{"gene":"SERPINA5","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2013,"finding":"SERPINA5 inhibits hepatocellular carcinoma (HCC) cell migration and metastasis through direct interaction with fibronectin and disruption of the fibronectin-integrin β1 signaling pathway. Secreted SERPINA5 protein also inhibits metastatic ability of HCC cells.","method":"Co-immunoprecipitation/pulldown (direct interaction with fibronectin), in vitro migration/invasion assays, in vivo metastasis model, overexpression/knockdown experiments","journal":"Molecular oncology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction demonstrated, multiple orthogonal methods (binding assay, in vitro functional assay, in vivo model), moderate evidence","pmids":["24388360"],"is_preprint":false},{"year":2016,"finding":"SERPINA5 (protein C inhibitor, PCI) is internalized by cells (platelets, granulocytes, HL-60, Jurkat cells) and translocated to the nucleus. Internalization depends on the phospholipid phosphatidylethanolamine and on an intact N-terminus of SERPINA5, which functions as a cell-penetrating peptide.","method":"Cell fractionation, fluorescence microscopy, phospholipid binding assays, N-terminal deletion/mutation experiments","journal":"Seminars in cell & developmental biology","confidence":"Medium","confidence_rationale":"Tier 2/3 — multiple localization and functional experiments cited in review, single lab","pmids":["27989561"],"is_preprint":false},{"year":2007,"finding":"SERPINA5 (protein C inhibitor) binds oxidized phosphatidylethanolamine (OxPE) and phosphatidylserine (PS), and these phospholipids stimulate SERPINA5-mediated inhibition of activated protein C (aPC) in a Ca2+-dependent and heparin-binding-site-dependent manner, mimicking a heparin-like effect specific to SERPINA5 (not seen with antithrombin III).","method":"ELISA-based phospholipid binding, competition assays with heparin and annexin V, in vitro aPC inhibition assays, PCI heparin-binding site mutant, immunohistochemistry of atherosclerotic plaques","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution with mutagenesis and multiple controls, multiple orthogonal methods in single study","pmids":["17332248"],"is_preprint":false},{"year":1996,"finding":"SERPINA5 (protein C inhibitor) is a non-specific serpin that inhibits activated protein C, urokinase plasminogen activator, plasma and tissue kallikreins, and the sperm protease acrosin. Heparin and other glycosaminoglycans (GAGs) modulate both SERPINA5 activity and specificity, and GAGs on renal epithelial cell surfaces bind SERPINA5. Endogenous SERPINA5 localizes to disrupted acrosomal membranes of morphologically abnormal spermatozoa, and human SERPINA5 inhibits sperm/egg binding and reduces fertilization rate in a mouse in vitro fertilization model.","method":"In vitro protease inhibition assays, heparin affinity, immunocytochemistry, mouse in vitro fertilization model, Northern blotting","journal":"Immunopharmacology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple in vitro enzymatic assays, in vivo fertilization model, localization data; replicated across contexts in a single comprehensive study","pmids":["8796266"],"is_preprint":false},{"year":2022,"finding":"SERPINA5 overexpression or exosomal delivery inhibits endometrial cancer (EC) cell migration and invasion by suppressing integrin β1/FAK signaling pathway activation. Exosomal SERPINA5 also impeded tumor growth and metastasis in xenograft models.","method":"Overexpression/knockdown, cell migration/invasion assays, Western blot for integrin β1/FAK pathway, xenograft mouse model, ELISA for exosomal SERPINA5","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods including in vivo model, single lab","pmids":["35951287"],"is_preprint":false},{"year":2022,"finding":"SERPINA5 promotes gastric cancer cell proliferation by inhibiting CBL to activate the PI3K/AKT/mTOR signaling pathway.","method":"Knockdown experiments, pathway analysis (Western blot for PI3K/AKT/mTOR), cell proliferation assays","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 — single lab, limited mechanistic validation of CBL interaction","pmids":["36000536"],"is_preprint":false},{"year":2023,"finding":"SERPINA5 (SerpinA5), identified as an interferon-stimulated gene (ISG), promotes antiviral immunity by upregulating STAT1 phosphorylation and promoting STAT1 nuclear translocation, thereby activating transcription of IFN-related signaling pathway genes.","method":"Overexpression/knockdown, Western blot for STAT1 phosphorylation, nuclear fractionation, viral infection assays, reporter assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (phosphorylation, nuclear translocation, antiviral functional assay), single lab","pmids":["36982532"],"is_preprint":false},{"year":2017,"finding":"SERPINA5 membrane penetration/internalization requires an intact N-terminus (which acts as a cell-penetrating peptide) and the phospholipid phosphatidylethanolamine. SERPINA5 can directly cross the phospholipid bilayer of cellular membranes.","method":"Phospholipid vesicle penetration assays, N-terminal deletion mutants, cell internalization assays with fractionation","journal":"Advances in experimental medicine and biology","confidence":"Medium","confidence_rationale":"Tier 2/3 — multiple experimental approaches described, but review article synthesizing prior findings","pmids":["28639251"],"is_preprint":false},{"year":2023,"finding":"In a rat preeclampsia-like model, overexpression of SERPINA5 exacerbated hypertension and proteinuria and increased coagulation cascade activation in placenta (by mRNA sequencing), while suppression of SERPINA5 mitigated hypertension, proteinuria, and improved placental development, indicating SERPINA5 promotes coagulation activation to worsen preeclampsia-like features.","method":"Adenoviral overexpression/suppression in rats, blood pressure and urine protein measurement, placental histology, mRNA sequencing","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo gain- and loss-of-function with mechanistic pathway data, single lab","pmids":["38136662"],"is_preprint":false},{"year":2021,"finding":"In trophoblast cells, SerpinA5 may interfere with trophoblastic invasion by inhibiting macrophage-stimulating protein (MSP), and SERPINA5 is elevated in preeclamptic placenta.","method":"SerpinA5 overexpression/downregulation in TEV-1 cells (trophoblast line), invasion assay, immunohistochemistry, ELISA","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 — single lab, limited mechanistic characterization of MSP interaction","pmids":["34648566"],"is_preprint":false},{"year":2004,"finding":"Sequencing of the SERPINA5 (PCI) gene in subfertile men with severe teratozoospermia or idiopathic azoospermia found no causal mutations, and PCI antigen levels in seminal plasma were not decreased in the three men with identified variants, indicating PCI gene mutations are not a common cause of reduced semen parameters in men.","method":"Direct sequencing of PCI gene, RFLP analysis, ELISA of PCI antigen in seminal plasma","journal":"Molecular human reproduction","confidence":"Low","confidence_rationale":"Tier 3 — genetic screen with functional assay, but negative result and small cohort","pmids":["15377716"],"is_preprint":false}],"current_model":"SERPINA5 (protein C inhibitor/PCI) is a secreted broad-specificity serpin that inhibits activated protein C, urokinase, kallikreins, and acrosin; its activity and specificity are modulated by heparin, glycosaminoglycans, and phospholipids (especially phosphatidylethanolamine and oxidized PS), which act via its heparin-binding site; it can penetrate cell membranes via its N-terminal cell-penetrating peptide in a phosphatidylethanolamine-dependent manner and translocate to the nucleus; extracellularly it suppresses tumor cell migration by binding fibronectin and disrupting integrin β1/FAK signaling; and intracellularly it promotes antiviral immunity by upregulating STAT1 phosphorylation and nuclear translocation."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing SERPINA5 as a broad-specificity serpin resolved the question of whether PCI acts only on activated protein C or has wider protease targets, and revealed its role in reproduction by showing it inhibits acrosin and blocks sperm-egg binding.","evidence":"In vitro protease inhibition assays against multiple substrates, heparin modulation studies, immunocytochemistry on spermatozoa, and mouse in vitro fertilization model","pmids":["8796266"],"confidence":"High","gaps":["Structural basis for broad specificity not determined","Physiological relevance of GAG modulation in vivo not established","Whether SERPINA5 is essential for fertility in humans remained unclear"]},{"year":2004,"claim":"Genetic screening addressed whether SERPINA5 mutations underlie male subfertility, finding no causal variants and indicating that PCI deficiency is not a common genetic cause of teratozoospermia or azoospermia.","evidence":"Direct sequencing of SERPINA5 gene and seminal plasma PCI antigen ELISA in subfertile men","pmids":["15377716"],"confidence":"Low","gaps":["Small cohort limits generalizability","Functional consequences of identified rare variants not tested in protease inhibition assays","Does not exclude a role for SERPINA5 in other aspects of reproductive biology"]},{"year":2007,"claim":"Demonstrating that oxidized phospholipids (OxPE, PS) stimulate SERPINA5 inhibition of activated protein C through its heparin-binding site revealed a novel lipid-dependent regulatory mechanism distinct from classical GAG modulation.","evidence":"ELISA-based phospholipid binding, competition assays with heparin and annexin V, in vitro aPC inhibition with heparin-binding site mutant, immunohistochemistry of atherosclerotic plaques","pmids":["17332248"],"confidence":"High","gaps":["In vivo contribution of OxPE/PS-mediated activation in thrombosis or atherosclerosis not tested","Structural details of phospholipid interaction with the heparin-binding site unresolved"]},{"year":2013,"claim":"Discovery that SERPINA5 directly binds fibronectin and disrupts integrin β1 signaling to suppress HCC cell migration established a non-protease-inhibitory anti-metastatic mechanism for this serpin.","evidence":"Co-immunoprecipitation/pulldown for fibronectin interaction, in vitro migration/invasion assays, in vivo metastasis model with overexpression and knockdown","pmids":["24388360"],"confidence":"High","gaps":["Whether anti-metastatic effect requires serpin protease-inhibitory activity or is independent","Fibronectin binding site on SERPINA5 not mapped"]},{"year":2016,"claim":"Showing that SERPINA5 is internalized and translocated to the nucleus via an N-terminal cell-penetrating peptide in a phosphatidylethanolamine-dependent manner revealed an unexpected intracellular life for this secreted serpin.","evidence":"Cell fractionation, fluorescence microscopy, phospholipid binding assays, N-terminal deletion/mutation experiments in platelets, granulocytes, HL-60, and Jurkat cells","pmids":["27989561","28639251"],"confidence":"Medium","gaps":["Nuclear function of internalized SERPINA5 not identified","Findings from a single lab and partly presented in review format","Mechanism of membrane translocation at the biophysical level not resolved"]},{"year":2022,"claim":"Replication of the integrin β1/FAK suppression mechanism in endometrial cancer, including exosomal delivery, confirmed that SERPINA5's anti-invasive activity generalizes across tumor types and can be mediated by exosomes.","evidence":"Overexpression/knockdown in EC cells, Western blot for integrin β1/FAK pathway, xenograft mouse model, ELISA for exosomal SERPINA5","pmids":["35951287"],"confidence":"Medium","gaps":["Whether exosomal SERPINA5 acts identically to free secreted protein not distinguished","Receptor or uptake mechanism for exosomal delivery not characterized"]},{"year":2023,"claim":"Identification of SERPINA5 as an interferon-stimulated gene that enhances STAT1 phosphorylation and nuclear translocation linked its intracellular function to innate antiviral immunity, providing a functional consequence for nuclear translocation.","evidence":"Overexpression/knockdown, Western blot for STAT1 phosphorylation, nuclear fractionation, viral infection assays, reporter assays","pmids":["36982532"],"confidence":"Medium","gaps":["Direct molecular target through which SERPINA5 enhances STAT1 phosphorylation unknown","Whether antiviral function requires serpin protease-inhibitory activity or cell-penetrating peptide not tested","Findings from single lab"]},{"year":2023,"claim":"In vivo gain- and loss-of-function in a rat preeclampsia model showed SERPINA5 promotes coagulation activation and worsens disease features, connecting its hemostatic function to placental pathology.","evidence":"Adenoviral overexpression/suppression in rats, blood pressure and proteinuria measurement, placental histology, mRNA sequencing","pmids":["38136662"],"confidence":"Medium","gaps":["Specific protease target(s) mediating placental coagulation activation not identified","Relevance to human preeclampsia not validated"]},{"year":null,"claim":"The direct molecular target by which intracellular SERPINA5 activates STAT1 signaling, the nuclear function of translocated SERPINA5, and whether its protease-inhibitory and non-inhibitory (fibronectin-binding, cell-penetrating) activities are functionally separable in vivo remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of SERPINA5 in complex with fibronectin or phospholipids","No separation-of-function mutant distinguishing protease inhibition from anti-metastatic or antiviral activities","Nuclear targets or gene-regulatory role of internalized SERPINA5 uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2,7]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,7]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,7]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[2,3,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[3]}],"complexes":[],"partners":["FN1","ITGB1","PROC","PLAU","STAT1"],"other_free_text":[]},"mechanistic_narrative":"SERPINA5 (protein C inhibitor/PCI) is a secreted serpin-family serine protease inhibitor with broad specificity that functions in hemostasis, reproduction, cell invasion, and innate immunity. It inhibits activated protein C, urokinase, kallikreins, and acrosin, with its activity and target specificity modulated by heparin, glycosaminoglycans, and phospholipids—oxidized phosphatidylethanolamine and phosphatidylserine stimulate its inhibition of activated protein C through its heparin-binding site in a Ca²⁺-dependent manner [PMID:8796266, PMID:17332248]. Extracellularly, SERPINA5 suppresses tumor cell migration and metastasis by binding fibronectin and disrupting integrin β1/FAK signaling [PMID:24388360, PMID:35951287], and it can penetrate cell membranes via an N-terminal cell-penetrating peptide in a phosphatidylethanolamine-dependent manner, translocating to the nucleus [PMID:27989561, PMID:28639251]. As an interferon-stimulated gene, intracellular SERPINA5 promotes antiviral responses by enhancing STAT1 phosphorylation and nuclear translocation [PMID:36982532]."},"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":1259,"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":921,"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":889,"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":"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":379,"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. Cardiovascular interventions","url":"https://pubmed.ncbi.nlm.nih.gov/32295417","citation_count":140,"is_preprint":false},{"pmid":"23425038","id":"PMC_23425038","title":"Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765).","date":"2013","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/23425038","citation_count":120,"is_preprint":false},{"pmid":"15904532","id":"PMC_15904532","title":"PCI proteins eIF3e and eIF3m define distinct translation initiation factor 3 complexes.","date":"2005","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/15904532","citation_count":120,"is_preprint":false},{"pmid":"19683491","id":"PMC_19683491","title":"PCI complexes: Beyond the proteasome, CSN, and eIF3 Troika.","date":"2009","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/19683491","citation_count":96,"is_preprint":false},{"pmid":"28230176","id":"PMC_28230176","title":"Antithrombotic therapy for patients with STEMI undergoing primary PCI.","date":"2017","source":"Nature reviews. Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/28230176","citation_count":91,"is_preprint":false},{"pmid":"27196998","id":"PMC_27196998","title":"P2Y12 receptor inhibition and effect of morphine in patients undergoing primary PCI for ST-segment elevation myocardial infarction. 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":84,"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":77,"is_preprint":false},{"pmid":"23296407","id":"PMC_23296407","title":"Ibrutinib (PCI-32765), the first BTK (Bruton's tyrosine kinase) inhibitor in clinical trials.","date":"2013","source":"Current hematologic malignancy reports","url":"https://pubmed.ncbi.nlm.nih.gov/23296407","citation_count":76,"is_preprint":false},{"pmid":"20552345","id":"PMC_20552345","title":"Photochemical internalization (PCI): a technology for drug delivery.","date":"2010","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/20552345","citation_count":62,"is_preprint":false},{"pmid":"11199268","id":"PMC_11199268","title":"Role of endosomes in gene transfection mediated by photochemical internalisation (PCI).","date":"2000","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11199268","citation_count":58,"is_preprint":false},{"pmid":"21450602","id":"PMC_21450602","title":"High intensity interval training reduces systemic inflammation in post-PCI patients.","date":"2011","source":"European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21450602","citation_count":53,"is_preprint":false},{"pmid":"32178526","id":"PMC_32178526","title":"Rivaroxaban Plus Aspirin Versus Aspirin Alone in Patients With Prior Percutaneous Coronary Intervention (COMPASS-PCI).","date":"2020","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/32178526","citation_count":45,"is_preprint":false},{"pmid":"28882584","id":"PMC_28882584","title":"Prophylactic Cranial Irradiation (PCI) versus Active MRI Surveillance for Small Cell Lung Cancer: The Case for Equipoise.","date":"2017","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28882584","citation_count":43,"is_preprint":false},{"pmid":"18006784","id":"PMC_18006784","title":"Radiosensitization by the histone deacetylase inhibitor PCI-24781.","date":"2007","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/18006784","citation_count":41,"is_preprint":false},{"pmid":"20461381","id":"PMC_20461381","title":"Histone deacetylase inhibitor (HDACI) PCI-24781 potentiates cytotoxic effects of doxorubicin in bone sarcoma cells.","date":"2010","source":"Cancer chemotherapy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20461381","citation_count":41,"is_preprint":false},{"pmid":"24388360","id":"PMC_24388360","title":"SERPINA5 inhibits tumor cell migration by modulating the fibronectin-integrin β1 signaling pathway in hepatocellular carcinoma.","date":"2013","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24388360","citation_count":40,"is_preprint":false},{"pmid":"11172589","id":"PMC_11172589","title":"Potential role of caspase-3 and -9 in arsenic trioxide-mediated apoptosis in PCI-1 head and neck cancer cells.","date":"2001","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/11172589","citation_count":38,"is_preprint":false},{"pmid":"23567040","id":"PMC_23567040","title":"Photochemical internalization (PCI) of immunotoxins targeting CD133 is specific and highly potent at femtomolar levels in cells with cancer stem cell properties.","date":"2013","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/23567040","citation_count":38,"is_preprint":false},{"pmid":"34353593","id":"PMC_34353593","title":"Implications of Periprocedural Myocardial Biomarker Elevations and Commonly Used MI Definitions After Left Main PCI.","date":"2021","source":"JACC. 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\"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"SERPINA5 inhibits hepatocellular carcinoma (HCC) cell migration and metastasis through direct interaction with fibronectin and disruption of the fibronectin-integrin β1 signaling pathway. Secreted SERPINA5 protein also inhibits metastatic ability of HCC cells.\",\n      \"method\": \"Co-immunoprecipitation/pulldown (direct interaction with fibronectin), in vitro migration/invasion assays, in vivo metastasis model, overexpression/knockdown experiments\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction demonstrated, multiple orthogonal methods (binding assay, in vitro functional assay, in vivo model), moderate evidence\",\n      \"pmids\": [\"24388360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SERPINA5 (protein C inhibitor, PCI) is internalized by cells (platelets, granulocytes, HL-60, Jurkat cells) and translocated to the nucleus. Internalization depends on the phospholipid phosphatidylethanolamine and on an intact N-terminus of SERPINA5, which functions as a cell-penetrating peptide.\",\n      \"method\": \"Cell fractionation, fluorescence microscopy, phospholipid binding assays, N-terminal deletion/mutation experiments\",\n      \"journal\": \"Seminars in cell & developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — multiple localization and functional experiments cited in review, single lab\",\n      \"pmids\": [\"27989561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SERPINA5 (protein C inhibitor) binds oxidized phosphatidylethanolamine (OxPE) and phosphatidylserine (PS), and these phospholipids stimulate SERPINA5-mediated inhibition of activated protein C (aPC) in a Ca2+-dependent and heparin-binding-site-dependent manner, mimicking a heparin-like effect specific to SERPINA5 (not seen with antithrombin III).\",\n      \"method\": \"ELISA-based phospholipid binding, competition assays with heparin and annexin V, in vitro aPC inhibition assays, PCI heparin-binding site mutant, immunohistochemistry of atherosclerotic plaques\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution with mutagenesis and multiple controls, multiple orthogonal methods in single study\",\n      \"pmids\": [\"17332248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SERPINA5 (protein C inhibitor) is a non-specific serpin that inhibits activated protein C, urokinase plasminogen activator, plasma and tissue kallikreins, and the sperm protease acrosin. Heparin and other glycosaminoglycans (GAGs) modulate both SERPINA5 activity and specificity, and GAGs on renal epithelial cell surfaces bind SERPINA5. Endogenous SERPINA5 localizes to disrupted acrosomal membranes of morphologically abnormal spermatozoa, and human SERPINA5 inhibits sperm/egg binding and reduces fertilization rate in a mouse in vitro fertilization model.\",\n      \"method\": \"In vitro protease inhibition assays, heparin affinity, immunocytochemistry, mouse in vitro fertilization model, Northern blotting\",\n      \"journal\": \"Immunopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple in vitro enzymatic assays, in vivo fertilization model, localization data; replicated across contexts in a single comprehensive study\",\n      \"pmids\": [\"8796266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SERPINA5 overexpression or exosomal delivery inhibits endometrial cancer (EC) cell migration and invasion by suppressing integrin β1/FAK signaling pathway activation. Exosomal SERPINA5 also impeded tumor growth and metastasis in xenograft models.\",\n      \"method\": \"Overexpression/knockdown, cell migration/invasion assays, Western blot for integrin β1/FAK pathway, xenograft mouse model, ELISA for exosomal SERPINA5\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods including in vivo model, 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 to activate the PI3K/AKT/mTOR signaling pathway.\",\n      \"method\": \"Knockdown experiments, pathway analysis (Western blot for PI3K/AKT/mTOR), cell proliferation assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, limited mechanistic validation of CBL interaction\",\n      \"pmids\": [\"36000536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SERPINA5 (SerpinA5), identified as an interferon-stimulated gene (ISG), promotes antiviral immunity by upregulating STAT1 phosphorylation and promoting STAT1 nuclear translocation, thereby activating transcription of IFN-related signaling pathway genes.\",\n      \"method\": \"Overexpression/knockdown, Western blot for STAT1 phosphorylation, nuclear fractionation, viral infection assays, reporter assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (phosphorylation, nuclear translocation, antiviral functional assay), single lab\",\n      \"pmids\": [\"36982532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SERPINA5 membrane penetration/internalization requires an intact N-terminus (which acts as a cell-penetrating peptide) and the phospholipid phosphatidylethanolamine. SERPINA5 can directly cross the phospholipid bilayer of cellular membranes.\",\n      \"method\": \"Phospholipid vesicle penetration assays, N-terminal deletion mutants, cell internalization assays with fractionation\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — multiple experimental approaches described, but review article synthesizing prior findings\",\n      \"pmids\": [\"28639251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In a rat preeclampsia-like model, overexpression of SERPINA5 exacerbated hypertension and proteinuria and increased coagulation cascade activation in placenta (by mRNA sequencing), while suppression of SERPINA5 mitigated hypertension, proteinuria, and improved placental development, indicating SERPINA5 promotes coagulation activation to worsen preeclampsia-like features.\",\n      \"method\": \"Adenoviral overexpression/suppression in rats, blood pressure and urine protein measurement, placental histology, mRNA sequencing\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain- and loss-of-function with mechanistic pathway data, single lab\",\n      \"pmids\": [\"38136662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In trophoblast cells, SerpinA5 may interfere with trophoblastic invasion by inhibiting macrophage-stimulating protein (MSP), and SERPINA5 is elevated in preeclamptic placenta.\",\n      \"method\": \"SerpinA5 overexpression/downregulation in TEV-1 cells (trophoblast line), invasion assay, immunohistochemistry, ELISA\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, limited mechanistic characterization of MSP interaction\",\n      \"pmids\": [\"34648566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Sequencing of the SERPINA5 (PCI) gene in subfertile men with severe teratozoospermia or idiopathic azoospermia found no causal mutations, and PCI antigen levels in seminal plasma were not decreased in the three men with identified variants, indicating PCI gene mutations are not a common cause of reduced semen parameters in men.\",\n      \"method\": \"Direct sequencing of PCI gene, RFLP analysis, ELISA of PCI antigen in seminal plasma\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic screen with functional assay, but negative result and small cohort\",\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 activated protein C, urokinase, kallikreins, and acrosin; its activity and specificity are modulated by heparin, glycosaminoglycans, and phospholipids (especially phosphatidylethanolamine and oxidized PS), which act via its heparin-binding site; it can penetrate cell membranes via its N-terminal cell-penetrating peptide in a phosphatidylethanolamine-dependent manner and translocate to the nucleus; extracellularly it suppresses tumor cell migration by binding fibronectin and disrupting integrin β1/FAK signaling; and intracellularly it promotes antiviral immunity by upregulating STAT1 phosphorylation and nuclear translocation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SERPINA5 (protein C inhibitor/PCI) is a secreted serpin-family serine protease inhibitor with broad specificity that functions in hemostasis, reproduction, cell invasion, and innate immunity. It inhibits activated protein C, urokinase, kallikreins, and acrosin, with its activity and target specificity modulated by heparin, glycosaminoglycans, and phospholipids—oxidized phosphatidylethanolamine and phosphatidylserine stimulate its inhibition of activated protein C through its heparin-binding site in a Ca²⁺-dependent manner [PMID:8796266, PMID:17332248]. Extracellularly, SERPINA5 suppresses tumor cell migration and metastasis by binding fibronectin and disrupting integrin β1/FAK signaling [PMID:24388360, PMID:35951287], and it can penetrate cell membranes via an N-terminal cell-penetrating peptide in a phosphatidylethanolamine-dependent manner, translocating to the nucleus [PMID:27989561, PMID:28639251]. As an interferon-stimulated gene, intracellular SERPINA5 promotes antiviral responses by enhancing STAT1 phosphorylation and nuclear translocation [PMID:36982532].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing SERPINA5 as a broad-specificity serpin resolved the question of whether PCI acts only on activated protein C or has wider protease targets, and revealed its role in reproduction by showing it inhibits acrosin and blocks sperm-egg binding.\",\n      \"evidence\": \"In vitro protease inhibition assays against multiple substrates, heparin modulation studies, immunocytochemistry on spermatozoa, and mouse in vitro fertilization model\",\n      \"pmids\": [\"8796266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for broad specificity not determined\",\n        \"Physiological relevance of GAG modulation in vivo not established\",\n        \"Whether SERPINA5 is essential for fertility in humans remained unclear\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Genetic screening addressed whether SERPINA5 mutations underlie male subfertility, finding no causal variants and indicating that PCI deficiency is not a common genetic cause of teratozoospermia or azoospermia.\",\n      \"evidence\": \"Direct sequencing of SERPINA5 gene and seminal plasma PCI antigen ELISA in subfertile men\",\n      \"pmids\": [\"15377716\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Small cohort limits generalizability\",\n        \"Functional consequences of identified rare variants not tested in protease inhibition assays\",\n        \"Does not exclude a role for SERPINA5 in other aspects of reproductive biology\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that oxidized phospholipids (OxPE, PS) stimulate SERPINA5 inhibition of activated protein C through its heparin-binding site revealed a novel lipid-dependent regulatory mechanism distinct from classical GAG modulation.\",\n      \"evidence\": \"ELISA-based phospholipid binding, competition assays with heparin and annexin V, in vitro aPC inhibition with heparin-binding site mutant, immunohistochemistry of atherosclerotic plaques\",\n      \"pmids\": [\"17332248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo contribution of OxPE/PS-mediated activation in thrombosis or atherosclerosis not tested\",\n        \"Structural details of phospholipid interaction with the heparin-binding site unresolved\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that SERPINA5 directly binds fibronectin and disrupts integrin β1 signaling to suppress HCC cell migration established a non-protease-inhibitory anti-metastatic mechanism for this serpin.\",\n      \"evidence\": \"Co-immunoprecipitation/pulldown for fibronectin interaction, in vitro migration/invasion assays, in vivo metastasis model with overexpression and knockdown\",\n      \"pmids\": [\"24388360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether anti-metastatic effect requires serpin protease-inhibitory activity or is independent\",\n        \"Fibronectin binding site on SERPINA5 not mapped\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing that SERPINA5 is internalized and translocated to the nucleus via an N-terminal cell-penetrating peptide in a phosphatidylethanolamine-dependent manner revealed an unexpected intracellular life for this secreted serpin.\",\n      \"evidence\": \"Cell fractionation, fluorescence microscopy, phospholipid binding assays, N-terminal deletion/mutation experiments in platelets, granulocytes, HL-60, and Jurkat cells\",\n      \"pmids\": [\"27989561\", \"28639251\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Nuclear function of internalized SERPINA5 not identified\",\n        \"Findings from a single lab and partly presented in review format\",\n        \"Mechanism of membrane translocation at the biophysical level not resolved\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Replication of the integrin β1/FAK suppression mechanism in endometrial cancer, including exosomal delivery, confirmed that SERPINA5's anti-invasive activity generalizes across tumor types and can be mediated by exosomes.\",\n      \"evidence\": \"Overexpression/knockdown in EC cells, Western blot for integrin β1/FAK pathway, xenograft mouse model, ELISA for exosomal SERPINA5\",\n      \"pmids\": [\"35951287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether exosomal SERPINA5 acts identically to free secreted protein not distinguished\",\n        \"Receptor or uptake mechanism for exosomal delivery not characterized\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of SERPINA5 as an interferon-stimulated gene that enhances STAT1 phosphorylation and nuclear translocation linked its intracellular function to innate antiviral immunity, providing a functional consequence for nuclear translocation.\",\n      \"evidence\": \"Overexpression/knockdown, Western blot for STAT1 phosphorylation, nuclear fractionation, viral infection assays, reporter assays\",\n      \"pmids\": [\"36982532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct molecular target through which SERPINA5 enhances STAT1 phosphorylation unknown\",\n        \"Whether antiviral function requires serpin protease-inhibitory activity or cell-penetrating peptide not tested\",\n        \"Findings from single lab\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In vivo gain- and loss-of-function in a rat preeclampsia model showed SERPINA5 promotes coagulation activation and worsens disease features, connecting its hemostatic function to placental pathology.\",\n      \"evidence\": \"Adenoviral overexpression/suppression in rats, blood pressure and proteinuria measurement, placental histology, mRNA sequencing\",\n      \"pmids\": [\"38136662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific protease target(s) mediating placental coagulation activation not identified\",\n        \"Relevance to human preeclampsia not validated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular target by which intracellular SERPINA5 activates STAT1 signaling, the nuclear function of translocated SERPINA5, and whether its protease-inhibitory and non-inhibitory (fibronectin-binding, cell-penetrating) activities are functionally separable in vivo remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of SERPINA5 in complex with fibronectin or phospholipids\",\n        \"No separation-of-function mutant distinguishing protease inhibition from anti-metastatic or antiviral activities\",\n        \"Nuclear targets or gene-regulatory role of internalized SERPINA5 uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [2, 3, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FN1\",\n      \"ITGB1\",\n      \"PROC\",\n      \"PLAU\",\n      \"STAT1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}