{"gene":"SERPINA5","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":1996,"finding":"SERPINA5 (PCI) is a non-specific serpin that inhibits multiple proteases of coagulation and fibrinolytic systems, plasma and tissue kallikreins, and the sperm protease acrosin. Heparin stimulates most SERPINA5/protease reactions but interferes with the tissue kallikrein/SERPINA5 interaction, thereby regulating both activity and specificity. SERPINA5 also binds glycosaminoglycans on the surface of epithelial kidney cells, which modulate its activity similarly to heparin.","method":"In vitro protease inhibition assays, cell-binding studies, mouse in vitro fertilization model","journal":"Immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro assays and cell-based experiments from a single lab establishing substrate scope and GAG-mediated regulation","pmids":["8796266"],"is_preprint":false},{"year":2007,"finding":"SERPINA5 binds oxidized phosphatidylethanolamine (OxPE) and phosphatidylserine (PS) immobilized on microtiter plates and in aqueous suspension. This binding is competed by heparin. PS and OxPE stimulate SERPINA5 inhibition of activated protein C (aPC) in a Ca2+-dependent manner, requiring binding of both aPC (Ca2+-dependent) and SERPINA5 (Ca2+-independent) to phospholipids. A peptide corresponding to the heparin-binding site of SERPINA5 abolished the stimulatory effect of PS, and a SERPINA5 mutant lacking the heparin-binding site lost this phospholipid stimulation. This heparin-like effect of phospholipids was not observed with antithrombin III, indicating specificity for SERPINA5.","method":"ELISA-based phospholipid binding assays, competitive inhibition with heparin and annexin V, in vitro aPC inhibition assays with Ca2+ manipulation, site-directed mutagenesis (heparin-binding site mutant), immunolocalization in atherosclerotic plaques","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro biochemical assays with mutagenesis and multiple orthogonal methods (binding assay, activity assay, mutant, in vivo colocalization) in a single rigorous study","pmids":["17332248"],"is_preprint":false},{"year":2013,"finding":"SERPINA5 inhibits tumor cell migration in hepatocellular carcinoma (HCC) through direct interaction with fibronectin, which disrupts the fibronectin-integrin signaling pathway. Secreted SERPINA5 protein also inhibits metastatic ability of HCC cells. DNA dosage and expression of SERPINA5 were decreased in HCC, and expression levels negatively correlated with malignant progression.","method":"In vitro migration/invasion assays, in vivo metastasis model, co-immunoprecipitation/direct interaction assay between SERPINA5 and fibronectin, exogenous secreted protein treatment","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding to fibronectin established, loss-of-function and gain-of-function with defined phenotypic readout, single lab with multiple orthogonal methods","pmids":["24388360"],"is_preprint":false},{"year":2014,"finding":"The N-terminal A+-helix of SERPINA5 functions as a cell-penetrating peptide that mediates cell membrane permeation of the intact protein. Testisin, a GPI-anchored serine protease, cleaves SERPINA5 at the reactive site and near the N-terminus, releasing basic peptides corresponding to His1-Arg11 (human) and Arg1-Ala18 (mouse). These synthetic N-terminal peptides function as cell-penetrating peptides. A truncated mouse SERPINA5 lacking 18 N-terminal amino acids was not internalized by Jurkat T cells, whereas intact SERPINA5 was, indicating that the N-terminus is required for internalization and that testisin cleavage can regulate cellular uptake of SERPINA5.","method":"Recombinant protease cleavage assays (testisin in solution and membrane-anchored on U937 cells), synthetic peptide cell penetration assays, truncation mutant internalization in Jurkat T cells (flow cytometry/imaging)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with recombinant proteins, mutagenesis (truncation), synthetic peptide validation, cell-based internalization assays; multiple orthogonal methods in one rigorous study","pmids":["25488662"],"is_preprint":false},{"year":2016,"finding":"SERPINA5 is internalized by cells (platelets, granulocytes, HL-60, and Jurkat cells) and translocated to the nucleus. Internalization is dependent on the phospholipid phosphatidylethanolamine (PE) and on the intact N-terminus of SERPINA5, which functions as a cell-penetrating peptide. SERPINA5 can directly cross the phospholipid bilayer of the cell membrane and penetrate pure phospholipid vesicles.","method":"Cell fractionation, immunofluorescence/nuclear translocation assays, phospholipid vesicle penetration experiments, N-terminal truncation studies","journal":"Seminars in cell & developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review synthesizing direct experimental evidence from multiple studies; cell fractionation and vesicle assays, single research group","pmids":["27989561"],"is_preprint":false},{"year":2022,"finding":"SERPINA5 inhibits migration and invasion of endometrial cancer cells by suppressing integrin β1/FAK signaling pathway activation. Overexpression of SERPINA5 or delivery of exosomal SERPINA5 reduced integrin β1 and FAK phosphorylation in EC cell lines. Exosomal SERPINA5 also impeded tumor growth and metastasis in xenograft models.","method":"Cell migration/invasion assays, Western blotting of integrin β1/FAK pathway components, SERPINA5 overexpression constructs, therapeutic exosome delivery, xenograft mouse models","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined pathway placement via gain-of-function with mechanistic readout (phospho-FAK), in vitro and in vivo validation, single lab","pmids":["35951287"],"is_preprint":false},{"year":2022,"finding":"SERPINA5 promotes gastric cancer cell proliferation by inhibiting CBL, which leads to activation of the PI3K/AKT/mTOR signaling pathway. Knockdown of SERPINA5 reduced cell proliferation and migration in gastric cancer cell lines.","method":"qPCR expression analysis, SERPINA5 knockdown (siRNA/shRNA), cell proliferation and migration assays, pathway analysis (PI3K/AKT/mTOR signaling components by Western blot), public database survival analysis","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with phenotypic readout and pathway placement, but CBL interaction not directly validated by co-IP or pull-down in abstract","pmids":["36000536"],"is_preprint":false},{"year":2023,"finding":"SERPINA5 functions as an interferon-stimulated gene (ISG) that promotes antiviral immunity by upregulating STAT1 phosphorylation and promoting STAT1 nuclear translocation, thereby activating transcription of IFN-related signaling pathways.","method":"Overexpression and knockdown of SerpinA5, Western blotting for phospho-STAT1 and nuclear STAT1 fractionation, reporter assays for IFN-pathway transcription, viral infection models","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assays with gain/loss-of-function establishing pathway position (STAT1 phosphorylation and nuclear translocation), single lab with multiple readouts","pmids":["36982532"],"is_preprint":false},{"year":2023,"finding":"Elevated SERPINA5 levels in a preeclampsia-like rat model (L-NAME-induced) exacerbated hypertension and proteinuria, while suppression of SERPINA5 expression mitigated these features and improved placental development. Placental mRNA sequencing following SERPINA5 overexpression indicated increased coagulation cascade activation, suggesting SERPINA5 worsens preeclampsia-like features by promoting coagulation.","method":"Adenoviral overexpression/suppression of SERPINA5 in pregnant rats, blood pressure measurement, urine protein quantification, placental histology, mRNA sequencing of placental tissue","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain and loss-of-function with defined phenotypic readouts and transcriptomic pathway analysis; single lab","pmids":["38136662"],"is_preprint":false},{"year":2003,"finding":"SERPINA5 (PCI) is expressed in benign prostatic epithelium, PIN lesions, and prostate tumor cells. PCI inhibits human glandular kallikrein-2 (hK2) and, less readily, prostate-specific antigen (PSA), suggesting a role as a local regulator of enzymatic activity in seminal fluid.","method":"Immunohistochemistry on tissue microarray, in situ hybridization, Western blotting in prostate cell lines (PC-3, DU-145, LNCaP)","journal":"The Prostate","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization and expression established by IHC/ISH/WB; inhibitory activity inferred from prior literature rather than directly demonstrated in this paper","pmids":["14518028"],"is_preprint":false},{"year":2004,"finding":"Screening of the SERPINA5 (PCI) gene in subfertile men with severe teratozoospermia or idiopathic azoospermia found no causal mutations; PCI antigen levels in seminal plasma were not decreased in the three patients with novel variants. This negative result indicates that mutations in the human PCI gene are not a common cause of reduced semen parameters.","method":"Direct sequencing of PCI gene in subfertile men, RFLP analysis in controls, ELISA measurement of PCI antigen in seminal plasma","journal":"Molecular human reproduction","confidence":"Low","confidence_rationale":"Tier 3 / Weak — negative finding; single study, genetic screening with seminal plasma antigen measurement","pmids":["15377716"],"is_preprint":false}],"current_model":"SERPINA5 (protein C inhibitor/PCI) is a secreted, broad-specificity serpin that inhibits multiple coagulation, fibrinolytic, and kallikrein-family proteases; its inhibitory activity and substrate specificity are modulated by glycosaminoglycans (especially heparin) and phospholipids (including oxidized PE and PS) acting at its heparin-binding site. The intact N-terminal A+-helix functions as a cell-penetrating peptide enabling SERPINA5 to cross the plasma membrane via a phosphatidylethanolamine-dependent mechanism and translocate to the nucleus, a process regulated by N-terminal cleavage by testisin. Extracellularly, secreted SERPINA5 suppresses tumor cell migration in hepatocellular and endometrial cancers by directly binding fibronectin and disrupting fibronectin-integrin β1/FAK signaling; in gastric cancer it paradoxically promotes proliferation by inhibiting CBL to activate PI3K/AKT/mTOR. SERPINA5 also acts as an interferon-stimulated gene that enhances antiviral innate immunity by upregulating STAT1 phosphorylation and nuclear translocation."},"narrative":{"mechanistic_narrative":"SERPINA5 (protein C inhibitor/PCI) is a secreted, broad-specificity serpin that inhibits multiple coagulation, fibrinolytic, and kallikrein-family proteases, including activated protein C, plasma and tissue kallikreins, and the sperm protease acrosin [PMID:8796266]. Its inhibitory activity and substrate selectivity are tuned by cofactors that engage its heparin-binding site: heparin and surface glycosaminoglycans stimulate most protease reactions while interfering with the tissue kallikrein interaction [PMID:8796266], and anionic phospholipids—oxidized phosphatidylethanolamine and phosphatidylserine—act as heparin-like cofactors that stimulate activated protein C inhibition in a Ca2+-dependent manner, an effect lost in a heparin-binding-site mutant [PMID:17332248]. Beyond protease inhibition, the intact N-terminal A+-helix of SERPINA5 functions as a cell-penetrating peptide that drives phosphatidylethanolamine-dependent membrane crossing and nuclear translocation; cleavage near the N-terminus by the GPI-anchored protease testisin removes this element and regulates cellular uptake [PMID:25488662, PMID:27989561]. Extracellularly, secreted SERPINA5 suppresses tumor cell migration and invasion by binding fibronectin and disrupting fibronectin–integrin β1/FAK signaling in hepatocellular and endometrial cancers [PMID:24388360, PMID:35951287], whereas in gastric cancer it promotes proliferation via inhibition of CBL and activation of PI3K/AKT/mTOR signaling [PMID:36000536]. SERPINA5 additionally acts as an interferon-stimulated gene that enhances antiviral innate immunity by promoting STAT1 phosphorylation and nuclear translocation [PMID:36982532], and elevated SERPINA5 worsens preeclampsia-like features in a rat model through enhanced coagulation cascade activation [PMID:38136662].","teleology":[{"year":1996,"claim":"Established SERPINA5 as a broad-specificity serpin and showed that glycosaminoglycans set both its activity and protease selectivity, framing it as a cofactor-regulated inhibitor rather than a single-target enzyme.","evidence":"In vitro protease inhibition assays, epithelial cell-binding studies, and a mouse IVF model defining substrate scope and heparin/GAG modulation","pmids":["8796266"],"confidence":"Medium","gaps":["Structural basis of how GAG binding redirects specificity not resolved","Physiological cofactor identity in each tissue not defined","Relative contribution of each protease target in vivo unknown"]},{"year":2003,"claim":"Placed SERPINA5 in prostate epithelium as a candidate local regulator of seminal kallikrein activity, extending its protease targets to hK2 and PSA.","evidence":"Immunohistochemistry, in situ hybridization, and Western blotting across benign, PIN, and tumor prostate tissue and cell lines","pmids":["14518028"],"confidence":"Low","gaps":["Inhibitory activity inferred rather than directly demonstrated in this study","No functional consequence in seminal fluid established","Causal role in prostate pathology untested"]},{"year":2004,"claim":"Tested whether SERPINA5 mutations underlie male subfertility and found none, excluding the gene as a common genetic cause of impaired semen parameters.","evidence":"Direct gene sequencing in subfertile men, RFLP in controls, and ELISA of seminal plasma antigen","pmids":["15377716"],"confidence":"Low","gaps":["Negative result; does not exclude rare or regulatory variants","Small variant-carrier sample","Functional role in fertility not directly addressed"]},{"year":2007,"claim":"Showed that anionic phospholipids act as heparin-like cofactors specific to SERPINA5, defining a phospholipid-dependent, Ca2+-regulated route to enhanced activated protein C inhibition.","evidence":"ELISA phospholipid-binding assays, heparin/annexin V competition, Ca2+-controlled aPC inhibition, heparin-binding-site mutagenesis and peptide competition, plus atherosclerotic plaque colocalization","pmids":["17332248"],"confidence":"High","gaps":["In vivo relevance of phospholipid cofactor at lesion sites not quantified","Which physiological membranes present these lipids to SERPINA5 unclear","Structural model of the lipid-bound inhibitor absent"]},{"year":2013,"claim":"Identified a non-inhibitory extracellular function: SERPINA5 binds fibronectin to disrupt fibronectin-integrin signaling and suppress HCC migration and metastasis, linking it to tumor suppression.","evidence":"Migration/invasion and in vivo metastasis assays, direct SERPINA5-fibronectin interaction assay, and exogenous secreted protein treatment with DNA dosage/expression correlation in HCC","pmids":["24388360"],"confidence":"Medium","gaps":["Binding interface on fibronectin not mapped","Whether protease-inhibitory activity contributes unknown","Mechanism of integrin signaling disruption not fully resolved"]},{"year":2014,"claim":"Defined the N-terminal A+-helix as a cell-penetrating peptide and testisin as a protease that cleaves SERPINA5 to regulate its internalization, establishing a mechanism for cellular uptake.","evidence":"Recombinant and membrane-anchored testisin cleavage assays, synthetic N-terminal peptide penetration tests, and truncation-mutant internalization in Jurkat T cells","pmids":["25488662"],"confidence":"High","gaps":["Functional consequence of nuclear SERPINA5 not defined here","Physiological context where testisin gates uptake unclear","Receptor/transport machinery beyond the peptide not identified"]},{"year":2016,"claim":"Extended the uptake model by showing PE-dependent membrane crossing and nuclear translocation across multiple cell types and into pure lipid vesicles, demonstrating receptor-independent bilayer penetration.","evidence":"Cell fractionation, immunofluorescence nuclear translocation, phospholipid vesicle penetration, and N-terminal truncation studies","pmids":["27989561"],"confidence":"Medium","gaps":["Nuclear function of internalized SERPINA5 unknown","Quantitative contribution of PE versus other lipids unresolved","Synthesizes single-group data"]},{"year":2022,"claim":"Showed context-dependent roles in cancer: SERPINA5 suppresses endometrial cancer via integrin β1/FAK inhibition but promotes gastric cancer proliferation by inhibiting CBL to activate PI3K/AKT/mTOR.","evidence":"Overexpression/knockdown with phospho-FAK and PI3K/AKT/mTOR Western blots, migration/invasion assays, exosomal delivery, and xenograft models","pmids":["35951287","36000536"],"confidence":"Medium","gaps":["SERPINA5-CBL interaction not directly validated by co-IP","Basis of opposing tumor roles across tissues unexplained","Whether intracellular versus secreted pools drive each phenotype unclear"]},{"year":2023,"claim":"Placed SERPINA5 in innate immunity as an interferon-stimulated gene that amplifies STAT1 signaling, and in vascular pathology as a coagulation-promoting aggravator of preeclampsia-like disease.","evidence":"Gain/loss-of-function with phospho- and nuclear-STAT1 readouts, IFN reporter assays, and viral infection models; plus adenoviral SERPINA5 manipulation in a rat preeclampsia model with placental mRNA-seq","pmids":["36982532","38136662"],"confidence":"Medium","gaps":["Molecular link between SERPINA5 and STAT1 phosphorylation not defined","Whether antiviral and coagulation roles share a mechanism unknown","Direct protease targets driving preeclampsia phenotype not identified"]},{"year":null,"claim":"How a single secreted serpin integrates cofactor-tuned protease inhibition, cell penetration and nuclear localization, fibronectin/integrin signaling, and STAT1-dependent immunity into coherent physiology remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism connecting extracellular inhibitory and intracellular signaling functions","Functional output of nuclear-translocated SERPINA5 unknown","Structural basis of cofactor-switched specificity not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[0,1,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,7]}],"complexes":[],"partners":["F2RL..."],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P05154","full_name":"Plasma serine protease inhibitor","aliases":["Acrosomal serine protease inhibitor","Plasminogen activator inhibitor 3","PAI-3","PAI3","Protein C inhibitor","PCI","Serpin A5"],"length_aa":406,"mass_kda":45.7,"function":"Heparin-dependent serine protease inhibitor acting in body fluids and secretions. Inactivates serine proteases by binding irreversibly to their serine activation site. Involved in the regulation of intravascular and extravascular proteolytic activities. Plays hemostatic roles in the blood plasma. Acts as a procoagulant and pro-inflammatory factor by inhibiting the anticoagulant activated protein C factor as well as the generation of activated protein C factor by the thrombin/thrombomodulin complex. Acts as an anticoagulant factor by inhibiting blood coagulation factors like prothrombin, factor XI, factor Xa, plasma kallikrein and fibrinolytic enzymes such as tissue- and urinary-type plasminogen activators. In seminal plasma, inactivates several serine proteases implicated in the reproductive system. Inhibits the serpin acrosin; indirectly protects component of the male genital tract from being degraded by excessive released acrosin. Inhibits tissue- and urinary-type plasminogen activator, prostate-specific antigen and kallikrein activities; has a control on the sperm motility and fertilization. Inhibits the activated protein C-catalyzed degradation of SEMG1 and SEMG2; regulates the degradation of semenogelin during the process of transfer of spermatozoa from the male reproductive tract into the female tract. In urine, inhibits urinary-type plasminogen activator and kallikrein activities. Inactivates membrane-anchored serine proteases activities such as MPRSS7 and TMPRSS11E. Inhibits urinary-type plasminogen activator-dependent tumor cell invasion and metastasis. May also play a non-inhibitory role in seminal plasma and urine as a hydrophobic hormone carrier by its binding to retinoic acid","subcellular_location":"Secreted, extracellular space","url":"https://www.uniprot.org/uniprotkb/P05154/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SERPINA5","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SERPINA5","total_profiled":1310},"omim":[{"mim_id":"619538","title":"CEREBRAL CAVERNOUS MALFORMATIONS 4; CCM4","url":"https://www.omim.org/entry/619538"},{"mim_id":"601841","title":"SERPIN PEPTIDASE INHIBITOR, CLADE A, MEMBER 5; SERPINA5","url":"https://www.omim.org/entry/601841"},{"mim_id":"171834","title":"PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, ALPHA; PIK3CA","url":"https://www.omim.org/entry/171834"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adrenal gland","ntpm":460.9},{"tissue":"liver","ntpm":734.5},{"tissue":"testis","ntpm":404.5}],"url":"https://www.proteinatlas.org/search/SERPINA5"},"hgnc":{"alias_symbol":["PAI3","PROCI"],"prev_symbol":["PLANH3","PCI"]},"alphafold":{"accession":"P05154","domains":[{"cath_id":"3.30.497.10","chopping":"47-206_307-353","consensus_level":"medium","plddt":94.0983,"start":47,"end":353},{"cath_id":"2.30.39.10","chopping":"209-303_376-402","consensus_level":"medium","plddt":94.6022,"start":209,"end":402}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P05154","model_url":"https://alphafold.ebi.ac.uk/files/AF-P05154-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P05154-F1-predicted_aligned_error_v6.png","plddt_mean":85.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SERPINA5","jax_strain_url":"https://www.jax.org/strain/search?query=SERPINA5"},"sequence":{"accession":"P05154","fasta_url":"https://rest.uniprot.org/uniprotkb/P05154.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P05154/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P05154"}},"corpus_meta":[{"pmid":"20615965","id":"PMC_20615965","title":"The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20615965","citation_count":1268,"is_preprint":false},{"pmid":"23045577","id":"PMC_23045577","title":"Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies.","date":"2012","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23045577","citation_count":927,"is_preprint":false},{"pmid":"29083953","id":"PMC_29083953","title":"PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock.","date":"2017","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29083953","citation_count":909,"is_preprint":false},{"pmid":"21422473","id":"PMC_21422473","title":"Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/21422473","citation_count":662,"is_preprint":false},{"pmid":"22180443","id":"PMC_22180443","title":"The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22180443","citation_count":545,"is_preprint":false},{"pmid":"22279054","id":"PMC_22279054","title":"The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22279054","citation_count":467,"is_preprint":false},{"pmid":"18256683","id":"PMC_18256683","title":"A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas.","date":"2008","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/18256683","citation_count":382,"is_preprint":false},{"pmid":"19386548","id":"PMC_19386548","title":"Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial.","date":"2009","source":"The Lancet. Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/19386548","citation_count":248,"is_preprint":false},{"pmid":"21752263","id":"PMC_21752263","title":"The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells.","date":"2011","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/21752263","citation_count":195,"is_preprint":false},{"pmid":"18042714","id":"PMC_18042714","title":"HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18042714","citation_count":190,"is_preprint":false},{"pmid":"32295417","id":"PMC_32295417","title":"Effects of Acute Colchicine Administration Prior to Percutaneous Coronary Intervention: COLCHICINE-PCI Randomized Trial.","date":"2020","source":"Circulation. 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The PRIVATE-ATLANTIC study.","date":"2015","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/27196998","citation_count":89,"is_preprint":false},{"pmid":"19417023","id":"PMC_19417023","title":"PCI-24781 induces caspase and reactive oxygen species-dependent apoptosis through NF-kappaB mechanisms and is synergistic with bortezomib in lymphoma cells.","date":"2009","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/19417023","citation_count":86,"is_preprint":false},{"pmid":"32646565","id":"PMC_32646565","title":"Post-Discharge Bleeding and Mortality Following Acute Coronary Syndromes With or Without PCI.","date":"2020","source":"Journal of the American College of Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/32646565","citation_count":81,"is_preprint":false},{"pmid":"10558879","id":"PMC_10558879","title":"Effect of arsenic trioxide on cell cycle arrest in head and 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Between Them.","date":"2018","source":"Current drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/27358059","citation_count":21,"is_preprint":false},{"pmid":"15678152","id":"PMC_15678152","title":"PCI-enhanced adenoviral transduction employs the known uptake mechanism of adenoviral particles.","date":"2005","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/15678152","citation_count":21,"is_preprint":false},{"pmid":"20036718","id":"PMC_20036718","title":"Cloning and molecular characterization of Dashurin encoded by C20orf116, a PCI-domain containing protein.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/20036718","citation_count":19,"is_preprint":false},{"pmid":"33500709","id":"PMC_33500709","title":"The histone deacetylase inhibitor PCI-24781 impairs calcium influx and inhibits proliferation and metastasis in breast 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39076545","citation_count":17,"is_preprint":false},{"pmid":"31533763","id":"PMC_31533763","title":"Patterns of brain metastasis immediately before prophylactic cranial irradiation (PCI): implications for PCI optimization in limited-stage small cell lung cancer.","date":"2019","source":"Radiation oncology (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/31533763","citation_count":17,"is_preprint":false},{"pmid":"28383427","id":"PMC_28383427","title":"Associations between P2RY12 gene polymorphisms and risks of clopidogrel resistance and adverse cardiovascular events after PCI in patients with acute coronary syndrome.","date":"2017","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28383427","citation_count":17,"is_preprint":false},{"pmid":"28783717","id":"PMC_28783717","title":"Effects of Dual-Dose Clopidogrel, Clopidogrel Combined with Tongxinluo Capsule, and Ticagrelor on Patients with Coronary Heart Disease and 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America","url":"https://pubmed.ncbi.nlm.nih.gov/23915749","citation_count":12,"is_preprint":false},{"pmid":"34740750","id":"PMC_34740750","title":"HDAC8-inhibitor PCI-34051-induced exosomes inhibit human bronchial smooth muscle cell proliferation via miR-381-3p mediated TGFB3.","date":"2021","source":"Pulmonary pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/34740750","citation_count":12,"is_preprint":false},{"pmid":"34625711","id":"PMC_34625711","title":"A novel amplification gene PCI domain containing 2 (PCID2) promotes colorectal cancer through directly degrading a tumor suppressor promyelocytic leukemia (PML).","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34625711","citation_count":12,"is_preprint":false},{"pmid":"26850062","id":"PMC_26850062","title":"Controversies in the treatment of patients with STEMI and multivessel disease: is it time for PCI of all lesions?","date":"2016","source":"Clinical research in cardiology : official journal of the German Cardiac Society","url":"https://pubmed.ncbi.nlm.nih.gov/26850062","citation_count":10,"is_preprint":false},{"pmid":"25488662","id":"PMC_25488662","title":"A+-helix of protein C inhibitor (PCI) is a cell-penetrating peptide that mediates cell membrane permeation of PCI.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25488662","citation_count":10,"is_preprint":false},{"pmid":"32493215","id":"PMC_32493215","title":"Bedside testing of CYP2C19 gene for treatment of patients with PCI with antiplatelet therapy.","date":"2020","source":"BMC cardiovascular disorders","url":"https://pubmed.ncbi.nlm.nih.gov/32493215","citation_count":10,"is_preprint":false},{"pmid":"30221557","id":"PMC_30221557","title":"Optimal duration of dual antiplatelet therapy after PCI: integrating procedural complexity, bleeding risk and the acuteness of clinical presentation.","date":"2018","source":"Expert review of cardiovascular 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disorders","url":"https://pubmed.ncbi.nlm.nih.gov/37735625","citation_count":8,"is_preprint":false},{"pmid":"34837923","id":"PMC_34837923","title":"Evaluation the Presence of SERPINA5 (Exon 3) and FTO rs9939609 Polymorphisms in Papillary Thyroid Cancer Patients.","date":"2021","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/34837923","citation_count":8,"is_preprint":false},{"pmid":"36982532","id":"PMC_36982532","title":"IFN-Inducible SerpinA5 Triggers Antiviral Immunity by Regulating STAT1 Phosphorylation and Nuclear Translocation.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36982532","citation_count":8,"is_preprint":false},{"pmid":"34964303","id":"PMC_34964303","title":"Proteomic analysis of human articular cartilage unravels the dyscoagulation in osteoarthritis and the potential value of serpinA5 as a biomarker for osteoarthritis.","date":"2022","source":"Proteomics. Clinical applications","url":"https://pubmed.ncbi.nlm.nih.gov/34964303","citation_count":8,"is_preprint":false},{"pmid":"37723117","id":"PMC_37723117","title":"Effects of PCSK9 inhibitors on coronary microcirculation, inflammation and cardiac function in patients with CHD after PCI: a protocol for systematic review and meta-analysis.","date":"2023","source":"BMJ open","url":"https://pubmed.ncbi.nlm.nih.gov/37723117","citation_count":8,"is_preprint":false},{"pmid":"35099783","id":"PMC_35099783","title":"An Economic Evaluation Supported by Qualitative Data About the Patient Concerns Inventory (PCI) versus Standard Treatment Pathway in the Management of Patients with Head and Neck Cancer.","date":"2022","source":"PharmacoEconomics - open","url":"https://pubmed.ncbi.nlm.nih.gov/35099783","citation_count":8,"is_preprint":false},{"pmid":"39563799","id":"PMC_39563799","title":"Exploring the Polypharmacological Potential of PCI-27483: A Selective Inhibitor of Carbonic Anhydrases IX and XII.","date":"2024","source":"ACS medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/39563799","citation_count":8,"is_preprint":false},{"pmid":"40234091","id":"PMC_40234091","title":"PCI-DB: a novel primary tissue immunopeptidome database to guide next-generation peptide-based immunotherapy development.","date":"2025","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40234091","citation_count":7,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55685,"output_tokens":3548,"usd":0.110137,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10906,"output_tokens":3781,"usd":0.074527,"stage2_stop_reason":"end_turn"},"total_usd":0.184664,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers that are actually about SERPINA5 (also known as PAI3, PROCI, PLANH3, PCI - protein C inhibitor). \n\nThe vast majority of papers are about:\n- PCI = percutaneous coronary intervention (medical procedure)\n- PCI-32765 = ibrutinib (BTK inhibitor)\n- PCI-24781 = abexinostat (HDAC inhibitor)\n- PCI-34051 = HDAC8 inhibitor\n- PCI domain proteins (proteasome lid, CSN, eIF3)\n- Prophylactic cranial irradiation\n- Photochemical internalization\n\nPapers genuinely about SERPINA5 (protein C inhibitor/PCI serpin): [30], [41], [43], [44], [50], [51], [82], [85], [86], [90], [92], [94], [95], [96]\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"SERPINA5 (PCI) is a non-specific serpin that inhibits multiple proteases of coagulation and fibrinolytic systems, plasma and tissue kallikreins, and the sperm protease acrosin. Heparin stimulates most SERPINA5/protease reactions but interferes with the tissue kallikrein/SERPINA5 interaction, thereby regulating both activity and specificity. SERPINA5 also binds glycosaminoglycans on the surface of epithelial kidney cells, which modulate its activity similarly to heparin.\",\n      \"method\": \"In vitro protease inhibition assays, cell-binding studies, mouse in vitro fertilization model\",\n      \"journal\": \"Immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro assays and cell-based experiments from a single lab establishing substrate scope and GAG-mediated regulation\",\n      \"pmids\": [\"8796266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SERPINA5 binds oxidized phosphatidylethanolamine (OxPE) and phosphatidylserine (PS) immobilized on microtiter plates and in aqueous suspension. This binding is competed by heparin. PS and OxPE stimulate SERPINA5 inhibition of activated protein C (aPC) in a Ca2+-dependent manner, requiring binding of both aPC (Ca2+-dependent) and SERPINA5 (Ca2+-independent) to phospholipids. A peptide corresponding to the heparin-binding site of SERPINA5 abolished the stimulatory effect of PS, and a SERPINA5 mutant lacking the heparin-binding site lost this phospholipid stimulation. This heparin-like effect of phospholipids was not observed with antithrombin III, indicating specificity for SERPINA5.\",\n      \"method\": \"ELISA-based phospholipid binding assays, competitive inhibition with heparin and annexin V, in vitro aPC inhibition assays with Ca2+ manipulation, site-directed mutagenesis (heparin-binding site mutant), immunolocalization in atherosclerotic plaques\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro biochemical assays with mutagenesis and multiple orthogonal methods (binding assay, activity assay, mutant, in vivo colocalization) in a single rigorous study\",\n      \"pmids\": [\"17332248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SERPINA5 inhibits tumor cell migration in hepatocellular carcinoma (HCC) through direct interaction with fibronectin, which disrupts the fibronectin-integrin signaling pathway. Secreted SERPINA5 protein also inhibits metastatic ability of HCC cells. DNA dosage and expression of SERPINA5 were decreased in HCC, and expression levels negatively correlated with malignant progression.\",\n      \"method\": \"In vitro migration/invasion assays, in vivo metastasis model, co-immunoprecipitation/direct interaction assay between SERPINA5 and fibronectin, exogenous secreted protein treatment\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding to fibronectin established, loss-of-function and gain-of-function with defined phenotypic readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24388360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The N-terminal A+-helix of SERPINA5 functions as a cell-penetrating peptide that mediates cell membrane permeation of the intact protein. Testisin, a GPI-anchored serine protease, cleaves SERPINA5 at the reactive site and near the N-terminus, releasing basic peptides corresponding to His1-Arg11 (human) and Arg1-Ala18 (mouse). These synthetic N-terminal peptides function as cell-penetrating peptides. A truncated mouse SERPINA5 lacking 18 N-terminal amino acids was not internalized by Jurkat T cells, whereas intact SERPINA5 was, indicating that the N-terminus is required for internalization and that testisin cleavage can regulate cellular uptake of SERPINA5.\",\n      \"method\": \"Recombinant protease cleavage assays (testisin in solution and membrane-anchored on U937 cells), synthetic peptide cell penetration assays, truncation mutant internalization in Jurkat T cells (flow cytometry/imaging)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with recombinant proteins, mutagenesis (truncation), synthetic peptide validation, cell-based internalization assays; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"25488662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SERPINA5 is internalized by cells (platelets, granulocytes, HL-60, and Jurkat cells) and translocated to the nucleus. Internalization is dependent on the phospholipid phosphatidylethanolamine (PE) and on the intact N-terminus of SERPINA5, which functions as a cell-penetrating peptide. SERPINA5 can directly cross the phospholipid bilayer of the cell membrane and penetrate pure phospholipid vesicles.\",\n      \"method\": \"Cell fractionation, immunofluorescence/nuclear translocation assays, phospholipid vesicle penetration experiments, N-terminal truncation studies\",\n      \"journal\": \"Seminars in cell & developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review synthesizing direct experimental evidence from multiple studies; cell fractionation and vesicle assays, single research group\",\n      \"pmids\": [\"27989561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SERPINA5 inhibits migration and invasion of endometrial cancer cells by suppressing integrin β1/FAK signaling pathway activation. Overexpression of SERPINA5 or delivery of exosomal SERPINA5 reduced integrin β1 and FAK phosphorylation in EC cell lines. Exosomal SERPINA5 also impeded tumor growth and metastasis in xenograft models.\",\n      \"method\": \"Cell migration/invasion assays, Western blotting of integrin β1/FAK pathway components, SERPINA5 overexpression constructs, therapeutic exosome delivery, xenograft mouse models\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined pathway placement via gain-of-function with mechanistic readout (phospho-FAK), in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"35951287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SERPINA5 promotes gastric cancer cell proliferation by inhibiting CBL, which leads to activation of the PI3K/AKT/mTOR signaling pathway. Knockdown of SERPINA5 reduced cell proliferation and migration in gastric cancer cell lines.\",\n      \"method\": \"qPCR expression analysis, SERPINA5 knockdown (siRNA/shRNA), cell proliferation and migration assays, pathway analysis (PI3K/AKT/mTOR signaling components by Western blot), public database survival analysis\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with phenotypic readout and pathway placement, but CBL interaction not directly validated by co-IP or pull-down in abstract\",\n      \"pmids\": [\"36000536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SERPINA5 functions as an interferon-stimulated gene (ISG) that promotes antiviral immunity by upregulating STAT1 phosphorylation and promoting STAT1 nuclear translocation, thereby activating transcription of IFN-related signaling pathways.\",\n      \"method\": \"Overexpression and knockdown of SerpinA5, Western blotting for phospho-STAT1 and nuclear STAT1 fractionation, reporter assays for IFN-pathway transcription, viral infection models\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assays with gain/loss-of-function establishing pathway position (STAT1 phosphorylation and nuclear translocation), single lab with multiple readouts\",\n      \"pmids\": [\"36982532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Elevated SERPINA5 levels in a preeclampsia-like rat model (L-NAME-induced) exacerbated hypertension and proteinuria, while suppression of SERPINA5 expression mitigated these features and improved placental development. Placental mRNA sequencing following SERPINA5 overexpression indicated increased coagulation cascade activation, suggesting SERPINA5 worsens preeclampsia-like features by promoting coagulation.\",\n      \"method\": \"Adenoviral overexpression/suppression of SERPINA5 in pregnant rats, blood pressure measurement, urine protein quantification, placental histology, mRNA sequencing of placental tissue\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain and loss-of-function with defined phenotypic readouts and transcriptomic pathway analysis; single lab\",\n      \"pmids\": [\"38136662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SERPINA5 (PCI) is expressed in benign prostatic epithelium, PIN lesions, and prostate tumor cells. PCI inhibits human glandular kallikrein-2 (hK2) and, less readily, prostate-specific antigen (PSA), suggesting a role as a local regulator of enzymatic activity in seminal fluid.\",\n      \"method\": \"Immunohistochemistry on tissue microarray, in situ hybridization, Western blotting in prostate cell lines (PC-3, DU-145, LNCaP)\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization and expression established by IHC/ISH/WB; inhibitory activity inferred from prior literature rather than directly demonstrated in this paper\",\n      \"pmids\": [\"14518028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Screening of the SERPINA5 (PCI) gene in subfertile men with severe teratozoospermia or idiopathic azoospermia found no causal mutations; PCI antigen levels in seminal plasma were not decreased in the three patients with novel variants. This negative result indicates that mutations in the human PCI gene are not a common cause of reduced semen parameters.\",\n      \"method\": \"Direct sequencing of PCI gene in subfertile men, RFLP analysis in controls, ELISA measurement of PCI antigen in seminal plasma\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — negative finding; single study, genetic screening with seminal plasma antigen measurement\",\n      \"pmids\": [\"15377716\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SERPINA5 (protein C inhibitor/PCI) is a secreted, broad-specificity serpin that inhibits multiple coagulation, fibrinolytic, and kallikrein-family proteases; its inhibitory activity and substrate specificity are modulated by glycosaminoglycans (especially heparin) and phospholipids (including oxidized PE and PS) acting at its heparin-binding site. The intact N-terminal A+-helix functions as a cell-penetrating peptide enabling SERPINA5 to cross the plasma membrane via a phosphatidylethanolamine-dependent mechanism and translocate to the nucleus, a process regulated by N-terminal cleavage by testisin. Extracellularly, secreted SERPINA5 suppresses tumor cell migration in hepatocellular and endometrial cancers by directly binding fibronectin and disrupting fibronectin-integrin β1/FAK signaling; in gastric cancer it paradoxically promotes proliferation by inhibiting CBL to activate PI3K/AKT/mTOR. SERPINA5 also acts as an interferon-stimulated gene that enhances antiviral innate immunity by upregulating STAT1 phosphorylation and nuclear translocation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SERPINA5 (protein C inhibitor/PCI) is a secreted, broad-specificity serpin that inhibits multiple coagulation, fibrinolytic, and kallikrein-family proteases, including activated protein C, plasma and tissue kallikreins, and the sperm protease acrosin [#0]. Its inhibitory activity and substrate selectivity are tuned by cofactors that engage its heparin-binding site: heparin and surface glycosaminoglycans stimulate most protease reactions while interfering with the tissue kallikrein interaction [#0], and anionic phospholipids—oxidized phosphatidylethanolamine and phosphatidylserine—act as heparin-like cofactors that stimulate activated protein C inhibition in a Ca2+-dependent manner, an effect lost in a heparin-binding-site mutant [#1]. Beyond protease inhibition, the intact N-terminal A+-helix of SERPINA5 functions as a cell-penetrating peptide that drives phosphatidylethanolamine-dependent membrane crossing and nuclear translocation; cleavage near the N-terminus by the GPI-anchored protease testisin removes this element and regulates cellular uptake [#3, #4]. Extracellularly, secreted SERPINA5 suppresses tumor cell migration and invasion by binding fibronectin and disrupting fibronectin–integrin β1/FAK signaling in hepatocellular and endometrial cancers [#2, #5], whereas in gastric cancer it promotes proliferation via inhibition of CBL and activation of PI3K/AKT/mTOR signaling [#6]. SERPINA5 additionally acts as an interferon-stimulated gene that enhances antiviral innate immunity by promoting STAT1 phosphorylation and nuclear translocation [#7], and elevated SERPINA5 worsens preeclampsia-like features in a rat model through enhanced coagulation cascade activation [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established SERPINA5 as a broad-specificity serpin and showed that glycosaminoglycans set both its activity and protease selectivity, framing it as a cofactor-regulated inhibitor rather than a single-target enzyme.\",\n      \"evidence\": \"In vitro protease inhibition assays, epithelial cell-binding studies, and a mouse IVF model defining substrate scope and heparin/GAG modulation\",\n      \"pmids\": [\"8796266\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of how GAG binding redirects specificity not resolved\", \"Physiological cofactor identity in each tissue not defined\", \"Relative contribution of each protease target in vivo unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placed SERPINA5 in prostate epithelium as a candidate local regulator of seminal kallikrein activity, extending its protease targets to hK2 and PSA.\",\n      \"evidence\": \"Immunohistochemistry, in situ hybridization, and Western blotting across benign, PIN, and tumor prostate tissue and cell lines\",\n      \"pmids\": [\"14518028\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Inhibitory activity inferred rather than directly demonstrated in this study\", \"No functional consequence in seminal fluid established\", \"Causal role in prostate pathology untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Tested whether SERPINA5 mutations underlie male subfertility and found none, excluding the gene as a common genetic cause of impaired semen parameters.\",\n      \"evidence\": \"Direct gene sequencing in subfertile men, RFLP in controls, and ELISA of seminal plasma antigen\",\n      \"pmids\": [\"15377716\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Negative result; does not exclude rare or regulatory variants\", \"Small variant-carrier sample\", \"Functional role in fertility not directly addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that anionic phospholipids act as heparin-like cofactors specific to SERPINA5, defining a phospholipid-dependent, Ca2+-regulated route to enhanced activated protein C inhibition.\",\n      \"evidence\": \"ELISA phospholipid-binding assays, heparin/annexin V competition, Ca2+-controlled aPC inhibition, heparin-binding-site mutagenesis and peptide competition, plus atherosclerotic plaque colocalization\",\n      \"pmids\": [\"17332248\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"In vivo relevance of phospholipid cofactor at lesion sites not quantified\", \"Which physiological membranes present these lipids to SERPINA5 unclear\", \"Structural model of the lipid-bound inhibitor absent\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a non-inhibitory extracellular function: SERPINA5 binds fibronectin to disrupt fibronectin-integrin signaling and suppress HCC migration and metastasis, linking it to tumor suppression.\",\n      \"evidence\": \"Migration/invasion and in vivo metastasis assays, direct SERPINA5-fibronectin interaction assay, and exogenous secreted protein treatment with DNA dosage/expression correlation in HCC\",\n      \"pmids\": [\"24388360\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Binding interface on fibronectin not mapped\", \"Whether protease-inhibitory activity contributes unknown\", \"Mechanism of integrin signaling disruption not fully resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the N-terminal A+-helix as a cell-penetrating peptide and testisin as a protease that cleaves SERPINA5 to regulate its internalization, establishing a mechanism for cellular uptake.\",\n      \"evidence\": \"Recombinant and membrane-anchored testisin cleavage assays, synthetic N-terminal peptide penetration tests, and truncation-mutant internalization in Jurkat T cells\",\n      \"pmids\": [\"25488662\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional consequence of nuclear SERPINA5 not defined here\", \"Physiological context where testisin gates uptake unclear\", \"Receptor/transport machinery beyond the peptide not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the uptake model by showing PE-dependent membrane crossing and nuclear translocation across multiple cell types and into pure lipid vesicles, demonstrating receptor-independent bilayer penetration.\",\n      \"evidence\": \"Cell fractionation, immunofluorescence nuclear translocation, phospholipid vesicle penetration, and N-terminal truncation studies\",\n      \"pmids\": [\"27989561\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Nuclear function of internalized SERPINA5 unknown\", \"Quantitative contribution of PE versus other lipids unresolved\", \"Synthesizes single-group data\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed context-dependent roles in cancer: SERPINA5 suppresses endometrial cancer via integrin β1/FAK inhibition but promotes gastric cancer proliferation by inhibiting CBL to activate PI3K/AKT/mTOR.\",\n      \"evidence\": \"Overexpression/knockdown with phospho-FAK and PI3K/AKT/mTOR Western blots, migration/invasion assays, exosomal delivery, and xenograft models\",\n      \"pmids\": [\"35951287\", \"36000536\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"SERPINA5-CBL interaction not directly validated by co-IP\", \"Basis of opposing tumor roles across tissues unexplained\", \"Whether intracellular versus secreted pools drive each phenotype unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed SERPINA5 in innate immunity as an interferon-stimulated gene that amplifies STAT1 signaling, and in vascular pathology as a coagulation-promoting aggravator of preeclampsia-like disease.\",\n      \"evidence\": \"Gain/loss-of-function with phospho- and nuclear-STAT1 readouts, IFN reporter assays, and viral infection models; plus adenoviral SERPINA5 manipulation in a rat preeclampsia model with placental mRNA-seq\",\n      \"pmids\": [\"36982532\", \"38136662\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular link between SERPINA5 and STAT1 phosphorylation not defined\", \"Whether antiviral and coagulation roles share a mechanism unknown\", \"Direct protease targets driving preeclampsia phenotype not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single secreted serpin integrates cofactor-tuned protease inhibition, cell penetration and nuclear localization, fibronectin/integrin signaling, and STAT1-dependent immunity into coherent physiology remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No unifying mechanism connecting extracellular inhibitory and intracellular signaling functions\", \"Functional output of nuclear-translocated SERPINA5 unknown\", \"Structural basis of cofactor-switched specificity not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"F2RL... \"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}