{"gene":"KLK3","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2006,"finding":"The G-158A SNP in the KLK3 proximal promoter (within the androgen response element I, AREI) functionally increases binding of AREI to the androgen receptor and increases transcriptional response to androgens; the A allele confers enhanced AR-mediated transcription of KLK3.","method":"Electrophoretic mobility shift assay (EMSA) for AR binding; transcriptional reporter assay for androgen response","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal functional assays (binding + transcription) in a single lab","pmids":["17151093"],"is_preprint":false},{"year":2002,"finding":"Unusual alternative splicing of KLK3 incorporating intronic sequences adjacent to exon 1 produces a novel protein (PSA-linked molecule, PSA-LM) that shares only the signal peptide with canonical PSA; PSA-LM is expressed in prostatic secretory epithelial cells and is androgen-regulated, like canonical KLK3.","method":"RT-PCR, cDNA cloning, sequence analysis, immunohistochemistry, androgen stimulation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular cloning and expression characterization in a single lab with multiple methods","pmids":["11834722"],"is_preprint":false},{"year":2008,"finding":"Synthetic cyclic peptides were developed that specifically stimulate the proteolytic activity of KLK3 (PSA) in vitro, establishing that KLK3 enzymatic activity can be modulated by exogenous peptide binding; a distinct set of peptides specifically inhibits KLK2 activity without cross-reactivity.","method":"In vitro peptide-binding and enzymatic activity assays; peptide cyclization and stability testing","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with defined peptide modulators, single lab","pmids":["18627344"],"is_preprint":false},{"year":2009,"finding":"Structure-activity relationship studies of the KLK3-stimulating peptide B-2 showed that the disulfide bridge between N- and C-terminal cysteines is required for activity; replacement with a γ-aminobutyric acid/aspartic acid cyclization mimic retained stimulatory activity at high concentrations and improved plasma stability and resistance to KLK3-mediated degradation.","method":"Peptide analogue synthesis, in vitro KLK3 enzymatic activity assay, plasma stability assay","journal":"Amino acids","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic and stability assays with mutagenesis-equivalent peptide analogues, single lab","pmids":["19967419"],"is_preprint":false},{"year":2012,"finding":"Molecular dynamics simulation of the KLK3 promoter -158G>A SNP showed that extra hydrophobic contacts caused by the methyl group on the mutated thymine (A allele) are the dominant factor stabilizing AR homodimer binding to the AREI element, changing the motion of recognition helix B from swaying to vibrating around an equilibrium position.","method":"Molecular dynamics simulation; intermolecular force analysis","journal":"Journal of biomolecular structure & dynamics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational simulation only, no experimental validation in this paper","pmids":["22877366"],"is_preprint":false},{"year":2012,"finding":"Comparative primate evolution analysis provided evidence that KLK3 has undergone adaptive evolution toward an expanded enzymatic spectrum with effect on hydrolysis of semen coagulum substrates; associations between mating system, semenogelins (SEMG1/2 repeat units), and functional KLK2/KLK3 copy number suggest coevolution between KLK3 and its substrates driven by sperm competition.","method":"Comparative genomics, dN/dS ratio analysis, phylogenetic reconstruction across 22 primate species","journal":"Genome biology and evolution","confidence":"Low","confidence_rationale":"Tier 4 / Weak — evolutionary/computational analysis, no direct biochemical validation","pmids":["23204305"],"is_preprint":false},{"year":2018,"finding":"MRGBP promotes androgen receptor (AR)-mediated transactivation of KLK3 by interacting with MRG15 and TIP60; MRGBP is recruited to H3K4me1/3-marked AR binding regions at the KLK3 locus, where it promotes TIP60 recruitment and acetylation of histone variant H2A.Z, increasing AR occupancy and KLK3 expression.","method":"Co-immunoprecipitation, ChIP assay, knockdown/overexpression with gene expression readout, histone modification analysis","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, and functional gene expression assays in single lab with multiple orthogonal methods","pmids":["30076933"],"is_preprint":false},{"year":2025,"finding":"Functional assays using recombinant primate KLK3 proteins showed that chimpanzee KLK3 has greater enzyme velocity and higher catalytic efficiency than human KLK3 and other ape orthologs; gorilla and gibbon possess a chimeric KLK2/KLK3 enzyme (from independent genomic deletions) with reduced efficiency; the reconstructed human-chimpanzee last common ancestor KLK3 has kinetics identical to modern humans.","method":"Recombinant protein production, in vitro enzymatic kinetics assay, ancestral sequence reconstruction","journal":"Evolution; international journal of organic evolution","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted recombinant proteins with direct enzymatic kinetics measurements across multiple species and ancestral reconstruction","pmids":["39878341"],"is_preprint":false},{"year":2025,"finding":"TRβ (thyroid hormone receptor beta) signaling drives AR target gene expression including KLK3/PSA; the TRβ-selective antagonist NH-3 downregulates AR and the AR target genes NKX3.1 and KLK3 in prostate cancer cells and reduces tumor size in xenograft models.","method":"In vitro cell proliferation assay, xenograft mouse model, gene expression analysis (KLK3 mRNA/protein levels)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo loss-of-function with KLK3 expression as specific readout, single lab preprint","pmids":[],"is_preprint":true}],"current_model":"KLK3 (PSA) is an androgen-regulated serine protease whose transcription is driven by AR binding to promoter androgen response elements (enhanced by the -158A allele and the MRGBP/MRG15/TIP60/H2A.Z epigenetic complex); its enzymatic activity can be stimulated by specific cyclic peptides binding to the protease domain; across primates, adaptive evolution has tuned its catalytic efficiency in correlation with sperm competition levels, and in humans it functions in semen coagulum liquefaction by hydrolyzing semenogelins."},"narrative":{"mechanistic_narrative":"KLK3 (PSA) is an androgen-regulated serine protease whose physiological role centers on semen coagulum liquefaction through hydrolysis of semenogelin substrates, a function shaped by adaptive evolution across primates [PMID:23204305, PMID:39878341]. Its transcription is driven by androgen receptor (AR) binding to androgen response elements in the proximal promoter; the G-158A SNP within AREI increases AR binding affinity and amplifies the androgen-induced transcriptional response, with the A allele conferring enhanced expression [PMID:17151093]. AR-mediated transactivation at the KLK3 locus is potentiated by the MRGBP–MRG15–TIP60 epigenetic complex, which is recruited to H3K4me1/3-marked AR binding regions where TIP60 acetylates histone variant H2A.Z, increasing AR occupancy and KLK3 expression [PMID:30076933]. KLK3 transcription is additionally driven downstream of TRβ signaling, alongside other AR target genes. At the protein level, the proteolytic activity of KLK3 is modulable by exogenous synthetic cyclic peptides that bind the protease domain and stimulate catalysis, with a disulfide bridge between terminal cysteines required for stimulatory activity [PMID:18627344, PMID:19967419]. Comparative enzymatic analysis of recombinant primate orthologs shows that catalytic efficiency has been tuned during evolution, with chimpanzee KLK3 exhibiting higher velocity and efficiency than human KLK3 [PMID:39878341]. An unusual alternatively spliced product, PSA-LM, sharing only the signal peptide with canonical PSA, is also expressed in prostatic secretory epithelium under androgen regulation [PMID:11834722].","teleology":[{"year":2002,"claim":"Establishing that the KLK3 locus produces more than the canonical protease, alternative splicing was shown to generate a distinct androgen-regulated protein, broadening the locus's output beyond PSA itself.","evidence":"RT-PCR, cDNA cloning, immunohistochemistry, and androgen stimulation in prostatic epithelial cells","pmids":["11834722"],"confidence":"Medium","gaps":["Function of the PSA-LM product is undefined","No enzymatic or interaction characterization of PSA-LM"]},{"year":2006,"claim":"To explain why a common promoter polymorphism affects PSA levels, the G-158A SNP within AREI was shown to functionally increase AR binding and androgen-driven transcription, mechanistically linking genotype to expression.","evidence":"EMSA for AR binding and reporter assay for androgen response","pmids":["17151093"],"confidence":"Medium","gaps":["Effect measured in reporter systems, not endogenous chromatin","Population-level consequences not addressed in this finding"]},{"year":2008,"claim":"Addressing whether KLK3 catalytic activity is pharmacologically tractable, synthetic cyclic peptides were shown to specifically stimulate KLK3 proteolysis in vitro, establishing exogenous modulation of the protease domain.","evidence":"In vitro peptide-binding and enzymatic activity assays with cyclized peptides","pmids":["18627344"],"confidence":"Medium","gaps":["Mechanism of stimulation at the structural level not resolved","In vivo relevance of peptide activation not tested"]},{"year":2009,"claim":"Refining the activating peptide chemistry, structure-activity work identified the disulfide bridge as required for stimulatory activity and produced a more stable cyclization mimic, clarifying the determinants of KLK3 activation.","evidence":"Peptide analogue synthesis, in vitro KLK3 enzymatic activity, and plasma stability assays","pmids":["19967419"],"confidence":"Medium","gaps":["No co-structure of peptide bound to KLK3","Therapeutic utility not demonstrated"]},{"year":2012,"claim":"Two complementary studies probed the SNP mechanism and evolutionary context: simulation rationalized how the A allele stabilizes AR homodimer binding, while comparative genomics implicated sperm-competition-driven coevolution of KLK3 with semenogelin substrates.","evidence":"Molecular dynamics simulation of the -158 AREI element; dN/dS and phylogenetic analysis across 22 primate species","pmids":["22877366","23204305"],"confidence":"Low","gaps":["Both findings are computational without experimental validation in these papers","Predicted catalytic-spectrum expansion not biochemically tested here"]},{"year":2018,"claim":"To define the chromatin machinery enabling AR transactivation, MRGBP was shown to bridge MRG15 and TIP60 at H3K4-methylated AR binding regions, driving H2A.Z acetylation and increased AR occupancy and KLK3 expression.","evidence":"Co-IP, ChIP, knockdown/overexpression, and histone modification analysis","pmids":["30076933"],"confidence":"Medium","gaps":["Generality of this complex across other AR targets not fully established","Direct causal link between H2A.Z acetylation and AR loading not isolated"]},{"year":2025,"claim":"Resolving whether evolutionary sequence change altered KLK3 enzymology, recombinant primate orthologs and ancestral reconstruction directly measured catalytic differences, showing chimpanzee KLK3 is more efficient than human and that chimeric KLK2/KLK3 enzymes arose independently in some apes.","evidence":"Recombinant protein production, in vitro enzymatic kinetics, and ancestral sequence reconstruction","pmids":["39878341"],"confidence":"High","gaps":["In vivo consequence of kinetic differences for reproductive fitness not directly demonstrated","Substrate specificity beyond bulk kinetics not fully mapped"]},{"year":2025,"claim":"Extending the transcriptional regulation of KLK3, TRβ signaling was shown to drive AR target gene expression including KLK3, with a TRβ antagonist downregulating AR and reducing tumor growth.","evidence":"In vitro proliferation, xenograft model, and KLK3 expression readout (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint not peer-reviewed","Direct vs AR-mediated effect on KLK3 promoter not dissected"]},{"year":null,"claim":"How KLK3 proteolytic activity is regulated in vivo and how the locus's alternative products contribute to prostate physiology and cancer remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No endogenous physiological activator/inhibitor of KLK3 protease defined","Function of PSA-LM unknown","Structural basis of peptide stimulation unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[5,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,7]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[5,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,6]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P03952","full_name":"Plasma kallikrein","aliases":["Fletcher factor","Kininogenin","Plasma prekallikrein","PKK"],"length_aa":638,"mass_kda":71.3,"function":"Participates in the surface-dependent activation of blood coagulation. Activates, in a reciprocal reaction, coagulation factor XII/F12 after binding to negatively charged surfaces. Releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P03952/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KLK3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KLK3","total_profiled":1310},"omim":[{"mim_id":"614510","title":"MICRO RNA 99B; MIR99B","url":"https://www.omim.org/entry/614510"},{"mim_id":"614509","title":"MICRO RNA 99A; MIR99A","url":"https://www.omim.org/entry/614509"},{"mim_id":"613186","title":"MICRO RNA 100; MIR100","url":"https://www.omim.org/entry/613186"},{"mim_id":"613184","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 68; TRIM68","url":"https://www.omim.org/entry/613184"},{"mim_id":"611959","title":"PROSTATE CANCER, HEREDITARY, 15; HPC15","url":"https://www.omim.org/entry/611959"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"prostate","ntpm":7518.2}],"url":"https://www.proteinatlas.org/search/KLK3"},"hgnc":{"alias_symbol":["PSA"],"prev_symbol":["APS"]},"alphafold":{"accession":"P03952","domains":[{"cath_id":"3.50.4.10","chopping":"26-108","consensus_level":"high","plddt":93.4858,"start":26,"end":108},{"cath_id":"3.50.4.10","chopping":"116-195","consensus_level":"high","plddt":95.449,"start":116,"end":195},{"cath_id":"3.50.4.10","chopping":"206-280","consensus_level":"medium","plddt":95.2908,"start":206,"end":280},{"cath_id":"3.50.4.10","chopping":"294-371","consensus_level":"medium","plddt":96.0522,"start":294,"end":371},{"cath_id":"2.40.10.10","chopping":"396-620","consensus_level":"medium","plddt":88.8388,"start":396,"end":620}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P03952","model_url":"https://alphafold.ebi.ac.uk/files/AF-P03952-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P03952-F1-predicted_aligned_error_v6.png","plddt_mean":87.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KLK3","jax_strain_url":"https://www.jax.org/strain/search?query=KLK3"},"sequence":{"accession":"P03952","fasta_url":"https://rest.uniprot.org/uniprotkb/P03952.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P03952/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P03952"}},"corpus_meta":[{"pmid":"21465221","id":"PMC_21465221","title":"Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript.","date":"2011","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21465221","citation_count":77,"is_preprint":false},{"pmid":"17151093","id":"PMC_17151093","title":"PSA/KLK3 AREI promoter polymorphism alters androgen receptor binding and is associated with prostate cancer susceptibility.","date":"2006","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/17151093","citation_count":55,"is_preprint":false},{"pmid":"11834722","id":"PMC_11834722","title":"Unusual alternative splicing within the human kallikrein genes KLK2 and KLK3 gives rise to novel prostate-specific proteins.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11834722","citation_count":50,"is_preprint":false},{"pmid":"21318478","id":"PMC_21318478","title":"Fine mapping the KLK3 locus on chromosome 19q13.33 associated with prostate cancer susceptibility and PSA levels.","date":"2011","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21318478","citation_count":45,"is_preprint":false},{"pmid":"21421545","id":"PMC_21421545","title":"Association of KLK3 (PSA) genetic variants with prostate cancer risk and PSA levels.","date":"2011","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/21421545","citation_count":36,"is_preprint":false},{"pmid":"25274378","id":"PMC_25274378","title":"The prostate cancer susceptibility variant rs2735839 near KLK3 gene is associated with aggressive prostate cancer and can stratify gleason score 7 patients.","date":"2014","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/25274378","citation_count":29,"is_preprint":false},{"pmid":"25043536","id":"PMC_25043536","title":"KLK3, PCA3, and TMPRSS2-ERG expression in the peripheral blood mononuclear cell fraction from castration-resistant prostate cancer patients and response to docetaxel treatment.","date":"2014","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/25043536","citation_count":28,"is_preprint":false},{"pmid":"28894123","id":"PMC_28894123","title":"Mutations in the prostate specific antigen (PSA/KLK3) correlate with male infertility.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28894123","citation_count":27,"is_preprint":false},{"pmid":"19823874","id":"PMC_19823874","title":"A comprehensive resequence analysis of the KLK15-KLK3-KLK2 locus on chromosome 19q13.33.","date":"2009","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19823874","citation_count":25,"is_preprint":false},{"pmid":"18627344","id":"PMC_18627344","title":"Development of peptides specifically modulating the activity of KLK2 and KLK3.","date":"2008","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18627344","citation_count":24,"is_preprint":false},{"pmid":"30076933","id":"PMC_30076933","title":"MRGBP promotes AR-mediated transactivation of KLK3 and TMPRSS2 via acetylation of histone H2A.Z in prostate cancer cells.","date":"2018","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/30076933","citation_count":23,"is_preprint":false},{"pmid":"24270797","id":"PMC_24270797","title":"Genetic variation in KLK2 and KLK3 is associated with concentrations of hK2 and PSA in serum and seminal plasma in young men.","date":"2013","source":"Clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24270797","citation_count":21,"is_preprint":false},{"pmid":"36327902","id":"PMC_36327902","title":"Accurate diagnosis of prostate cancer with CRISPR-based nucleic acid test strip by simultaneously identifying PCA3 and KLK3 genes.","date":"2022","source":"Biosensors & bioelectronics","url":"https://pubmed.ncbi.nlm.nih.gov/36327902","citation_count":16,"is_preprint":false},{"pmid":"23204305","id":"PMC_23204305","title":"Birth-and-death of KLK3 and KLK2 in primates: evolution driven by reproductive biology.","date":"2012","source":"Genome biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/23204305","citation_count":13,"is_preprint":false},{"pmid":"33927218","id":"PMC_33927218","title":"KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33927218","citation_count":11,"is_preprint":false},{"pmid":"32978525","id":"PMC_32978525","title":"KLK3 and TMPRSS2 for molecular lymph-node staging in prostate cancer patients undergoing radical prostatectomy.","date":"2020","source":"Prostate cancer and prostatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/32978525","citation_count":11,"is_preprint":false},{"pmid":"23169475","id":"PMC_23169475","title":"Very low PSA concentrations and deletions of the KLK3 gene.","date":"2012","source":"Clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23169475","citation_count":10,"is_preprint":false},{"pmid":"21787114","id":"PMC_21787114","title":"Kallikrein-related peptidase 3 (KLK3/PSA) single nucleotide polymorphisms and ovarian cancer survival.","date":"2011","source":"Twin research and human genetics : the official journal of the International Society for Twin Studies","url":"https://pubmed.ncbi.nlm.nih.gov/21787114","citation_count":9,"is_preprint":false},{"pmid":"32556890","id":"PMC_32556890","title":"Association of KLK3, VAMP8 and MDM4 Genetic Variants within microRNA Binding Sites with Prostate Cancer: Evidence from Serbian Population.","date":"2020","source":"Pathology oncology research : POR","url":"https://pubmed.ncbi.nlm.nih.gov/32556890","citation_count":8,"is_preprint":false},{"pmid":"22901566","id":"PMC_22901566","title":"Effectiveness of the combined evaluation of KLK3 genetics and free-to-total prostate specific antigen ratio for prostate cancer diagnosis.","date":"2012","source":"The Journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/22901566","citation_count":8,"is_preprint":false},{"pmid":"19967419","id":"PMC_19967419","title":"Mimetics of the disulfide bridge between the N- and C-terminal cysteines of the KLK3-stimulating peptide B-2.","date":"2009","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/19967419","citation_count":8,"is_preprint":false},{"pmid":"35818212","id":"PMC_35818212","title":"Correlation analysis between CD133, Klk3 and grhl2 expression and tumor characteristics in prostate cancer.","date":"2022","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/35818212","citation_count":6,"is_preprint":false},{"pmid":"35149774","id":"PMC_35149774","title":"KLK3 germline mutation I179T complements DNA repair genes for predicting prostate cancer progression.","date":"2022","source":"Prostate cancer and prostatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/35149774","citation_count":6,"is_preprint":false},{"pmid":"32869960","id":"PMC_32869960","title":"Association of gene polymorphisms of KLK3 and prostate cancer: A meta-analysis.","date":"2020","source":"Advances in clinical and experimental medicine : official organ Wroclaw Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/32869960","citation_count":6,"is_preprint":false},{"pmid":"28272245","id":"PMC_28272245","title":"Single-nucleotide polymorphism rs1058205 of KLK3 is associated with the risk of prostate cancer: A case-control study of Han Chinese men in Northeast China.","date":"2017","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28272245","citation_count":5,"is_preprint":false},{"pmid":"22877366","id":"PMC_22877366","title":"Exploring the mechanism of a regulatory SNP of KLK3 by molecular dynamics simulation.","date":"2012","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/22877366","citation_count":3,"is_preprint":false},{"pmid":"37592324","id":"PMC_37592324","title":"Association of Kallikrein Related Peptidase 3 (KLK3) gene with dermatophytosis in the UK biobank cohort.","date":"2023","source":"Mycoses","url":"https://pubmed.ncbi.nlm.nih.gov/37592324","citation_count":2,"is_preprint":false},{"pmid":"40932598","id":"PMC_40932598","title":"Identifying drug targets and evaluating KLK3-targeted inhibitors for prostate cancer using in-silico and in-vitro approaches.","date":"2025","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/40932598","citation_count":2,"is_preprint":false},{"pmid":"24084379","id":"PMC_24084379","title":"Lanthanide chelate complementation and hydrolysis enhanced luminescent chelate in real-time reverse transcription polymerase chain reaction assays for KLK3 transcripts.","date":"2013","source":"Analytical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24084379","citation_count":2,"is_preprint":false},{"pmid":"39878341","id":"PMC_39878341","title":"Comparative functional analyses of the prostate-specific KLK3 enzyme in primates reveal the impact of sexual selection.","date":"2025","source":"Evolution; international journal of organic evolution","url":"https://pubmed.ncbi.nlm.nih.gov/39878341","citation_count":1,"is_preprint":false},{"pmid":"27555663","id":"PMC_27555663","title":"Frequency of KLK3 gene deletions in the general population.","date":"2016","source":"Annals of clinical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27555663","citation_count":0,"is_preprint":false},{"pmid":"41843002","id":"PMC_41843002","title":"Enhanced nodal staging by molecular detection of KLK3, FOLH1, and PCA3 in prostate cancer.","date":"2026","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41843002","citation_count":0,"is_preprint":false},{"pmid":"42204244","id":"PMC_42204244","title":"Polygenic risk score with KLK3 SNP-SNP interaction pairs for predicting prostate cancer aggressiveness.","date":"2026","source":"Communications medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42204244","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.21.25334151","title":"Prostate cancer risk-stratification using proteomic estimation of KLK3 improves accuracy in screening applications: a population-based cohort study in the UK Biobank","date":"2025-08-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.21.25334151","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.01.25332841","title":"Multi-omics integration predicts 17 disease incidences in the UK Biobank","date":"2025-08-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.01.25332841","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.26.25330371","title":"Identification and Quantification of Autoantibodies against Prostate-Specific Antigens by Immunoaffinity-Mass Spectrometry","date":"2025-06-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.26.25330371","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.05.641137","title":"Thyroid Hormone Receptor Beta Signaling is a Targetable Driver of Prostate Cancer Growth","date":"2025-03-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.05.641137","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.17.24312688","title":"Causal associations between plasma proteins and prostate cancer: a Proteome-Wide Mendelian Randomization","date":"2024-09-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.17.24312688","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24288,"output_tokens":2116,"usd":0.052302,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9173,"output_tokens":2830,"usd":0.058307,"stage2_stop_reason":"end_turn"},"total_usd":0.110609,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"The G-158A SNP in the KLK3 proximal promoter (within the androgen response element I, AREI) functionally increases binding of AREI to the androgen receptor and increases transcriptional response to androgens; the A allele confers enhanced AR-mediated transcription of KLK3.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA) for AR binding; transcriptional reporter assay for androgen response\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal functional assays (binding + transcription) in a single lab\",\n      \"pmids\": [\"17151093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Unusual alternative splicing of KLK3 incorporating intronic sequences adjacent to exon 1 produces a novel protein (PSA-linked molecule, PSA-LM) that shares only the signal peptide with canonical PSA; PSA-LM is expressed in prostatic secretory epithelial cells and is androgen-regulated, like canonical KLK3.\",\n      \"method\": \"RT-PCR, cDNA cloning, sequence analysis, immunohistochemistry, androgen stimulation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular cloning and expression characterization in a single lab with multiple methods\",\n      \"pmids\": [\"11834722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Synthetic cyclic peptides were developed that specifically stimulate the proteolytic activity of KLK3 (PSA) in vitro, establishing that KLK3 enzymatic activity can be modulated by exogenous peptide binding; a distinct set of peptides specifically inhibits KLK2 activity without cross-reactivity.\",\n      \"method\": \"In vitro peptide-binding and enzymatic activity assays; peptide cyclization and stability testing\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with defined peptide modulators, single lab\",\n      \"pmids\": [\"18627344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Structure-activity relationship studies of the KLK3-stimulating peptide B-2 showed that the disulfide bridge between N- and C-terminal cysteines is required for activity; replacement with a γ-aminobutyric acid/aspartic acid cyclization mimic retained stimulatory activity at high concentrations and improved plasma stability and resistance to KLK3-mediated degradation.\",\n      \"method\": \"Peptide analogue synthesis, in vitro KLK3 enzymatic activity assay, plasma stability assay\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic and stability assays with mutagenesis-equivalent peptide analogues, single lab\",\n      \"pmids\": [\"19967419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Molecular dynamics simulation of the KLK3 promoter -158G>A SNP showed that extra hydrophobic contacts caused by the methyl group on the mutated thymine (A allele) are the dominant factor stabilizing AR homodimer binding to the AREI element, changing the motion of recognition helix B from swaying to vibrating around an equilibrium position.\",\n      \"method\": \"Molecular dynamics simulation; intermolecular force analysis\",\n      \"journal\": \"Journal of biomolecular structure & dynamics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational simulation only, no experimental validation in this paper\",\n      \"pmids\": [\"22877366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Comparative primate evolution analysis provided evidence that KLK3 has undergone adaptive evolution toward an expanded enzymatic spectrum with effect on hydrolysis of semen coagulum substrates; associations between mating system, semenogelins (SEMG1/2 repeat units), and functional KLK2/KLK3 copy number suggest coevolution between KLK3 and its substrates driven by sperm competition.\",\n      \"method\": \"Comparative genomics, dN/dS ratio analysis, phylogenetic reconstruction across 22 primate species\",\n      \"journal\": \"Genome biology and evolution\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — evolutionary/computational analysis, no direct biochemical validation\",\n      \"pmids\": [\"23204305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MRGBP promotes androgen receptor (AR)-mediated transactivation of KLK3 by interacting with MRG15 and TIP60; MRGBP is recruited to H3K4me1/3-marked AR binding regions at the KLK3 locus, where it promotes TIP60 recruitment and acetylation of histone variant H2A.Z, increasing AR occupancy and KLK3 expression.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay, knockdown/overexpression with gene expression readout, histone modification analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, and functional gene expression assays in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30076933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Functional assays using recombinant primate KLK3 proteins showed that chimpanzee KLK3 has greater enzyme velocity and higher catalytic efficiency than human KLK3 and other ape orthologs; gorilla and gibbon possess a chimeric KLK2/KLK3 enzyme (from independent genomic deletions) with reduced efficiency; the reconstructed human-chimpanzee last common ancestor KLK3 has kinetics identical to modern humans.\",\n      \"method\": \"Recombinant protein production, in vitro enzymatic kinetics assay, ancestral sequence reconstruction\",\n      \"journal\": \"Evolution; international journal of organic evolution\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted recombinant proteins with direct enzymatic kinetics measurements across multiple species and ancestral reconstruction\",\n      \"pmids\": [\"39878341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRβ (thyroid hormone receptor beta) signaling drives AR target gene expression including KLK3/PSA; the TRβ-selective antagonist NH-3 downregulates AR and the AR target genes NKX3.1 and KLK3 in prostate cancer cells and reduces tumor size in xenograft models.\",\n      \"method\": \"In vitro cell proliferation assay, xenograft mouse model, gene expression analysis (KLK3 mRNA/protein levels)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo loss-of-function with KLK3 expression as specific readout, single lab preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"KLK3 (PSA) is an androgen-regulated serine protease whose transcription is driven by AR binding to promoter androgen response elements (enhanced by the -158A allele and the MRGBP/MRG15/TIP60/H2A.Z epigenetic complex); its enzymatic activity can be stimulated by specific cyclic peptides binding to the protease domain; across primates, adaptive evolution has tuned its catalytic efficiency in correlation with sperm competition levels, and in humans it functions in semen coagulum liquefaction by hydrolyzing semenogelins.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KLK3 (PSA) is an androgen-regulated serine protease whose physiological role centers on semen coagulum liquefaction through hydrolysis of semenogelin substrates, a function shaped by adaptive evolution across primates [#5, #7]. Its transcription is driven by androgen receptor (AR) binding to androgen response elements in the proximal promoter; the G-158A SNP within AREI increases AR binding affinity and amplifies the androgen-induced transcriptional response, with the A allele conferring enhanced expression [#0]. AR-mediated transactivation at the KLK3 locus is potentiated by the MRGBP–MRG15–TIP60 epigenetic complex, which is recruited to H3K4me1/3-marked AR binding regions where TIP60 acetylates histone variant H2A.Z, increasing AR occupancy and KLK3 expression [#6]. KLK3 transcription is additionally driven downstream of TRβ signaling, alongside other AR target genes [#8]. At the protein level, the proteolytic activity of KLK3 is modulable by exogenous synthetic cyclic peptides that bind the protease domain and stimulate catalysis, with a disulfide bridge between terminal cysteines required for stimulatory activity [#2, #3]. Comparative enzymatic analysis of recombinant primate orthologs shows that catalytic efficiency has been tuned during evolution, with chimpanzee KLK3 exhibiting higher velocity and efficiency than human KLK3 [#7]. An unusual alternatively spliced product, PSA-LM, sharing only the signal peptide with canonical PSA, is also expressed in prostatic secretory epithelium under androgen regulation [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that the KLK3 locus produces more than the canonical protease, alternative splicing was shown to generate a distinct androgen-regulated protein, broadening the locus's output beyond PSA itself.\",\n      \"evidence\": \"RT-PCR, cDNA cloning, immunohistochemistry, and androgen stimulation in prostatic epithelial cells\",\n      \"pmids\": [\"11834722\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of the PSA-LM product is undefined\", \"No enzymatic or interaction characterization of PSA-LM\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"To explain why a common promoter polymorphism affects PSA levels, the G-158A SNP within AREI was shown to functionally increase AR binding and androgen-driven transcription, mechanistically linking genotype to expression.\",\n      \"evidence\": \"EMSA for AR binding and reporter assay for androgen response\",\n      \"pmids\": [\"17151093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect measured in reporter systems, not endogenous chromatin\", \"Population-level consequences not addressed in this finding\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Addressing whether KLK3 catalytic activity is pharmacologically tractable, synthetic cyclic peptides were shown to specifically stimulate KLK3 proteolysis in vitro, establishing exogenous modulation of the protease domain.\",\n      \"evidence\": \"In vitro peptide-binding and enzymatic activity assays with cyclized peptides\",\n      \"pmids\": [\"18627344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of stimulation at the structural level not resolved\", \"In vivo relevance of peptide activation not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Refining the activating peptide chemistry, structure-activity work identified the disulfide bridge as required for stimulatory activity and produced a more stable cyclization mimic, clarifying the determinants of KLK3 activation.\",\n      \"evidence\": \"Peptide analogue synthesis, in vitro KLK3 enzymatic activity, and plasma stability assays\",\n      \"pmids\": [\"19967419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No co-structure of peptide bound to KLK3\", \"Therapeutic utility not demonstrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Two complementary studies probed the SNP mechanism and evolutionary context: simulation rationalized how the A allele stabilizes AR homodimer binding, while comparative genomics implicated sperm-competition-driven coevolution of KLK3 with semenogelin substrates.\",\n      \"evidence\": \"Molecular dynamics simulation of the -158 AREI element; dN/dS and phylogenetic analysis across 22 primate species\",\n      \"pmids\": [\"22877366\", \"23204305\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Both findings are computational without experimental validation in these papers\", \"Predicted catalytic-spectrum expansion not biochemically tested here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"To define the chromatin machinery enabling AR transactivation, MRGBP was shown to bridge MRG15 and TIP60 at H3K4-methylated AR binding regions, driving H2A.Z acetylation and increased AR occupancy and KLK3 expression.\",\n      \"evidence\": \"Co-IP, ChIP, knockdown/overexpression, and histone modification analysis\",\n      \"pmids\": [\"30076933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of this complex across other AR targets not fully established\", \"Direct causal link between H2A.Z acetylation and AR loading not isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolving whether evolutionary sequence change altered KLK3 enzymology, recombinant primate orthologs and ancestral reconstruction directly measured catalytic differences, showing chimpanzee KLK3 is more efficient than human and that chimeric KLK2/KLK3 enzymes arose independently in some apes.\",\n      \"evidence\": \"Recombinant protein production, in vitro enzymatic kinetics, and ancestral sequence reconstruction\",\n      \"pmids\": [\"39878341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequence of kinetic differences for reproductive fitness not directly demonstrated\", \"Substrate specificity beyond bulk kinetics not fully mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extending the transcriptional regulation of KLK3, TRβ signaling was shown to drive AR target gene expression including KLK3, with a TRβ antagonist downregulating AR and reducing tumor growth.\",\n      \"evidence\": \"In vitro proliferation, xenograft model, and KLK3 expression readout (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not peer-reviewed\", \"Direct vs AR-mediated effect on KLK3 promoter not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KLK3 proteolytic activity is regulated in vivo and how the locus's alternative products contribute to prostate physiology and cancer remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No endogenous physiological activator/inhibitor of KLK3 protease defined\", \"Function of PSA-LM unknown\", \"Structural basis of peptide stimulation unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}