{"gene":"SERPIND1","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":1988,"finding":"The SERPIND1 (hLS2/HCF2 alias in serpin context) gene spans ~14.5 kb, consists of 5 exons and 4 introns, and shares equivalent exon-intron structure with alpha1-antitrypsin, alpha1-antichymotrypsin, and rat angiotensinogen, placing it in a distinct subgroup of the serpin gene family.","method":"Genomic clone analysis, exon-intron mapping, sequence comparison","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic structural analysis with sequence comparison across family members, single lab","pmids":["2841345"],"is_preprint":false},{"year":2001,"finding":"A Pro443Leu missense mutation at the reactive P2 site of SERPIND1 (HC II) causes type I congenital HC II deficiency by impairing secretion: mutant HC II molecules show enhanced intracellular association with the chaperone GRP78/BiP, are retained in the perinuclear region, and are degraded intracellularly, while mRNA transcription is unaffected.","method":"Site-directed mutagenesis, transient transfection in COS-1 and CHO-K1 cells, metabolic labeling, pulse-chase experiments, immunoprecipitation, Northern blot, immunohistochemistry","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (pulse-chase, co-IP with chaperone, immunohistochemistry, Northern blot) in a single rigorous study establishing the molecular pathogenesis","pmids":["11204559"],"is_preprint":false},{"year":2019,"finding":"SERPIND1 promotes proliferation, migration, invasion, G1-to-S phase transition, and EMT of ovarian cancer cells, and inhibits apoptosis, by activating (promoting phosphorylation of) the PI3K/AKT pathway; inhibition of SERPIND1 reverses these effects, and addition of the PI3K/AKT inhibitor LY294002 rescues the SERPIND1-overexpression phenotype.","method":"SERPIND1 knockdown and overexpression in ovarian cancer cell lines, PI3K/AKT inhibitor rescue (LY294002), cell proliferation/migration/invasion/apoptosis/cell-cycle assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotypes plus pharmacological rescue, single lab","pmids":["31637210"],"is_preprint":false},{"year":2019,"finding":"NF-κB subunit 1 (NFKB1) was identified as a transcription factor that binds to the promoter region of SERPIND1 and regulates its expression.","method":"Transcription factor binding/promoter analysis (chromatin binding assay reported in the study)","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method inferred from abstract description without full methodological detail","pmids":["31637210"],"is_preprint":false}],"current_model":"SERPIND1 (Heparin Cofactor II) is a serine protease inhibitor whose secretion requires proper folding at the reactive P2 site (Pro443); mutations there cause intracellular retention via GRP78/BiP chaperone association and proteasomal degradation. In cancer contexts, SERPIND1 promotes malignant cell behavior (proliferation, migration, invasion, EMT) by activating the PI3K/AKT signaling pathway, with NFKB1 acting as a transcriptional regulator of its expression."},"narrative":{"mechanistic_narrative":"SERPIND1 (Heparin Cofactor II) is a secreted serine protease inhibitor belonging to a distinct structural subgroup of the serpin gene family, sharing its five-exon, four-intron architecture with alpha1-antitrypsin, alpha1-antichymotrypsin, and rat angiotensinogen [PMID:2841345]. Productive secretion depends on correct folding at the reactive-center region: a Pro443Leu substitution at the P2 site impairs secretion, causing mutant molecules to associate intracellularly with the chaperone GRP78/BiP, be retained in the perinuclear region, and undergo intracellular degradation without affecting mRNA transcription, thereby producing type I congenital HC II deficiency [PMID:11204559]. Beyond its canonical inhibitory role, SERPIND1 promotes malignant cell behavior in ovarian cancer—driving proliferation, migration, invasion, G1-to-S transition, and EMT while suppressing apoptosis—through activation of PI3K/AKT signaling, as overexpression phenotypes are reversed by the PI3K/AKT inhibitor LY294002 [PMID:31637210]. The protease specificity, structural basis of inhibition, and physiological substrates of SERPIND1 have not been characterized in the available corpus.","teleology":[{"year":1988,"claim":"Establishing the gene's exon-intron architecture placed SERPIND1 within a defined serpin subgroup, framing it as a structurally classical serine protease inhibitor.","evidence":"Genomic clone analysis and exon-intron mapping with cross-family sequence comparison","pmids":["2841345"],"confidence":"Medium","gaps":["Genomic structure does not establish the inhibitory mechanism or target protease","No protein structural or biochemical characterization at this stage"]},{"year":2001,"claim":"Identifying a P2-site Pro443Leu mutation that triggers chaperone-mediated retention and degradation defined the molecular basis of type I HC II deficiency and showed that secretion depends on correct reactive-center folding.","evidence":"Site-directed mutagenesis with transfection in COS-1/CHO-K1, pulse-chase, co-immunoprecipitation with GRP78/BiP, immunohistochemistry, and Northern blot","pmids":["11204559"],"confidence":"High","gaps":["Does not define the degradation pathway components beyond GRP78/BiP association","Does not characterize the protease-inhibitory activity of wild-type protein","Generalization to other deficiency-causing mutations not addressed"]},{"year":2019,"claim":"Functional perturbation in ovarian cancer cells linked SERPIND1 to oncogenic phenotypes mediated by PI3K/AKT signaling, extending its role beyond protease inhibition.","evidence":"Knockdown and overexpression in ovarian cancer cell lines with phenotypic assays and LY294002 pharmacological rescue","pmids":["31637210"],"confidence":"Medium","gaps":["Mechanism connecting SERPIND1 to PI3K/AKT phosphorylation is not defined","Single cancer-type, single-lab evidence","No in vivo validation reported"]},{"year":2019,"claim":"Promoter analysis nominated NFKB1 as an upstream transcriptional regulator of SERPIND1 expression.","evidence":"Transcription factor promoter binding assay reported within the cancer study","pmids":["31637210"],"confidence":"Low","gaps":["Single method inferred from abstract-level description without full methodological detail","Functional consequence of NFKB1 binding on SERPIND1 transcription not quantified","No demonstration of direct binding by orthogonal assay"]},{"year":null,"claim":"The target protease specificity, structural mechanism of inhibition, and physiological substrates of SERPIND1 remain unresolved in this corpus.","evidence":"No discovery in the timeline addresses the inhibitory biochemistry or in vivo function","pmids":[],"confidence":"Low","gaps":["No protease substrate or kinetic characterization","No structural model of the reactive-center loop","No in vivo physiological role established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]}],"complexes":[],"partners":["HSPA5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P05546","full_name":"Heparin cofactor 2","aliases":["Heparin cofactor II","HC-II","Protease inhibitor leuserpin-2","HLS2","Serpin D1"],"length_aa":499,"mass_kda":57.1,"function":"Thrombin inhibitor activated by the glycosaminoglycans, heparin or dermatan sulfate. In the presence of the latter, HC-II becomes the predominant thrombin inhibitor in place of antithrombin III (AT-III). Also inhibits chymotrypsin, but in a glycosaminoglycan-independent manner Peptides at the N-terminal of HC-II have chemotactic activity for both monocytes and neutrophils Shows negligible inhibition, in vitro, of thrombin and tPA and no inhibition of factor Xa, in vitro","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P05546/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SERPIND1","classification":"Not Classified","n_dependent_lines":23,"n_total_lines":1208,"dependency_fraction":0.01903973509933775},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SERPIND1","total_profiled":1310},"omim":[{"mim_id":"142360","title":"HEPARIN COFACTOR II; HCF2","url":"https://www.omim.org/entry/142360"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":1171.6}],"url":"https://www.proteinatlas.org/search/SERPIND1"},"hgnc":{"alias_symbol":["HC-II","HLS2","HC2","D22S673"],"prev_symbol":["HCF2"]},"alphafold":{"accession":"P05546","domains":[{"cath_id":"3.30.497.10","chopping":"145-298_400-446","consensus_level":"medium","plddt":93.1831,"start":145,"end":446},{"cath_id":"2.30.39.10","chopping":"300-397_465-494","consensus_level":"medium","plddt":94.8056,"start":300,"end":494}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P05546","model_url":"https://alphafold.ebi.ac.uk/files/AF-P05546-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P05546-F1-predicted_aligned_error_v6.png","plddt_mean":79.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SERPIND1","jax_strain_url":"https://www.jax.org/strain/search?query=SERPIND1"},"sequence":{"accession":"P05546","fasta_url":"https://rest.uniprot.org/uniprotkb/P05546.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P05546/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P05546"}},"corpus_meta":[{"pmid":"10196288","id":"PMC_10196288","title":"Herpes simplex virus transactivator VP16 discriminates between HCF-1 and a novel family member, HCF-2.","date":"1999","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/10196288","citation_count":40,"is_preprint":false},{"pmid":"2841345","id":"PMC_2841345","title":"Structure and expression of the gene coding for the human serpin hLS2.","date":"1988","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2841345","citation_count":36,"is_preprint":false},{"pmid":"11204559","id":"PMC_11204559","title":"Molecular mechanism of type I congenital heparin cofactor (HC) II deficiency caused by a missense mutation at reactive P2 site: HC II Tokushima.","date":"2001","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/11204559","citation_count":22,"is_preprint":false},{"pmid":"16509611","id":"PMC_16509611","title":"Bond-forming reactions of dications with molecules: a computational and experimental study of the mechanisms for the formation of HCF2+ from CF3(2+) and H2.","date":"2006","source":"The journal of physical chemistry. A","url":"https://pubmed.ncbi.nlm.nih.gov/16509611","citation_count":20,"is_preprint":false},{"pmid":"31637210","id":"PMC_31637210","title":"SERPIND1 Affects the Malignant Biological Behavior of Epithelial Ovarian Cancer via the PI3K/AKT Pathway: A Mechanistic Study.","date":"2019","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31637210","citation_count":18,"is_preprint":false},{"pmid":"16810142","id":"PMC_16810142","title":"Screening for human papillomavirus (HPV) in Egyptian women by the second-generation hybrid capture (HC II) test.","date":"2006","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/16810142","citation_count":14,"is_preprint":false},{"pmid":"15830373","id":"PMC_15830373","title":"Stability of PreservCyt for Hybrid Capture (HC II) HPV test.","date":"2005","source":"Diagnostic cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/15830373","citation_count":6,"is_preprint":false},{"pmid":"1691489","id":"PMC_1691489","title":"MspI RFLP in the human heparin cofactor II (HCF2) gene.","date":"1990","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1691489","citation_count":5,"is_preprint":false},{"pmid":"14747034","id":"PMC_14747034","title":"Efficient treatment of paraffin-embedded cervical tissue for HPV DNA testing by HC-II and PCR assays.","date":"2004","source":"Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology","url":"https://pubmed.ncbi.nlm.nih.gov/14747034","citation_count":4,"is_preprint":false},{"pmid":"14595791","id":"PMC_14595791","title":"Correlation of manual screening and automated (AutoPap 300) analysis of conventional cervicovaginal smears with HPV typing using Digene HC II assay.","date":"2003","source":"Diagnostic cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/14595791","citation_count":3,"is_preprint":false},{"pmid":"39691603","id":"PMC_39691603","title":"Corrigendum: SERPIND1 affects the malignant biological behavior of epithelial ovarian cancer via the PI3K/AKT pathway: a mechanistic study.","date":"2024","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39691603","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.23.25323721","title":"Genetic and Phenotypic Architecture of Brain Glymphatic System","date":"2025-03-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.23.25323721","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7533,"output_tokens":1082,"usd":0.019415,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7624,"output_tokens":1826,"usd":0.041885,"stage2_stop_reason":"end_turn"},"total_usd":0.0613,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1988,\n      \"finding\": \"The SERPIND1 (hLS2/HCF2 alias in serpin context) gene spans ~14.5 kb, consists of 5 exons and 4 introns, and shares equivalent exon-intron structure with alpha1-antitrypsin, alpha1-antichymotrypsin, and rat angiotensinogen, placing it in a distinct subgroup of the serpin gene family.\",\n      \"method\": \"Genomic clone analysis, exon-intron mapping, sequence comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic structural analysis with sequence comparison across family members, single lab\",\n      \"pmids\": [\"2841345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"A Pro443Leu missense mutation at the reactive P2 site of SERPIND1 (HC II) causes type I congenital HC II deficiency by impairing secretion: mutant HC II molecules show enhanced intracellular association with the chaperone GRP78/BiP, are retained in the perinuclear region, and are degraded intracellularly, while mRNA transcription is unaffected.\",\n      \"method\": \"Site-directed mutagenesis, transient transfection in COS-1 and CHO-K1 cells, metabolic labeling, pulse-chase experiments, immunoprecipitation, Northern blot, immunohistochemistry\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (pulse-chase, co-IP with chaperone, immunohistochemistry, Northern blot) in a single rigorous study establishing the molecular pathogenesis\",\n      \"pmids\": [\"11204559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SERPIND1 promotes proliferation, migration, invasion, G1-to-S phase transition, and EMT of ovarian cancer cells, and inhibits apoptosis, by activating (promoting phosphorylation of) the PI3K/AKT pathway; inhibition of SERPIND1 reverses these effects, and addition of the PI3K/AKT inhibitor LY294002 rescues the SERPIND1-overexpression phenotype.\",\n      \"method\": \"SERPIND1 knockdown and overexpression in ovarian cancer cell lines, PI3K/AKT inhibitor rescue (LY294002), cell proliferation/migration/invasion/apoptosis/cell-cycle assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotypes plus pharmacological rescue, single lab\",\n      \"pmids\": [\"31637210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NF-κB subunit 1 (NFKB1) was identified as a transcription factor that binds to the promoter region of SERPIND1 and regulates its expression.\",\n      \"method\": \"Transcription factor binding/promoter analysis (chromatin binding assay reported in the study)\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method inferred from abstract description without full methodological detail\",\n      \"pmids\": [\"31637210\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SERPIND1 (Heparin Cofactor II) is a serine protease inhibitor whose secretion requires proper folding at the reactive P2 site (Pro443); mutations there cause intracellular retention via GRP78/BiP chaperone association and proteasomal degradation. In cancer contexts, SERPIND1 promotes malignant cell behavior (proliferation, migration, invasion, EMT) by activating the PI3K/AKT signaling pathway, with NFKB1 acting as a transcriptional regulator of its expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SERPIND1 (Heparin Cofactor II) is a secreted serine protease inhibitor belonging to a distinct structural subgroup of the serpin gene family, sharing its five-exon, four-intron architecture with alpha1-antitrypsin, alpha1-antichymotrypsin, and rat angiotensinogen [#0]. Productive secretion depends on correct folding at the reactive-center region: a Pro443Leu substitution at the P2 site impairs secretion, causing mutant molecules to associate intracellularly with the chaperone GRP78/BiP, be retained in the perinuclear region, and undergo intracellular degradation without affecting mRNA transcription, thereby producing type I congenital HC II deficiency [#1]. Beyond its canonical inhibitory role, SERPIND1 promotes malignant cell behavior in ovarian cancer—driving proliferation, migration, invasion, G1-to-S transition, and EMT while suppressing apoptosis—through activation of PI3K/AKT signaling, as overexpression phenotypes are reversed by the PI3K/AKT inhibitor LY294002 [#2]. The protease specificity, structural basis of inhibition, and physiological substrates of SERPIND1 have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Establishing the gene's exon-intron architecture placed SERPIND1 within a defined serpin subgroup, framing it as a structurally classical serine protease inhibitor.\",\n      \"evidence\": \"Genomic clone analysis and exon-intron mapping with cross-family sequence comparison\",\n      \"pmids\": [\"2841345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Genomic structure does not establish the inhibitory mechanism or target protease\",\n        \"No protein structural or biochemical characterization at this stage\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying a P2-site Pro443Leu mutation that triggers chaperone-mediated retention and degradation defined the molecular basis of type I HC II deficiency and showed that secretion depends on correct reactive-center folding.\",\n      \"evidence\": \"Site-directed mutagenesis with transfection in COS-1/CHO-K1, pulse-chase, co-immunoprecipitation with GRP78/BiP, immunohistochemistry, and Northern blot\",\n      \"pmids\": [\"11204559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not define the degradation pathway components beyond GRP78/BiP association\",\n        \"Does not characterize the protease-inhibitory activity of wild-type protein\",\n        \"Generalization to other deficiency-causing mutations not addressed\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Functional perturbation in ovarian cancer cells linked SERPIND1 to oncogenic phenotypes mediated by PI3K/AKT signaling, extending its role beyond protease inhibition.\",\n      \"evidence\": \"Knockdown and overexpression in ovarian cancer cell lines with phenotypic assays and LY294002 pharmacological rescue\",\n      \"pmids\": [\"31637210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism connecting SERPIND1 to PI3K/AKT phosphorylation is not defined\",\n        \"Single cancer-type, single-lab evidence\",\n        \"No in vivo validation reported\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Promoter analysis nominated NFKB1 as an upstream transcriptional regulator of SERPIND1 expression.\",\n      \"evidence\": \"Transcription factor promoter binding assay reported within the cancer study\",\n      \"pmids\": [\"31637210\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single method inferred from abstract-level description without full methodological detail\",\n        \"Functional consequence of NFKB1 binding on SERPIND1 transcription not quantified\",\n        \"No demonstration of direct binding by orthogonal assay\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The target protease specificity, structural mechanism of inhibition, and physiological substrates of SERPIND1 remain unresolved in this corpus.\",\n      \"evidence\": \"No discovery in the timeline addresses the inhibitory biochemistry or in vivo function\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No protease substrate or kinetic characterization\",\n        \"No structural model of the reactive-center loop\",\n        \"No in vivo physiological role established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HSPA5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":3,"faith_pct":100.0}}