{"gene":"KLK14","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2007,"finding":"LEKTI fragments (generated by furin cleavage of the LEKTI precursor) specifically inhibit KLK14 (as well as KLK5 and KLK7) in a pH-dependent manner; the inhibitory complex dissociates at acidic pH, releasing active protease. This mechanism controls desquamation through the epidermal pH gradient.","method":"Biochemical inhibition assays with recombinant LEKTI fragments tested against a panel of serine proteases; kinetics analysis of binding complex; pH-dependent release experiments","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with kinetics analysis, multiple orthogonal methods (inhibition assays + kinetics + pH titration), replicated across multiple LEKTI fragments","pmids":["17596512"],"is_preprint":false},{"year":2001,"finding":"KLK14 encodes a secreted serine protease of ~251 amino acids (~31 kDa) with predicted trypsin-like substrate specificity, translated in vitro from a seven-exon gene on chromosome 19q13.4.","method":"In vitro translation; Northern blot; in situ hybridization; genomic structure analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro translation confirming protein product and size; structural characterization by multiple methods in a single study","pmids":["11352573"],"is_preprint":false},{"year":2008,"finding":"KLK14 plays a major role in seminal clot liquefaction by: (1) directly cleaving semenogelins I and II; (2) activating KLK3 (PSA) and other KLKs in a proteolytic cascade; (3) inactivating KLK3 via internal cleavage at higher concentrations; and (4) being regulated by Zn2+ inhibition, which is reversed by semenogelins themselves.","method":"Ex vivo semen liquefaction assay; specific synthetic inhibitor (ACT(G9)) of KLK14; addition of recombinant active KLK14; measurement of chymotrypsin-like and KLK1 activity; Western blot for semenogelin cleavage; comparison of KLK14-expressing vs. delayed-liquefaction individuals","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (inhibitor, recombinant enzyme addition, direct substrate cleavage, activity assays), ex vivo system with functional readouts","pmids":["18482984"],"is_preprint":false},{"year":2012,"finding":"KLK14 activates proteinase-activated receptor 2 (PAR2) by cleaving and unmasking its receptor-activating sequence, triggering calcium transients, MAPK activation, β-arrestin interactions, and receptor internalization. KLK14 signals via both human and rat PAR2, while the related KLK8 cannot signal via human PAR2 (disarming PAR1 instead), demonstrating differential PAR signalling between KLK family members.","method":"Calcium transient assays; MAPK activation assays; β-arrestin interaction assays; receptor internalization assays in HEK and KNRK cells expressing human or rat PAR2; cleavage of synthetic PAR2-derived peptides","journal":"Biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal functional assays (calcium, MAPK, β-arrestin, internalization, peptide cleavage) in a single study with direct comparison to KLK8","pmids":["22505524"],"is_preprint":false},{"year":2025,"finding":"KLK14 mediates a pro-tumorigenic effect downstream of KLK5 and KLK7 by activating PAR-2-dependent RhoA and NF-κB signaling pathways in cervical carcinogenesis; genetic ablation of KLK5 and KLK7 ameliorates HPV-dependent phenotype via modulation of KLK14 activation.","method":"Genetically engineered mice (double KLK5/KLK7 knockout); bulk RNA-seq; reporter assays for NF-κB; analysis of human biopsies","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in mouse model plus reporter assays and transcriptomic analysis; single lab, multiple methods","pmids":["40753921"],"is_preprint":false}],"current_model":"KLK14 is a secreted trypsin-like serine protease that cleaves semenogelins and activates downstream kallikreins (including KLK3) during semen liquefaction, signals through PAR2 via cleavage-dependent unmasking to trigger RhoA/NF-κB and MAPK pathways, and is regulated in skin by pH-dependent inhibition via LEKTI fragments to control desquamation."},"narrative":{"mechanistic_narrative":"KLK14 is a secreted trypsin-like serine protease that operates in proteolytic cascades governing seminal clot liquefaction, epidermal desquamation, and PAR2-mediated signaling [PMID:11352573, PMID:18482984, PMID:22505524]. In semen, it drives liquefaction by directly cleaving semenogelins I and II and by activating KLK3 (PSA) and other kallikreins in a cascade, while also self-limiting through internal cleavage that inactivates KLK3 at higher concentrations and through Zn2+-mediated inhibition that semenogelins themselves relieve [PMID:18482984]. KLK14 acts as a biased agonist of proteinase-activated receptor 2 (PAR2), cleaving and unmasking its tethered activating sequence to trigger calcium transients, MAPK activation, β-arrestin recruitment, and receptor internalization—an activity that distinguishes it from KLK8, which cannot signal through human PAR2 [PMID:22505524]. This PAR2 axis is co-opted in cervical carcinogenesis, where KLK14 acts downstream of KLK5 and KLK7 to drive RhoA and NF-κB signaling, such that ablation of KLK5/KLK7 attenuates the HPV-dependent phenotype by limiting KLK14 activation [PMID:40753921]. In skin, KLK14 activity is restrained by LEKTI fragments through pH-dependent inhibition: the inhibitory complex dissociates at acidic pH to release active protease, coupling the epidermal pH gradient to controlled desquamation [PMID:17596512].","teleology":[{"year":2001,"claim":"Established the molecular identity of KLK14 as a secreted protein with predicted trypsin-like specificity, providing the foundation for all functional study of the enzyme.","evidence":"In vitro translation, Northern blot, in situ hybridization, and genomic structure analysis of the chromosome 19q13.4 gene","pmids":["11352573"],"confidence":"Medium","gaps":["Protease activity inferred from sequence, not demonstrated enzymatically","No substrates or physiological role established","Tissue distribution not linked to function"]},{"year":2007,"claim":"Resolved how KLK14 activity is restrained in skin by showing LEKTI fragments inhibit it in a pH-dependent manner, linking the epidermal pH gradient to controlled desquamation.","evidence":"Biochemical inhibition assays and kinetics with recombinant LEKTI fragments plus pH-dependent release experiments","pmids":["17596512"],"confidence":"High","gaps":["In vivo desquamation role of KLK14 specifically not isolated from KLK5/KLK7","Downstream substrates in skin not defined here","Physiological LEKTI fragment concentrations not established"]},{"year":2008,"claim":"Defined KLK14's physiological role in semen liquefaction, showing it both initiates a kallikrein cascade and is feedback-regulated, answering how seminal clot breakdown is controlled.","evidence":"Ex vivo semen liquefaction assays with a specific synthetic inhibitor, recombinant enzyme addition, activity assays, and Western blot for semenogelin cleavage","pmids":["18482984"],"confidence":"High","gaps":["Quantitative hierarchy among activated KLKs not fully resolved","In vivo fertility consequences not tested","Structural basis of Zn2+ inhibition not determined"]},{"year":2012,"claim":"Identified PAR2 as a signaling receptor activated by KLK14, establishing the enzyme as a biased agonist and distinguishing its signaling from other family members.","evidence":"Calcium, MAPK, β-arrestin, and internalization assays in HEK/KNRK cells expressing human or rat PAR2, plus PAR2-peptide cleavage, with direct comparison to KLK8","pmids":["22505524"],"confidence":"High","gaps":["Physiological tissue context of PAR2 activation not addressed","Downstream transcriptional consequences not mapped here","Endogenous KLK14 concentrations relative to signaling threshold unknown"]},{"year":2025,"claim":"Placed the KLK14-PAR2 axis in a disease pathway, showing KLK14 acts downstream of KLK5/KLK7 to drive RhoA and NF-κB signaling in HPV-dependent cervical carcinogenesis.","evidence":"KLK5/KLK7 double-knockout mice, bulk RNA-seq, NF-κB reporter assays, and human biopsy analysis","pmids":["40753921"],"confidence":"Medium","gaps":["Direct demonstration that KLK14 alone is sufficient for the tumorigenic phenotype not shown","Mechanism by which KLK5/KLK7 activate KLK14 in vivo not detailed","Single-lab finding"]},{"year":null,"claim":"How KLK14 activity is integrated and prioritized across its distinct contexts—semen, skin, and tumor signaling—and what determines substrate versus receptor engagement in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the active enzyme with substrate or inhibitor in the corpus","In vivo loss-of-function phenotype of KLK14 itself not characterized","Regulatory determinants selecting cascade activation vs PAR2 signaling unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2]}],"complexes":[],"partners":["KLK3","PAR2","LEKTI","KLK5","KLK7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P0G3","full_name":"Kallikrein-14","aliases":["Kallikrein-like protein 6","KLK-L6"],"length_aa":251,"mass_kda":27.5,"function":"Serine-type endopeptidase with a dual trypsin-like and chymotrypsin-like substrate specificity. May activate/inactivate the proteinase-activated receptors F2R, F2RL1 and F2RL3 and other kallikreins including KLK1, KLK3, KLK5 and KLK11. May function in seminal clot liquefaction through direct cleavage of the semenogelin SEMG1 and SEMG2 and activation of KLK3. May function through desmoglein DSG1 cleavage in epidermal desquamation a process by which the most superficial corneocytes are shed from the skin surface. May be involved in several aspects of tumor progression including growth, invasion and angiogenesis","subcellular_location":"Secreted, extracellular space","url":"https://www.uniprot.org/uniprotkb/Q9P0G3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KLK14","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/KLK14","total_profiled":1310},"omim":[{"mim_id":"615868","title":"SERINE PEPTIDASE INHIBITOR, KAZAL-TYPE, 6; SPINK6","url":"https://www.omim.org/entry/615868"},{"mim_id":"606135","title":"KALLIKREIN-RELATED PEPTIDASE 14; KLK14","url":"https://www.omim.org/entry/606135"},{"mim_id":"605644","title":"KALLIKREIN-RELATED PEPTIDASE 8; KLK8","url":"https://www.omim.org/entry/605644"},{"mim_id":"605643","title":"KALLIKREIN-RELATED PEPTIDASE 5; KLK5","url":"https://www.omim.org/entry/605643"},{"mim_id":"605640","title":"SIALIC ACID-BINDING IMMUNOGLOBULIN-LIKE LECTIN 9; SIGLEC9","url":"https://www.omim.org/entry/605640"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"skin 1","ntpm":9.9}],"url":"https://www.proteinatlas.org/search/KLK14"},"hgnc":{"alias_symbol":["KLK-L6"],"prev_symbol":[]},"alphafold":{"accession":"Q9P0G3","domains":[{"cath_id":"2.40.10.10","chopping":"53-145_257-264","consensus_level":"medium","plddt":97.6151,"start":53,"end":264},{"cath_id":"2.40.10.10","chopping":"156-255","consensus_level":"medium","plddt":90.5785,"start":156,"end":255}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0G3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0G3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0G3-F1-predicted_aligned_error_v6.png","plddt_mean":87.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KLK14","jax_strain_url":"https://www.jax.org/strain/search?query=KLK14"},"sequence":{"accession":"Q9P0G3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P0G3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P0G3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0G3"}},"corpus_meta":[{"pmid":"17596512","id":"PMC_17596512","title":"LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction.","date":"2007","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/17596512","citation_count":237,"is_preprint":false},{"pmid":"11309303","id":"PMC_11309303","title":"Cloning of a new member of the human kallikrein gene family, KLK14, which is down-regulated in different malignancies.","date":"2001","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11309303","citation_count":72,"is_preprint":false},{"pmid":"12858357","id":"PMC_12858357","title":"Differential expression of the human kallikrein gene 14 (KLK14) in normal and cancerous prostatic tissues.","date":"2003","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/12858357","citation_count":49,"is_preprint":false},{"pmid":"11352573","id":"PMC_11352573","title":"Identification and characterization of KLK14, a novel kallikrein serine protease gene located on human chromosome 19q13.4 and expressed in prostate and skeletal muscle.","date":"2001","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11352573","citation_count":48,"is_preprint":false},{"pmid":"18482984","id":"PMC_18482984","title":"Major role of human KLK14 in seminal clot liquefaction.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18482984","citation_count":34,"is_preprint":false},{"pmid":"16434994","id":"PMC_16434994","title":"Expression of human Kallikrein 14 (KLK14) in breast cancer is associated with higher tumour grades and positive nodal status.","date":"2006","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16434994","citation_count":23,"is_preprint":false},{"pmid":"22505524","id":"PMC_22505524","title":"Proteinase-activated receptors (PARs): differential signalling by kallikrein-related peptidases KLK8 and KLK14.","date":"2012","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22505524","citation_count":19,"is_preprint":false},{"pmid":"18497543","id":"PMC_18497543","title":"High expression of KLK14 in prostatic adenocarcinoma is associated with elevated risk of prostate-specific antigen relapse.","date":"2008","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18497543","citation_count":16,"is_preprint":false},{"pmid":"20155713","id":"PMC_20155713","title":"Human kallikrein 14 (KLK14) expression in salivary gland tumors.","date":"2010","source":"The International journal of biological markers","url":"https://pubmed.ncbi.nlm.nih.gov/20155713","citation_count":11,"is_preprint":false},{"pmid":"21057706","id":"PMC_21057706","title":"Quantitative expression analysis and study of the novel human kallikrein-related peptidase 14 gene (KLK14) in malignant and benign breast tissues.","date":"2010","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/21057706","citation_count":11,"is_preprint":false},{"pmid":"23086576","id":"PMC_23086576","title":"Significant alterations in the expression pattern of kallikrein-related peptidase genes KLK4, KLK5 and KLK14 after treatment of breast cancer cells with the chemotherapeutic agents epirubicin, docetaxel and methotrexate.","date":"2012","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23086576","citation_count":9,"is_preprint":false},{"pmid":"40753921","id":"PMC_40753921","title":"KLK5 and KLK7 drive cervical carcinoma via KLK14-dependent RhoA and NF-κB pathways.","date":"2025","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40753921","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8155,"output_tokens":1417,"usd":0.02286,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8084,"output_tokens":2342,"usd":0.049485,"stage2_stop_reason":"end_turn"},"total_usd":0.072345,"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\": 2007,\n      \"finding\": \"LEKTI fragments (generated by furin cleavage of the LEKTI precursor) specifically inhibit KLK14 (as well as KLK5 and KLK7) in a pH-dependent manner; the inhibitory complex dissociates at acidic pH, releasing active protease. This mechanism controls desquamation through the epidermal pH gradient.\",\n      \"method\": \"Biochemical inhibition assays with recombinant LEKTI fragments tested against a panel of serine proteases; kinetics analysis of binding complex; pH-dependent release experiments\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with kinetics analysis, multiple orthogonal methods (inhibition assays + kinetics + pH titration), replicated across multiple LEKTI fragments\",\n      \"pmids\": [\"17596512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"KLK14 encodes a secreted serine protease of ~251 amino acids (~31 kDa) with predicted trypsin-like substrate specificity, translated in vitro from a seven-exon gene on chromosome 19q13.4.\",\n      \"method\": \"In vitro translation; Northern blot; in situ hybridization; genomic structure analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro translation confirming protein product and size; structural characterization by multiple methods in a single study\",\n      \"pmids\": [\"11352573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KLK14 plays a major role in seminal clot liquefaction by: (1) directly cleaving semenogelins I and II; (2) activating KLK3 (PSA) and other KLKs in a proteolytic cascade; (3) inactivating KLK3 via internal cleavage at higher concentrations; and (4) being regulated by Zn2+ inhibition, which is reversed by semenogelins themselves.\",\n      \"method\": \"Ex vivo semen liquefaction assay; specific synthetic inhibitor (ACT(G9)) of KLK14; addition of recombinant active KLK14; measurement of chymotrypsin-like and KLK1 activity; Western blot for semenogelin cleavage; comparison of KLK14-expressing vs. delayed-liquefaction individuals\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (inhibitor, recombinant enzyme addition, direct substrate cleavage, activity assays), ex vivo system with functional readouts\",\n      \"pmids\": [\"18482984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KLK14 activates proteinase-activated receptor 2 (PAR2) by cleaving and unmasking its receptor-activating sequence, triggering calcium transients, MAPK activation, β-arrestin interactions, and receptor internalization. KLK14 signals via both human and rat PAR2, while the related KLK8 cannot signal via human PAR2 (disarming PAR1 instead), demonstrating differential PAR signalling between KLK family members.\",\n      \"method\": \"Calcium transient assays; MAPK activation assays; β-arrestin interaction assays; receptor internalization assays in HEK and KNRK cells expressing human or rat PAR2; cleavage of synthetic PAR2-derived peptides\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal functional assays (calcium, MAPK, β-arrestin, internalization, peptide cleavage) in a single study with direct comparison to KLK8\",\n      \"pmids\": [\"22505524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLK14 mediates a pro-tumorigenic effect downstream of KLK5 and KLK7 by activating PAR-2-dependent RhoA and NF-κB signaling pathways in cervical carcinogenesis; genetic ablation of KLK5 and KLK7 ameliorates HPV-dependent phenotype via modulation of KLK14 activation.\",\n      \"method\": \"Genetically engineered mice (double KLK5/KLK7 knockout); bulk RNA-seq; reporter assays for NF-κB; analysis of human biopsies\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in mouse model plus reporter assays and transcriptomic analysis; single lab, multiple methods\",\n      \"pmids\": [\"40753921\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KLK14 is a secreted trypsin-like serine protease that cleaves semenogelins and activates downstream kallikreins (including KLK3) during semen liquefaction, signals through PAR2 via cleavage-dependent unmasking to trigger RhoA/NF-κB and MAPK pathways, and is regulated in skin by pH-dependent inhibition via LEKTI fragments to control desquamation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KLK14 is a secreted trypsin-like serine protease that operates in proteolytic cascades governing seminal clot liquefaction, epidermal desquamation, and PAR2-mediated signaling [#1, #2, #3]. In semen, it drives liquefaction by directly cleaving semenogelins I and II and by activating KLK3 (PSA) and other kallikreins in a cascade, while also self-limiting through internal cleavage that inactivates KLK3 at higher concentrations and through Zn2+-mediated inhibition that semenogelins themselves relieve [#2]. KLK14 acts as a biased agonist of proteinase-activated receptor 2 (PAR2), cleaving and unmasking its tethered activating sequence to trigger calcium transients, MAPK activation, \\u03b2-arrestin recruitment, and receptor internalization—an activity that distinguishes it from KLK8, which cannot signal through human PAR2 [#3]. This PAR2 axis is co-opted in cervical carcinogenesis, where KLK14 acts downstream of KLK5 and KLK7 to drive RhoA and NF-\\u03baB signaling, such that ablation of KLK5/KLK7 attenuates the HPV-dependent phenotype by limiting KLK14 activation [#4]. In skin, KLK14 activity is restrained by LEKTI fragments through pH-dependent inhibition: the inhibitory complex dissociates at acidic pH to release active protease, coupling the epidermal pH gradient to controlled desquamation [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the molecular identity of KLK14 as a secreted protein with predicted trypsin-like specificity, providing the foundation for all functional study of the enzyme.\",\n      \"evidence\": \"In vitro translation, Northern blot, in situ hybridization, and genomic structure analysis of the chromosome 19q13.4 gene\",\n      \"pmids\": [\"11352573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protease activity inferred from sequence, not demonstrated enzymatically\", \"No substrates or physiological role established\", \"Tissue distribution not linked to function\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved how KLK14 activity is restrained in skin by showing LEKTI fragments inhibit it in a pH-dependent manner, linking the epidermal pH gradient to controlled desquamation.\",\n      \"evidence\": \"Biochemical inhibition assays and kinetics with recombinant LEKTI fragments plus pH-dependent release experiments\",\n      \"pmids\": [\"17596512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo desquamation role of KLK14 specifically not isolated from KLK5/KLK7\", \"Downstream substrates in skin not defined here\", \"Physiological LEKTI fragment concentrations not established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined KLK14's physiological role in semen liquefaction, showing it both initiates a kallikrein cascade and is feedback-regulated, answering how seminal clot breakdown is controlled.\",\n      \"evidence\": \"Ex vivo semen liquefaction assays with a specific synthetic inhibitor, recombinant enzyme addition, activity assays, and Western blot for semenogelin cleavage\",\n      \"pmids\": [\"18482984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative hierarchy among activated KLKs not fully resolved\", \"In vivo fertility consequences not tested\", \"Structural basis of Zn2+ inhibition not determined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified PAR2 as a signaling receptor activated by KLK14, establishing the enzyme as a biased agonist and distinguishing its signaling from other family members.\",\n      \"evidence\": \"Calcium, MAPK, \\u03b2-arrestin, and internalization assays in HEK/KNRK cells expressing human or rat PAR2, plus PAR2-peptide cleavage, with direct comparison to KLK8\",\n      \"pmids\": [\"22505524\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological tissue context of PAR2 activation not addressed\", \"Downstream transcriptional consequences not mapped here\", \"Endogenous KLK14 concentrations relative to signaling threshold unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed the KLK14-PAR2 axis in a disease pathway, showing KLK14 acts downstream of KLK5/KLK7 to drive RhoA and NF-\\u03baB signaling in HPV-dependent cervical carcinogenesis.\",\n      \"evidence\": \"KLK5/KLK7 double-knockout mice, bulk RNA-seq, NF-\\u03baB reporter assays, and human biopsy analysis\",\n      \"pmids\": [\"40753921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration that KLK14 alone is sufficient for the tumorigenic phenotype not shown\", \"Mechanism by which KLK5/KLK7 activate KLK14 in vivo not detailed\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KLK14 activity is integrated and prioritized across its distinct contexts—semen, skin, and tumor signaling—and what determines substrate versus receptor engagement in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the active enzyme with substrate or inhibitor in the corpus\", \"In vivo loss-of-function phenotype of KLK14 itself not characterized\", \"Regulatory determinants selecting cascade activation vs PAR2 signaling unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KLK3\", \"PAR2\", \"LEKTI\", \"KLK5\", \"KLK7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}