single lab
    • No cellular substrate identified for the catalytic activity
    • Does not distinguish Par14 from Par17 contributions
  2. 2007 High

    Resolved that PIN4 encodes two functionally divergent isoforms by showing the Hominidae-specific Par17 is imported into the mitochondrial matrix while Par14 is not, defining isoform-specific subcellular partitioning.

    Evidence Subcellular fractionation, EGFP co-localization, in vitro mitochondrial import assay, and DNA-binding assay

    PMID:17875217

    Open questions at the time
    • Mitochondrial matrix substrates of Par17 not identified
    • Functional consequence of DNA binding not yet established at this stage
  3. 2009 High

    Defined a nucleolar role for Par14 in ribosome biogenesis, showing it is required for pre-rRNA processing and that phosphorylation gates its association with pre-ribosomal complexes.

    Evidence LC-MS/MS of Par14-associated complexes, knockdown with pre-rRNA processing readout, immunofluorescence localization, and phospho-form fractionation

    PMID:19369196

    Open questions at the time
    • PPIase substrate within the pre-rRNP not identified
    • Kinase controlling the phospho-switch unknown
    • Mechanistic role at the spindle during mitosis not defined
  4. 2013 High

    Showed Par14 is a positive cofactor of insulin signaling, directly binding IRS-1 through a non-WW N-terminal basic domain and enhancing downstream PI3K/Akt activation, extending its role beyond the nucleus into metabolic signaling.

    Evidence Reciprocal Co-IP in HepG2 and mouse liver, deletion mapping, siRNA, and adenoviral overexpression in ob/ob mice

    PMID:23720771

    Open questions at the time
    • Whether IRS-1 prolyl isomerization is the direct catalytic event not shown
    • Proline target site on IRS-1 not mapped
  5. 2015 Medium

    Characterized Par14 biochemically as a non-histone chromatin-binding protein with cell-cycle-regulated expression, grounding its nuclear functions in direct chromatin association.

    Evidence Sub-nuclear fractionation, DNase I release, and cell-cycle synchronization with protein-level readout in human fibroblasts

    PMID:25645591

    Open questions at the time
    • Genomic loci bound by Par14 not mapped
    • Single lab; sequence specificity of DNA binding not defined
  6. 2020 Medium

    Identified actin as a parvulin partner and assigned Par17 a cytoskeletal function, demonstrating PPIase-dependent initiation of actin polymerization and a motility requirement.

    Evidence Crosslinking mass spectrometry, NMR of Par17-actin binding, fluorescence actin polymerization assay, and Par17 knockdown motility assays in HCT116

    PMID:32142471

    Open questions at the time
    • Proline residue on actin targeted for isomerization not identified
    • Single lab
    • In vivo relevance of Par17-driven polymerization not established
  7. 2022 Medium

    Demonstrated Par14 augments androgen receptor transcriptional activity through direct binding to the AR DNA-binding domain and is required for cell cycle progression via p21 and p53 control.

    Evidence Co-IP, siRNA/shRNA silencing, cell cycle analysis, and expression readouts for p21, p53 localization, and AR target genes in LNCaP cells

    PMID:36583514

    Open questions at the time
    • Whether AR augmentation requires PPIase catalysis not resolved
    • Single lab; direct prolyl substrate on AR not defined
  8. 2025 Medium

    Provided a structural rationale for isoform-specific substrate selectivity, showing the Par17 N-terminal extension allosterically engages the PPIase domain and carries an actin-binding motif distinguishing it from Par14.

    Evidence PPIase activity assays, NMR spectroscopy, and mass spectrometry

    PMID:40071814

    Open questions at the time
    • Full set of Par17-selective substrates not enumerated
    • Single lab
  9. 2025 Medium

    Extended the steroid-receptor cofactor role to estrogen signaling, showing Par14 drives ERα Ser167 phosphorylation and SRC-3 recruitment to sustain ERα-positive breast cancer proliferation.

    Evidence Co-IP, siRNA silencing, cell cycle analysis, and readouts for ERα phosphorylation, SRC-3 interaction, and E2-induced genes

    PMID:40796046

    Open questions at the time
    • Kinase mediating Ser167 phosphorylation downstream of Par14 not identified
    • Whether the effect requires PPIase catalysis not shown
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single PPIase coordinates its many roles — rRNA processing, steroid receptor potentiation, insulin signaling, and isoform-specific actin/mitochondrial functions — and which direct prolyl substrates underlie each remain unresolved.
  • Direct prolyl-isomerization substrates for most functions not identified
  • Regulatory phospho-switch kinase/phosphatase unknown
  • No structural model of substrate complexes for Par14

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016853 isomerase activity 3 GO:0098772 molecular function regulator activity 3 GO:0003677 DNA binding 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005634 nucleus 2 GO:0000228 nuclear chromosome 1 GO:0005730 nucleolus 1 GO:0005739 mitochondrion 1
Pathway
R-HSA-1640170 Cell Cycle 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-162582 Signal Transduction 1 R-HSA-8953854 Metabolism of RNA 1
Partners
ACTBARESR1IRS-1SRC-3
Complex memberships
pre-ribosomal ribonucleoprotein (pre-rRNP) complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Par14 (PIN4) possesses peptidyl-prolyl cis-trans isomerase (PPIase) activity that can be inhibited in vitro by small molecules (e.g., PiB), and inhibition of this PPIase activity blocks cancer cell proliferation. In vitro PPIase activity assay; cell proliferation assays with chemical inhibitors Chemistry & biology Medium 12573694
2007 Par17, the longer isoform encoded by PIN4 with an N-terminal extension unique to Hominidae, is targeted to the mitochondrial matrix in a membrane-potential-dependent manner, while Par14 is not mitochondrially targeted. Par17 also binds double-stranded DNA under physiological salt conditions. Subcellular fractionation, EGFP co-localization with mitochondrial stain, in vitro mitochondrial import assay, DNA-binding assay BMC biology High 17875217
2009 Par14 (PIN4) associates with pre-ribosomal ribonucleoprotein (pre-rRNP) complexes and is required for processing of pre-rRNA into mature 18S and 28S rRNAs; only the unphosphorylated form of Par14 associates with pre-40S and pre-60S ribosomal complexes. Par14 co-localizes with nucleolar protein B23 during interphase and with the spindle apparatus during mitosis, and is excluded from the nucleolus upon actinomycin D treatment. LC-MS/MS proteomics of Par14-associated complexes; Par14 knockdown followed by pre-rRNA processing analysis; subcellular co-localization by immunofluorescence; biochemical fractionation distinguishing phosphorylated vs. unphosphorylated forms Molecular & cellular proteomics High 19369196
2013 Par14 directly associates with insulin receptor substrate 1 (IRS-1) via its N-terminal basic domain (distinct from Pin1's WW domain interaction), and this interaction enhances insulin-induced IRS-1 phosphorylation, PI3K binding to IRS-1, and Akt phosphorylation. Overexpression of Par14 in ob/ob mouse liver improved hyperglycemia; Par14 siRNA suppressed insulin signaling. Co-immunoprecipitation in HepG2 cells (overexpressed and endogenous in mouse liver); deletion-mutant mapping; Par14 siRNA knockdown; adenoviral overexpression in ob/ob mice; downstream signaling readouts (IRS-1 phosphorylation, PI3K binding, Akt phosphorylation) The Journal of biological chemistry High 23720771
2015 Par14 is associated with chromatin in vivo (3-fold more than with the nuclear matrix), released by DNase I treatment, and elutes at high NaCl from nucleic acid-binding fractions, establishing it as a non-histone chromatin-binding protein. Par14 expression is upregulated during S and G2/M phases of the cell cycle. Sub-nuclear biochemical fractionation; DNase I treatment; qRT-PCR and western blotting in synchronized human foreskin fibroblasts BMC biochemistry Medium 25645591
2020 Par14 and Par17 interact with actin: Par17 binds β-actin via its N-terminal region (shown by NMR), and both parvulins initiate actin polymerization in a PPIase-activity-dependent manner. Knockdown of Par17 in HCT116 cells causes defects in cell motility and migration. Par14 is involved in RNP biogenesis, RNA processing, and DNA repair; Par17 participates in protein transport/translocation and cytoskeleton organization. Photo-affinity labeling and cross-linking mass spectrometry (diazirine-mediated) from HeLa lysates; NMR spectroscopy for Par17-actin binding; fluorescence spectroscopy actin polymerization assay; Par17 knockdown with cell motility/migration assay Biological chemistry Medium 32142471
2021 Par14 and Par17 (encoded by PIN4) bind to HBV core protein (HBc) and core particles via interaction with the conserved 133RP134 motif of HBc, utilizing their substrate-binding residues E46/D74 (Par14) and E71/D99 (Par17). These interactions enhance the stabilities of HBc and core particles. Par14/Par17 are recruited to cccDNA via their DNA-binding residues (S19/Par14, S44/Par17) and facilitate HBc recruitment to cccDNA, promoting HBV transcription. Native agarose gel electrophoresis (NAGE) immunoblotting; co-immunoprecipitation; site-directed mutagenesis of RP motif and substrate-binding residues; chromatin immunoprecipitation from HBV-infected cells Frontiers in microbiology Low 34970249 41725806
2022 Par14 directly associates with the androgen receptor (AR) in the nucleus via AR's DNA-binding domain and augments AR transcriptional activity. Par14 silencing causes cell cycle arrest, induces p21 at mRNA and protein levels, and modulates p53 localization in LNCaP cells. Co-immunoprecipitation; gene silencing (siRNA/shRNA); cell cycle analysis; RT-PCR and western blotting for p21, p53 localization, and androgen response genes Cancer medicine Medium 36583514
2023 PIN4 knockdown (Par14/Par17) reduces HBV core protein (HBc) and core particle stability, lowers HBV pgRNA, subgenomic RNA, HBV DNA synthesis, and abrogates extracellular virion release. Chromatin immunoprecipitation shows Par14 (but not Pin1) binds cccDNA, and Par14 KD abrogates HBc recruitment to cccDNA, restricting HBV transcriptional activity. siRNA knockdown; Northern and Southern blotting; NAGE immunoblotting; chromatin immunoprecipitation (ChIP); pharmacological inhibition with parvulin inhibitors Frontiers in microbiology Medium 36760500
2025 Par17's 25-residue N-terminal extension determines substrate selectivity through an intramolecular allosteric mechanism: the N-terminal extension interacts with the PPIase domain and contains a target-binding motif that engages actin, thereby differentiating Par17's substrate specificity from Par14. PPIase activity assays; NMR spectroscopy; mass spectrometry Proteins Medium 40071814
2025 Par14 (Pin4) interacts with estrogen receptor α (ERα), promotes phosphorylation of ERα at Ser167, and thereby enhances recruitment of steroid receptor coactivator-3 (SRC-3) to ERα to augment its transcriptional activity. Pin4 knockdown impairs E2-induced gene expression (including E2F1), induces cell cycle arrest, and reduces proliferation of ERα-positive breast cancer cells. Co-immunoprecipitation; gene silencing (siRNA); cell cycle analysis; RT-PCR and western blotting for ERα phosphorylation (Ser167), SRC-3 interaction, and E2-induced genes Biochimica et biophysica acta. Molecular cell research Medium 40796046

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Pin1 and Par14 peptidyl prolyl isomerase inhibitors block cell proliferation. Chemistry & biology 155 12573694
2009 Parvulin (Par14), a peptidyl-prolyl cis-trans isomerase, is a novel rRNA processing factor that evolved in the metazoan lineage. Molecular & cellular proteomics : MCP 38 19369196
2018 Structure and function of the human parvulins Pin1 and Par14/17. Biological chemistry 37 29040060
2007 The DNA binding parvulin Par17 is targeted to the mitochondrial matrix by a recently evolved prepeptide uniquely present in Hominidae. BMC biology 30 17875217
2008 Small family with key contacts: par14 and par17 parvulin proteins, relatives of pin1, now emerge in biomedical research. Perspectives in medicinal chemistry 28 19787094
2014 Immunohistochemical staining characteristics of nephrogenic adenoma using the PIN-4 cocktail (p63, AMACR, and CK903) and GATA-3. The American journal of surgical pathology 24 24921643
2023 PIN1 and PIN4 inhibition via parvulin impeders Juglone, PiB, ATRA, 6,7,4'-THIF, KPT6566, and EGCG thwarted hepatitis B virus replication. Frontiers in microbiology 21 36760500
2013 Par14 protein associates with insulin receptor substrate 1 (IRS-1), thereby enhancing insulin-induced IRS-1 phosphorylation and metabolic actions. The Journal of biological chemistry 20 23720771
2021 The HBV Core Protein and Core Particle Both Bind to the PPiase Par14 and Par17 to Enhance Their Stabilities and HBV Replication. Frontiers in microbiology 17 34970249
2015 Human DNA-binding peptidyl-prolyl cis/trans isomerase Par14 is cell cycle dependently expressed and associates with chromatin in vivo. BMC biochemistry 12 25645591
2024 The tomato WRKY-B transcription factor modulates lateral branching by targeting BLIND, PIN4, and IAA15. Horticulture research 10 39257542
2020 Endosidin 2 accelerates PIN2 endocytosis and disturbs intracellular trafficking of PIN2, PIN3, and PIN4 but not of SYT1. PloS one 10 32790800
2023 PPIases Par14/Par17 Affect HBV Replication in Multiple Ways. Viruses 4 36851672
2022 Par14 interacts with the androgen receptor, augmenting both its transcriptional activity and prostate cancer proliferation. Cancer medicine 4 36583514
2025 Casein Kinase I Protein Hrr25 Is Required for Pin4 Phosphorylation and Mediates Cell Wall Integrity Signaling in Saccharomyces cerevisiae. Genes 2 39858641
2020 Targeting of parvulin interactors by diazirine mediated cross-linking discloses a cellular role of human Par14/17 in actin polymerization. Biological chemistry 2 32142471
2020 Deletion of PIN4 Suppresses the Protein Transport Defects Caused by sec12-4 Mutation in Saccharomyces cerevisiae. Microbial physiology 2 32958726
2025 The Actin-Binding Prolyl-Isomerase Par17 Sustains Its Substrate Selectivity by Interdomain Allostery. Proteins 1 40071814
2026 Retraction: The HBV core protein and core particle both bind to the PPiase Par14 and Par17 to enhance their stabilities and HBV replication. Frontiers in microbiology 0 41725806
2025 Prolyl isomerase Pin4 impacts estrogen receptor transactivation by enhancing phosphorylation and consequently promotes the proliferation of breast cancer cells. Biochimica et biophysica acta. Molecular cell research 0 40796046

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