{"gene":"PIN4","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2003,"finding":"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.","method":"In vitro PPIase activity assay; cell proliferation assays with chemical inhibitors","journal":"Chemistry & biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay performed but in a study primarily focused on Pin1; Par14 inhibition data are secondary and from a single lab","pmids":["12573694"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Subcellular fractionation, EGFP co-localization with mitochondrial stain, in vitro mitochondrial import assay, DNA-binding assay","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, fluorescence co-localization, import assay, DNA binding) in a single focused study","pmids":["17875217"],"is_preprint":false},{"year":2009,"finding":"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.","method":"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","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (MS, knockdown with functional readout, localization, fractionation) in a single focused study","pmids":["19369196"],"is_preprint":false},{"year":2013,"finding":"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.","method":"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)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping, KD and KO with defined signaling phenotype, and in vivo validation across multiple systems","pmids":["23720771"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Sub-nuclear biochemical fractionation; DNase I treatment; qRT-PCR and western blotting in synchronized human foreskin fibroblasts","journal":"BMC biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fractionation with functional perturbation (DNase I), cell-cycle synchronization with protein-level readout, single lab","pmids":["25645591"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (crosslinking-MS, NMR, fluorescence assay, KD phenotype), single lab","pmids":["32142471"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Native agarose gel electrophoresis (NAGE) immunoblotting; co-immunoprecipitation; site-directed mutagenesis of RP motif and substrate-binding residues; chromatin immunoprecipitation from HBV-infected cells","journal":"Frontiers in microbiology","confidence":"Low","confidence_rationale":"Tier 2 / Weak — multiple methods but paper subsequently retracted (PMID 41725806); findings downgraded accordingly","pmids":["34970249","41725806"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation; gene silencing (siRNA/shRNA); cell cycle analysis; RT-PCR and western blotting for p21, p53 localization, and androgen response genes","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct association, KD with defined molecular phenotypes (p21, p53 localization, AR target genes), single lab","pmids":["36583514"],"is_preprint":false},{"year":2023,"finding":"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.","method":"siRNA knockdown; Northern and Southern blotting; NAGE immunoblotting; chromatin immunoprecipitation (ChIP); pharmacological inhibition with parvulin inhibitors","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (KD, ChIP, blotting), single lab; note overlap with retracted companion paper reduces confidence","pmids":["36760500"],"is_preprint":false},{"year":2025,"finding":"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.","method":"PPIase activity assays; NMR spectroscopy; mass spectrometry","journal":"Proteins","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro activity assay plus NMR structural analysis and MS, multiple orthogonal methods, single lab","pmids":["40071814"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation; gene silencing (siRNA); cell cycle analysis; RT-PCR and western blotting for ERα phosphorylation (Ser167), SRC-3 interaction, and E2-induced genes","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct association, KD with defined phosphorylation and co-activator recruitment phenotype, single lab","pmids":["40796046"],"is_preprint":false}],"current_model":"PIN4 encodes the parvulin-type peptidyl-prolyl cis/trans isomerases Par14 and Par17 (the latter uniquely expressed in Hominidae with a mitochondria-targeting N-terminal extension); Par14 resides in the nucleus as a non-histone chromatin-associated DNA-binding protein where its unphosphorylated form participates in pre-rRNA processing within pre-rRNP complexes, enhances insulin signaling by isomerizing IRS-1, augments androgen receptor and estrogen receptor transcriptional activity via direct nuclear interaction and promotion of receptor phosphorylation, and is required for cell cycle progression; Par17 is additionally imported into the mitochondrial matrix and, through its N-terminal extension, binds β-actin via an allosteric mechanism and initiates PPIase-dependent actin polymerization, with Par17 knockdown impairing cell motility."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2003,"claim":"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","pmids":["12573694"],"confidence":"Medium","gaps":["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"]},{"year":2007,"claim":"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","pmids":["17875217"],"confidence":"High","gaps":["Mitochondrial matrix substrates of Par17 not identified","Functional consequence of DNA binding not yet established at this stage"]},{"year":2009,"claim":"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","pmids":["19369196"],"confidence":"High","gaps":["PPIase substrate within the pre-rRNP not identified","Kinase controlling the phospho-switch unknown","Mechanistic role at the spindle during mitosis not defined"]},{"year":2013,"claim":"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","pmids":["23720771"],"confidence":"High","gaps":["Whether IRS-1 prolyl isomerization is the direct catalytic event not shown","Proline target site on IRS-1 not mapped"]},{"year":2015,"claim":"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","pmids":["25645591"],"confidence":"Medium","gaps":["Genomic loci bound by Par14 not mapped","Single lab; sequence specificity of DNA binding not defined"]},{"year":2020,"claim":"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","pmids":["32142471"],"confidence":"Medium","gaps":["Proline residue on actin targeted for isomerization not identified","Single lab","In vivo relevance of Par17-driven polymerization not established"]},{"year":2022,"claim":"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","pmids":["36583514"],"confidence":"Medium","gaps":["Whether AR augmentation requires PPIase catalysis not resolved","Single lab; direct prolyl substrate on AR not defined"]},{"year":2025,"claim":"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","pmids":["40071814"],"confidence":"Medium","gaps":["Full set of Par17-selective substrates not enumerated","Single lab"]},{"year":2025,"claim":"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","pmids":["40796046"],"confidence":"Medium","gaps":["Kinase mediating Ser167 phosphorylation downstream of Par14 not identified","Whether the effect requires PPIase catalysis not shown","Single lab"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[0,5,9]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,7,10]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[2]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,10]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,7]}],"complexes":["pre-ribosomal ribonucleoprotein (pre-rRNP) complex"],"partners":["IRS-1","AR","ESR1","SRC-3","ACTB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y237","full_name":"Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4","aliases":["Parvulin-14","Par14","hPar14","Parvulin-17","Par17","hPar17","Peptidyl-prolyl cis-trans isomerase Pin4","PPIase Pin4","Peptidyl-prolyl cis/trans isomerase EPVH","hEPVH","Rotamase Pin4"],"length_aa":131,"mass_kda":13.8,"function":"Isoform 1 is involved as a ribosomal RNA processing factor in ribosome biogenesis. Binds to tightly bent AT-rich stretches of double-stranded DNA Isoform 2 binds to double-stranded DNA","subcellular_location":"Mitochondrion; Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/Q9Y237/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIN4","classification":"Not Classified","n_dependent_lines":78,"n_total_lines":1208,"dependency_fraction":0.06456953642384106},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000102309","cell_line_id":"CID000912","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleolus_gc","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"SEC22B","stoichiometry":0.2},{"gene":"MAP4K4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000912","total_profiled":1310},"omim":[{"mim_id":"606093","title":"PEPTIDYL-PROLYL ISOMERASE G; PPIG","url":"https://www.omim.org/entry/606093"},{"mim_id":"605303","title":"TRANSFORMING, ACIDIC, COILED-COIL-CONTAINING PROTEIN 3; TACC3","url":"https://www.omim.org/entry/605303"},{"mim_id":"300252","title":"PEPTIDYL-PROLYL CIS/TRANS ISOMERASE, NIMA-INTERACTING, 4; PIN4","url":"https://www.omim.org/entry/300252"},{"mim_id":"134934","title":"FIBROBLAST GROWTH FACTOR RECEPTOR 3; FGFR3","url":"https://www.omim.org/entry/134934"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"},{"location":"Mitotic chromosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PIN4"},"hgnc":{"alias_symbol":["PAR14","PAR17","EPVH"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y237","domains":[{"cath_id":"3.10.50.40","chopping":"36-129","consensus_level":"medium","plddt":88.9746,"start":36,"end":129}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y237","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y237-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y237-F1-predicted_aligned_error_v6.png","plddt_mean":78.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIN4","jax_strain_url":"https://www.jax.org/strain/search?query=PIN4"},"sequence":{"accession":"Q9Y237","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y237.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y237/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y237"}},"corpus_meta":[{"pmid":"12573694","id":"PMC_12573694","title":"Pin1 and Par14 peptidyl prolyl isomerase inhibitors block cell proliferation.","date":"2003","source":"Chemistry & biology","url":"https://pubmed.ncbi.nlm.nih.gov/12573694","citation_count":155,"is_preprint":false},{"pmid":"19369196","id":"PMC_19369196","title":"Parvulin (Par14), a peptidyl-prolyl cis-trans isomerase, is a novel rRNA processing factor that evolved in the metazoan lineage.","date":"2009","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/19369196","citation_count":38,"is_preprint":false},{"pmid":"29040060","id":"PMC_29040060","title":"Structure and function of the human parvulins Pin1 and Par14/17.","date":"2018","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29040060","citation_count":37,"is_preprint":false},{"pmid":"17875217","id":"PMC_17875217","title":"The DNA binding parvulin Par17 is targeted to the mitochondrial matrix by a recently evolved prepeptide uniquely present in Hominidae.","date":"2007","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/17875217","citation_count":30,"is_preprint":false},{"pmid":"19787094","id":"PMC_19787094","title":"Small family with key contacts: par14 and par17 parvulin proteins, relatives of pin1, now emerge in biomedical research.","date":"2008","source":"Perspectives in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19787094","citation_count":28,"is_preprint":false},{"pmid":"24921643","id":"PMC_24921643","title":"Immunohistochemical staining characteristics of nephrogenic adenoma using the PIN-4 cocktail (p63, AMACR, and CK903) and GATA-3.","date":"2014","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24921643","citation_count":24,"is_preprint":false},{"pmid":"36760500","id":"PMC_36760500","title":"PIN1 and PIN4 inhibition via parvulin impeders Juglone, PiB, ATRA, 6,7,4'-THIF, KPT6566, and EGCG thwarted hepatitis B virus replication.","date":"2023","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/36760500","citation_count":21,"is_preprint":false},{"pmid":"23720771","id":"PMC_23720771","title":"Par14 protein associates with insulin receptor substrate 1 (IRS-1), thereby enhancing insulin-induced IRS-1 phosphorylation and metabolic actions.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23720771","citation_count":20,"is_preprint":false},{"pmid":"34970249","id":"PMC_34970249","title":"The HBV Core Protein and Core Particle Both Bind to the PPiase Par14 and Par17 to Enhance Their Stabilities and HBV Replication.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34970249","citation_count":17,"is_preprint":false},{"pmid":"25645591","id":"PMC_25645591","title":"Human DNA-binding peptidyl-prolyl cis/trans isomerase Par14 is cell cycle dependently expressed and associates with chromatin in vivo.","date":"2015","source":"BMC 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androgen receptor, augmenting both its transcriptional activity and prostate cancer proliferation.","date":"2022","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36583514","citation_count":4,"is_preprint":false},{"pmid":"32958726","id":"PMC_32958726","title":"Deletion of PIN4 Suppresses the Protein Transport Defects Caused by sec12-4 Mutation in Saccharomyces cerevisiae.","date":"2020","source":"Microbial physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32958726","citation_count":2,"is_preprint":false},{"pmid":"39858641","id":"PMC_39858641","title":"Casein Kinase I Protein Hrr25 Is Required for Pin4 Phosphorylation and Mediates Cell Wall Integrity Signaling in Saccharomyces cerevisiae.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/39858641","citation_count":2,"is_preprint":false},{"pmid":"32142471","id":"PMC_32142471","title":"Targeting of parvulin interactors by diazirine mediated cross-linking discloses a cellular role of human Par14/17 in 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Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/40796046","citation_count":0,"is_preprint":false},{"pmid":"41725806","id":"PMC_41725806","title":"Retraction: The HBV core protein and core particle both bind to the PPiase Par14 and Par17 to enhance their stabilities and HBV replication.","date":"2026","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41725806","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.13.623376","title":"Pin4 Links Post-transcriptional and Transcriptional Responses to Energy Depletion in Yeast","date":"2024-11-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.13.623376","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11961,"output_tokens":3092,"usd":0.041132,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10570,"output_tokens":3832,"usd":0.074325,"stage2_stop_reason":"end_turn"},"total_usd":0.115457,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro PPIase activity assay; cell proliferation assays with chemical inhibitors\",\n      \"journal\": \"Chemistry & biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay performed but in a study primarily focused on Pin1; Par14 inhibition data are secondary and from a single lab\",\n      \"pmids\": [\"12573694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Subcellular fractionation, EGFP co-localization with mitochondrial stain, in vitro mitochondrial import assay, DNA-binding assay\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, fluorescence co-localization, import assay, DNA binding) in a single focused study\",\n      \"pmids\": [\"17875217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (MS, knockdown with functional readout, localization, fractionation) in a single focused study\",\n      \"pmids\": [\"19369196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"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)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mapping, KD and KO with defined signaling phenotype, and in vivo validation across multiple systems\",\n      \"pmids\": [\"23720771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Sub-nuclear biochemical fractionation; DNase I treatment; qRT-PCR and western blotting in synchronized human foreskin fibroblasts\",\n      \"journal\": \"BMC biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation with functional perturbation (DNase I), cell-cycle synchronization with protein-level readout, single lab\",\n      \"pmids\": [\"25645591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (crosslinking-MS, NMR, fluorescence assay, KD phenotype), single lab\",\n      \"pmids\": [\"32142471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Native agarose gel electrophoresis (NAGE) immunoblotting; co-immunoprecipitation; site-directed mutagenesis of RP motif and substrate-binding residues; chromatin immunoprecipitation from HBV-infected cells\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple methods but paper subsequently retracted (PMID 41725806); findings downgraded accordingly\",\n      \"pmids\": [\"34970249\", \"41725806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; gene silencing (siRNA/shRNA); cell cycle analysis; RT-PCR and western blotting for p21, p53 localization, and androgen response genes\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct association, KD with defined molecular phenotypes (p21, p53 localization, AR target genes), single lab\",\n      \"pmids\": [\"36583514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown; Northern and Southern blotting; NAGE immunoblotting; chromatin immunoprecipitation (ChIP); pharmacological inhibition with parvulin inhibitors\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (KD, ChIP, blotting), single lab; note overlap with retracted companion paper reduces confidence\",\n      \"pmids\": [\"36760500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"PPIase activity assays; NMR spectroscopy; mass spectrometry\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro activity assay plus NMR structural analysis and MS, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40071814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; gene silencing (siRNA); cell cycle analysis; RT-PCR and western blotting for ERα phosphorylation (Ser167), SRC-3 interaction, and E2-induced genes\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct association, KD with defined phosphorylation and co-activator recruitment phenotype, single lab\",\n      \"pmids\": [\"40796046\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PIN4 encodes the parvulin-type peptidyl-prolyl cis/trans isomerases Par14 and Par17 (the latter uniquely expressed in Hominidae with a mitochondria-targeting N-terminal extension); Par14 resides in the nucleus as a non-histone chromatin-associated DNA-binding protein where its unphosphorylated form participates in pre-rRNA processing within pre-rRNP complexes, enhances insulin signaling by isomerizing IRS-1, augments androgen receptor and estrogen receptor transcriptional activity via direct nuclear interaction and promotion of receptor phosphorylation, and is required for cell cycle progression; Par17 is additionally imported into the mitochondrial matrix and, through its N-terminal extension, binds β-actin via an allosteric mechanism and initiates PPIase-dependent actin polymerization, with Par17 knockdown impairing cell motility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0]. 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 [#4]. 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 [#2]. 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 [#7] and interacts with estrogen receptor \\u03b1 to drive Ser167 phosphorylation and SRC-3 coactivator recruitment, sustaining proliferation of ER\\u03b1-positive breast cancer cells [#10]. 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 [#3]. The Par17 isoform carries an N-terminal extension that targets it to the mitochondrial matrix in a membrane-potential-dependent manner [#1] and, through an intramolecular allosteric mechanism, confers distinct substrate selectivity by engaging \\u03b2-actin and initiating PPIase-dependent actin polymerization, such that Par17 knockdown impairs cell motility [#5, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro PPIase activity assay with small-molecule inhibitors and cell proliferation assays\",\n      \"pmids\": [\"12573694\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Inhibitor data secondary to a Pin1-focused study from a single lab\",\n        \"No cellular substrate identified for the catalytic activity\",\n        \"Does not distinguish Par14 from Par17 contributions\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Subcellular fractionation, EGFP co-localization, in vitro mitochondrial import assay, and DNA-binding assay\",\n      \"pmids\": [\"17875217\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Mitochondrial matrix substrates of Par17 not identified\",\n        \"Functional consequence of DNA binding not yet established at this stage\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"LC-MS/MS of Par14-associated complexes, knockdown with pre-rRNA processing readout, immunofluorescence localization, and phospho-form fractionation\",\n      \"pmids\": [\"19369196\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"PPIase substrate within the pre-rRNP not identified\",\n        \"Kinase controlling the phospho-switch unknown\",\n        \"Mechanistic role at the spindle during mitosis not defined\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Reciprocal Co-IP in HepG2 and mouse liver, deletion mapping, siRNA, and adenoviral overexpression in ob/ob mice\",\n      \"pmids\": [\"23720771\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Whether IRS-1 prolyl isomerization is the direct catalytic event not shown\",\n        \"Proline target site on IRS-1 not mapped\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Characterized Par14 biochemically as a non-histone chromatin-binding protein with cell-cycle-regulated expression, grounding its nuclear functions in direct chromatin association.\",\n      \"evidence\": \"Sub-nuclear fractionation, DNase I release, and cell-cycle synchronization with protein-level readout in human fibroblasts\",\n      \"pmids\": [\"25645591\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Genomic loci bound by Par14 not mapped\",\n        \"Single lab; sequence specificity of DNA binding not defined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified actin as a parvulin partner and assigned Par17 a cytoskeletal function, demonstrating PPIase-dependent initiation of actin polymerization and a motility requirement.\",\n      \"evidence\": \"Crosslinking mass spectrometry, NMR of Par17-actin binding, fluorescence actin polymerization assay, and Par17 knockdown motility assays in HCT116\",\n      \"pmids\": [\"32142471\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Proline residue on actin targeted for isomerization not identified\",\n        \"Single lab\",\n        \"In vivo relevance of Par17-driven polymerization not established\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, siRNA/shRNA silencing, cell cycle analysis, and expression readouts for p21, p53 localization, and AR target genes in LNCaP cells\",\n      \"pmids\": [\"36583514\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Whether AR augmentation requires PPIase catalysis not resolved\",\n        \"Single lab; direct prolyl substrate on AR not defined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"PPIase activity assays, NMR spectroscopy, and mass spectrometry\",\n      \"pmids\": [\"40071814\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Full set of Par17-selective substrates not enumerated\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the steroid-receptor cofactor role to estrogen signaling, showing Par14 drives ER\\u03b1 Ser167 phosphorylation and SRC-3 recruitment to sustain ER\\u03b1-positive breast cancer proliferation.\",\n      \"evidence\": \"Co-IP, siRNA silencing, cell cycle analysis, and readouts for ER\\u03b1 phosphorylation, SRC-3 interaction, and E2-induced genes\",\n      \"pmids\": [\"40796046\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Kinase mediating Ser167 phosphorylation downstream of Par14 not identified\",\n        \"Whether the effect requires PPIase catalysis not shown\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single PPIase coordinates its many roles \\u2014 rRNA processing, steroid receptor potentiation, insulin signaling, and isoform-specific actin/mitochondrial functions \\u2014 and which direct prolyl substrates underlie each remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Direct prolyl-isomerization substrates for most functions not identified\",\n        \"Regulatory phospho-switch kinase/phosphatase unknown\",\n        \"No structural model of substrate complexes for Par14\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [0, 5, 9]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 7, 10]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"complexes\": [\n      \"pre-ribosomal ribonucleoprotein (pre-rRNP) complex\"\n    ],\n    \"partners\": [\n      \"IRS-1\",\n      \"AR\",\n      \"ESR1\",\n      \"SRC-3\",\n      \"ACTB\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}