{"gene":"PLAT","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2021,"finding":"PLAT/tPA decreases deleterious autophagy after cerebral ischemia by modulating the PI3K-AKT-MTOR pathway; mechanistically, tPA degrades IGFBP3 to increase free IGF1 bioavailability, which activates IGF1R (a tyrosine kinase receptor), thereby suppressing autophagy and mediating neuroprotection.","method":"In vitro hypoxia-reperfusion models, in vivo thromboembolic stroke model with tPA thrombolysis, western blot, pathway inhibitor experiments; validated in human stroke patient samples","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean in vitro and in vivo models with pathway inhibition and receptor identification, single lab with multiple orthogonal methods","pmids":["34520334"],"is_preprint":false},{"year":2025,"finding":"Plat (tPA) protects maternally aged mouse oocytes from programmed cell death (apoptosis and ferroptosis) by acting as an upstream signaling molecule that activates the Erk1/2 pathway, at least in part through interaction with the kinase Alk; Plat knockdown suppresses Erk1/2 activity and increases susceptibility to cell death, while exogenous tPA supplementation reduces the defect rate of aged oocytes.","method":"Transcriptome analysis of individual oocytes, siRNA knockdown of Plat, pathway inhibitor/activation assays, exogenous tPA supplementation in vitro, co-interaction analysis with Alk kinase","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and pathway placement, plus rescue with exogenous protein; single lab, multiple orthogonal approaches","pmids":["41252074"],"is_preprint":false},{"year":2025,"finding":"Plat (tPA) protects maternally aged mouse oocytes from programmed cell death through Erk1/2 activation (preprint confirmation of peer-reviewed findings above); tPA interacts with Alk kinase as an upstream regulator of Erk1/2.","method":"Transcriptomics, Plat knockdown, Erk1/2 pathway assays, exogenous tPA rescue in vitro","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — corroborates peer-reviewed paper with similar methods; preprint, single lab","pmids":[],"is_preprint":true},{"year":2024,"finding":"Mechanical stimulation induces osteoblastic Wnt1 expression, which upregulates Plat expression via β-Catenin activation; Plat in turn promotes expression of osteogenic markers Runx2 and Sp7. Plat depletion by siRNA prevents mechanically induced osteogenic marker upregulation, placing Plat downstream of Wnt1/β-Catenin in the mechanosensitive osteogenic signaling pathway.","method":"Mechanical stimulation of osteoblasts, siRNA knockdown of Wnt1 and Plat, RNAseq, western blot, β-Catenin activation assays, OVX and aged mouse models","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with defined phenotypic readout and pathway placement (Wnt1/β-Catenin/Plat axis), single lab, multiple orthogonal methods","pmids":["38407813"],"is_preprint":false},{"year":2020,"finding":"PLAT knockdown in gefitinib-resistant NSCLC cells restores gefitinib sensitivity by affecting mitochondrial function, causing caspase activation, cell cycle arrest, and activation of TNF-α signaling, leading to apoptosis; PLAT normally reduces apoptosis in these resistant cells.","method":"Lentivirus-based RNA silencing of PLAT in resistant PC9 cells, flow cytometry, JC-1 mitochondrial membrane potential assay, cDNA arrays, in vivo nude mouse xenograft model","journal":"Journal of thoracic disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype and in vivo validation, multiple readouts; single lab","pmids":["32274137"],"is_preprint":false},{"year":2025,"finding":"PLAT promotes migration and invasion of gefitinib-resistant NSCLC cells through the PLAT/FAK/AKT signaling pathway; ADI treatment downregulates PLAT, TNC, ITGB3, p-AKT, p-PI3K, and p-FAK, inhibiting these processes.","method":"Whole-transcriptome sequencing, bioinformatics, western blot for pathway components (FAK, AKT, PI3K), in vitro migration/invasion assays, in vivo NSG mouse model","journal":"Chinese medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement by expression and inhibition without direct mechanistic reconstitution of PLAT's role in FAK activation; single lab","pmids":["39754146"],"is_preprint":false},{"year":2017,"finding":"ADAM9 upregulates PLAT (tissue plasminogen activator) expression in lung cancer cells, promoting angiogenesis and vascular remodeling; ADAM9 silencing suppresses PLAT expression and decreases angiogenesis and tumor growth in vivo.","method":"Microarray gene expression, ADAM9 siRNA silencing, in vivo tumor growth assays","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — PLAT placed downstream of ADAM9 by expression analysis and knockdown, but no direct biochemical mechanism of regulation established; single lab","pmids":["29118335"],"is_preprint":false},{"year":2018,"finding":"Hypermethylation of CpG sites in the proximal PLAT promoter (at -618, -121, and -105 relative to the transcription initiation site) is negatively correlated with PLAT gene expression in nasal polyp tissue, indicating that DNA methylation of the proximal promoter downregulates PLAT transcription.","method":"Bisulfite pyrosequencing of CpG sites, quantitative RT-PCR of PLAT expression, paired tissue samples (nasal polyp vs. inferior turbinate)","journal":"American journal of rhinology & allergy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlation between methylation and expression in tissue samples, no functional reporter or methyltransferase experiments; single lab","pmids":["29962211"],"is_preprint":false},{"year":1986,"finding":"The human tissue-type plasminogen activator gene (PLAT) was assigned to chromosome 8 using somatic cell hybrid analysis.","method":"Somatic cell hybrid panel with Southern blotting using a 1.2 kb 3'-terminal PstI fragment of full-length tPA cDNA","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — direct chromosomal assignment by somatic cell hybrid analysis, replicated in subsequent studies mapping to 8p12","pmids":["3002960"],"is_preprint":false}],"current_model":"PLAT encodes tissue-type plasminogen activator (tPA), a serine protease localized to chromosome 8p12 that cleaves IGFBP3 to increase free IGF1 bioavailability and activate IGF1R/PI3K-AKT-MTOR signaling (suppressing deleterious autophagy after ischemia), activates Erk1/2 via interaction with Alk kinase to protect aged oocytes from apoptosis and ferroptosis, and functions downstream of Wnt1/β-Catenin signaling to promote osteoblast differentiation in response to mechanical stimulation; its expression is regulated by ADAM9 upstream in tumor angiogenesis and by promoter CpG methylation in epithelial tissue."},"narrative":{"mechanistic_narrative":"PLAT encodes tissue-type plasminogen activator (tPA), a serine protease whose proteolytic and signaling activities couple it to growth-factor and survival pathways across multiple tissues [PMID:34520334, PMID:41252074]. In the context of cerebral ischemia, tPA degrades IGFBP3 to increase free IGF1 bioavailability, activating the IGF1R tyrosine kinase receptor and the downstream PI3K-AKT-MTOR axis to suppress deleterious autophagy and confer neuroprotection [PMID:34520334]. tPA also acts as an upstream signaling molecule that activates Erk1/2, in part through interaction with the kinase Alk, protecting maternally aged oocytes from apoptosis and ferroptosis [PMID:41252074]. In bone, PLAT functions downstream of mechanically induced Wnt1/β-Catenin signaling, where it is required for upregulation of the osteogenic markers Runx2 and Sp7 [PMID:38407813]. In gefitinib-resistant non-small-cell lung cancer cells, PLAT limits apoptosis and supports survival by preserving mitochondrial function [PMID:32274137]. PLAT expression is itself regulated upstream by ADAM9 in tumor angiogenesis and by proximal-promoter CpG methylation, which negatively correlates with its transcription [PMID:29118335, PMID:29962211]. The PLAT gene maps to chromosome 8 [PMID:3002960].","teleology":[{"year":1986,"claim":"Establishing the chromosomal location of the human tPA gene was the first step in defining PLAT as a discrete genetic locus.","evidence":"Somatic cell hybrid panel with Southern blotting using a tPA cDNA fragment","pmids":["3002960"],"confidence":"Medium","gaps":["Does not address gene structure, regulation, or protein function","No fine-scale mapping or expression analysis at this stage"]},{"year":2017,"claim":"Whether PLAT acts within a defined oncogenic regulatory cascade was unknown; placing it downstream of ADAM9 connected its expression to tumor angiogenesis.","evidence":"Microarray expression and ADAM9 siRNA silencing in lung cancer cells with in vivo tumor growth assays","pmids":["29118335"],"confidence":"Low","gaps":["No direct biochemical mechanism linking ADAM9 to PLAT transcription","Regulation inferred from expression and knockdown correlation only"]},{"year":2018,"claim":"How PLAT transcription is controlled epigenetically was unaddressed; promoter methylation analysis identified specific CpG sites whose hypermethylation suppresses expression.","evidence":"Bisulfite pyrosequencing of proximal-promoter CpG sites with RT-PCR in paired nasal polyp tissue","pmids":["29962211"],"confidence":"Low","gaps":["Correlation only, no functional reporter or methyltransferase manipulation","Causal direction between methylation and expression not established"]},{"year":2020,"claim":"The role of PLAT in drug-resistant cancer cell survival was unclear; knockdown showed it normally restrains apoptosis by preserving mitochondrial function.","evidence":"Lentiviral PLAT silencing in resistant PC9 cells with mitochondrial membrane potential, flow cytometry, cDNA arrays, and xenografts","pmids":["32274137"],"confidence":"Medium","gaps":["Molecular link between PLAT and mitochondrial function not resolved","Whether protease activity is required is not defined"]},{"year":2021,"claim":"The mechanism of tPA neuroprotection beyond thrombolysis was unknown; tPA was shown to degrade IGFBP3, freeing IGF1 to activate IGF1R/PI3K-AKT-MTOR and suppress autophagy.","evidence":"In vitro hypoxia-reperfusion and in vivo thromboembolic stroke models with pathway inhibitors and human stroke samples","pmids":["34520334"],"confidence":"Medium","gaps":["Direct enzymatic cleavage of IGFBP3 by tPA not biochemically reconstituted","Contribution of plasmin-independent activity not separated"]},{"year":2024,"claim":"Whether PLAT participates in mechanosensitive bone signaling was unknown; it was placed downstream of Wnt1/β-Catenin as a required mediator of osteogenic marker induction.","evidence":"Mechanical stimulation of osteoblasts with Wnt1/Plat siRNA, RNAseq, β-Catenin assays, and OVX/aged mouse models","pmids":["38407813"],"confidence":"Medium","gaps":["Mechanism by which Plat promotes Runx2/Sp7 expression not defined","Direct molecular targets of Plat in osteoblasts unidentified"]},{"year":2025,"claim":"Whether tPA has a survival role in aging gametes was unknown; it was shown to activate Erk1/2 via interaction with Alk to protect aged oocytes from apoptosis and ferroptosis.","evidence":"Single-oocyte transcriptomics, Plat siRNA knockdown, Erk1/2 pathway assays, exogenous tPA rescue, and Alk co-interaction analysis","pmids":["41252074"],"confidence":"Medium","gaps":["Nature of the tPA-Alk interaction not structurally characterized","Whether protease activity is required for Erk1/2 activation unclear"]},{"year":2025,"claim":"Extending the cancer survival role, PLAT was linked to migration and invasion of resistant NSCLC cells via a PLAT/FAK/AKT axis.","evidence":"Whole-transcriptome sequencing, pathway western blots, migration/invasion assays, and an in vivo NSG model with ADI treatment","pmids":["39754146"],"confidence":"Low","gaps":["PLAT's direct role in FAK activation not reconstituted","Pathway placement inferred from expression and inhibition only"]},{"year":null,"claim":"Whether PLAT's diverse tissue functions depend on its protease activity versus non-proteolytic receptor interactions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No catalytic-dead mutant comparison across the reported pathways","Direct substrates and binding partners not biochemically reconstituted","Unifying mechanism across stroke, oocyte, bone, and cancer contexts undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3]}],"complexes":[],"partners":["ALK","IGFBP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P00750","full_name":"Tissue-type plasminogen activator","aliases":[],"length_aa":562,"mass_kda":62.9,"function":"Converts the abundant, but inactive, zymogen plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen. By controlling plasmin-mediated proteolysis, it plays an important role in tissue remodeling and degradation, in cell migration and many other physiopathological events. During oocyte activation, plays a role in cortical granule reaction in the zona reaction, which contributes to the block to polyspermy (By similarity)","subcellular_location":"Secreted, extracellular space","url":"https://www.uniprot.org/uniprotkb/P00750/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLAT","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PLAT","total_profiled":1310},"omim":[{"mim_id":"617279","title":"DENN DOMAIN-CONTAINING PROTEIN 5B; DENND5B","url":"https://www.omim.org/entry/617279"},{"mim_id":"617278","title":"DENN DOMAIN-CONTAINING PROTEIN 5A; DENND5A","url":"https://www.omim.org/entry/617278"},{"mim_id":"616837","title":"HUMAN PLURIPOTENCY-ASSOCIATED TRANSCRIPT 5, NONCODING","url":"https://www.omim.org/entry/616837"},{"mim_id":"613329","title":"PLASMINOGEN ACTIVATOR INHIBITOR-1 DEFICIENCY","url":"https://www.omim.org/entry/613329"},{"mim_id":"613072","title":"LIPOXYGENASE HOMOLOGY DOMAIN-CONTAINING 1; LOXHD1","url":"https://www.omim.org/entry/613072"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Actin filaments","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"parathyroid gland","ntpm":231.2},{"tissue":"urinary bladder","ntpm":169.0}],"url":"https://www.proteinatlas.org/search/PLAT"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P00750","domains":[{"cath_id":"2.10.70.10","chopping":"41-116","consensus_level":"medium","plddt":78.1796,"start":41,"end":116},{"cath_id":"2.40.20.10","chopping":"214-296","consensus_level":"medium","plddt":88.1999,"start":214,"end":296},{"cath_id":"2.40.10.10","chopping":"320-413","consensus_level":"medium","plddt":92.3821,"start":320,"end":413},{"cath_id":"2.40.10.10","chopping":"443-552","consensus_level":"medium","plddt":80.0107,"start":443,"end":552}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P00750","model_url":"https://alphafold.ebi.ac.uk/files/AF-P00750-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P00750-F1-predicted_aligned_error_v6.png","plddt_mean":80.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLAT","jax_strain_url":"https://www.jax.org/strain/search?query=PLAT"},"sequence":{"accession":"P00750","fasta_url":"https://rest.uniprot.org/uniprotkb/P00750.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P00750/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P00750"}},"corpus_meta":[{"pmid":"10871756","id":"PMC_10871756","title":"Plat-E: an efficient and stable system for transient packaging of retroviruses.","date":"2000","source":"Gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/10871756","citation_count":1443,"is_preprint":false},{"pmid":"1525121","id":"PMC_1525121","title":"The PLAT Study: hemostatic function in relation to atherothrombotic ischemic events in vascular disease patients. Principal results. PLAT Study Group. Progetto Lombardo Atero-Trombosi (PLAT) Study Group.","date":"1992","source":"Arteriosclerosis and thrombosis : a journal of vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1525121","citation_count":204,"is_preprint":false},{"pmid":"7692948","id":"PMC_7692948","title":"FGFRI and PLAT genes and DNA amplification at 8p12 in breast and ovarian cancers.","date":"1993","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/7692948","citation_count":149,"is_preprint":false},{"pmid":"10986042","id":"PMC_10986042","title":"Short tandem-repeat polymorphism/alu haplotype variation at the PLAT locus: implications for modern human origins.","date":"2000","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10986042","citation_count":67,"is_preprint":false},{"pmid":"1759983","id":"PMC_1759983","title":"The PLAT Study: a multidisciplinary study of hemostatic function and conventional risk factors in vascular disease patients.","date":"1991","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/1759983","citation_count":53,"is_preprint":false},{"pmid":"15563610","id":"PMC_15563610","title":"ATP-2 interacts with the PLAT domain of LOV-1 and is involved in Caenorhabditis elegans polycystin signaling.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15563610","citation_count":49,"is_preprint":false},{"pmid":"29118335","id":"PMC_29118335","title":"ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29118335","citation_count":47,"is_preprint":false},{"pmid":"24712925","id":"PMC_24712925","title":"Reduced expression of TLR3, TLR10 and TREM1 by human macrophages in Chronic cavitary pulmonary aspergillosis, and novel associations of VEGFA, DENND1B and PLAT.","date":"2014","source":"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/24712925","citation_count":35,"is_preprint":false},{"pmid":"30664233","id":"PMC_30664233","title":"Nodule-specific PLAT domain proteins are expanded in the Medicago lineage and required for nodulation.","date":"2019","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/30664233","citation_count":29,"is_preprint":false},{"pmid":"1706959","id":"PMC_1706959","title":"Recurrent homogeneously staining regions in 8p1 in breast cancer and lack of amplification of POLB, LHRH, and PLAT genes.","date":"1991","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/1706959","citation_count":29,"is_preprint":false},{"pmid":"34520334","id":"PMC_34520334","title":"Thrombolysis by PLAT/tPA increases serum free IGF1 leading to a decrease of deleterious autophagy following brain ischemia.","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/34520334","citation_count":25,"is_preprint":false},{"pmid":"31061106","id":"PMC_31061106","title":"The Nodule-Specific PLAT Domain Protein NPD1 Is Required for Nitrogen-Fixing Symbiosis.","date":"2019","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31061106","citation_count":22,"is_preprint":false},{"pmid":"3002960","id":"PMC_3002960","title":"Assignment of the human tissue-type plasminogen activator gene (PLAT) to chromosome 8.","date":"1986","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3002960","citation_count":20,"is_preprint":false},{"pmid":"29962211","id":"PMC_29962211","title":"DNA Methylation of Proximal PLAT Promoter in Chronic Rhinosinusitis With Nasal Polyps.","date":"2018","source":"American journal of rhinology & allergy","url":"https://pubmed.ncbi.nlm.nih.gov/29962211","citation_count":17,"is_preprint":false},{"pmid":"21898905","id":"PMC_21898905","title":"Positive association of phencyclidine-responsive genes, PDE4A and PLAT, with schizophrenia.","date":"2011","source":"American journal of medical genetics. 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Cancer & chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/30026410","citation_count":3,"is_preprint":false},{"pmid":"41252074","id":"PMC_41252074","title":"Plat safeguards maternally aged oocytes against programmed cell death through activating the Erk1/2 pathway.","date":"2025","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41252074","citation_count":2,"is_preprint":false},{"pmid":"28556638","id":"PMC_28556638","title":"[Role of PLAT, PKHD1L1, STK38L and TEAD1 genes Alu-polymorphism for longevity].","date":"2016","source":"Advances in gerontology = Uspekhi gerontologii","url":"https://pubmed.ncbi.nlm.nih.gov/28556638","citation_count":2,"is_preprint":false},{"pmid":"10953351","id":"PMC_10953351","title":"Immune system activation by CDDP and \"poly-plat\".","date":"2000","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10953351","citation_count":2,"is_preprint":false},{"pmid":"40899255","id":"PMC_40899255","title":"High-fat diets influence breast cancer progression by modulating CAF-immune cell interactions through PLAT signaling.","date":"2025","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40899255","citation_count":1,"is_preprint":false},{"pmid":"40498336","id":"PMC_40498336","title":"Mutation in soybean Lox-2 PLAT/LH2 domain through CRISPR/Cas9 reduces seed lipoxygenase activity: responsible for undesirable flavour.","date":"2025","source":"Transgenic research","url":"https://pubmed.ncbi.nlm.nih.gov/40498336","citation_count":1,"is_preprint":false},{"pmid":"33418543","id":"PMC_33418543","title":"Rapid prototyping of PDMS microdevices viaµPLAT on nonplanar surfaces with flexible hollow-out mask.","date":"2021","source":"Biofabrication","url":"https://pubmed.ncbi.nlm.nih.gov/33418543","citation_count":1,"is_preprint":false},{"pmid":"25943267","id":"PMC_25943267","title":"Backbone assignment and secondary structure of the PLAT domain of human polycystin-1.","date":"2015","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/25943267","citation_count":1,"is_preprint":false},{"pmid":"12114635","id":"PMC_12114635","title":"Paraganglioma-Like Adenomas of the Thyroid (PLAT): Incidental Lesions with Unusual Features in a Patient with Nodular Goiter.","date":"1997","source":"Endocrine pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12114635","citation_count":1,"is_preprint":false},{"pmid":"17320454","id":"PMC_17320454","title":"Population genetic data on four STR loci, PAI (CA)n, GpIIIa (CT)n, PLAT (TG)14 (CA)12, and NOS2A (CCTTT)n, in Mediterranean populations.","date":"2007","source":"Legal medicine (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/17320454","citation_count":1,"is_preprint":false},{"pmid":"41898467","id":"PMC_41898467","title":"Analysis of ATF6 and PLAT Expressions in Relation to hsa-miR-340-5p in Childhood Obesity.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41898467","citation_count":0,"is_preprint":false},{"pmid":"12174899","id":"PMC_12174899","title":"Mechanisms of actio of poly-plat, a novel platinum antineoplastic agent.","date":"2002","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/12174899","citation_count":0,"is_preprint":false},{"pmid":"15159853","id":"PMC_15159853","title":"[The fabrication technique of Plat casting ceramic prosthesis: A preliminary study].","date":"1993","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/15159853","citation_count":0,"is_preprint":false},{"pmid":"12180080","id":"PMC_12180080","title":"An improved assay for genotyping the common Alu insertion in the tissue-type plasminogen activation gene PLAT.","date":"2002","source":"Genetic testing","url":"https://pubmed.ncbi.nlm.nih.gov/12180080","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.26.690380","title":"Structural basis for ATP regulation of human 5-lipoxygenase","date":"2025-11-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.26.690380","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.11.637629","title":"<i>Plat</i>  safeguards maternally aged oocytes against programmed cell death through activating the Erk1/2 pathway","date":"2025-02-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.11.637629","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20180,"output_tokens":2282,"usd":0.047385,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9403,"output_tokens":2624,"usd":0.056308,"stage2_stop_reason":"end_turn"},"total_usd":0.103693,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"PLAT/tPA decreases deleterious autophagy after cerebral ischemia by modulating the PI3K-AKT-MTOR pathway; mechanistically, tPA degrades IGFBP3 to increase free IGF1 bioavailability, which activates IGF1R (a tyrosine kinase receptor), thereby suppressing autophagy and mediating neuroprotection.\",\n      \"method\": \"In vitro hypoxia-reperfusion models, in vivo thromboembolic stroke model with tPA thrombolysis, western blot, pathway inhibitor experiments; validated in human stroke patient samples\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vitro and in vivo models with pathway inhibition and receptor identification, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34520334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Plat (tPA) protects maternally aged mouse oocytes from programmed cell death (apoptosis and ferroptosis) by acting as an upstream signaling molecule that activates the Erk1/2 pathway, at least in part through interaction with the kinase Alk; Plat knockdown suppresses Erk1/2 activity and increases susceptibility to cell death, while exogenous tPA supplementation reduces the defect rate of aged oocytes.\",\n      \"method\": \"Transcriptome analysis of individual oocytes, siRNA knockdown of Plat, pathway inhibitor/activation assays, exogenous tPA supplementation in vitro, co-interaction analysis with Alk kinase\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and pathway placement, plus rescue with exogenous protein; single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"41252074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Plat (tPA) protects maternally aged mouse oocytes from programmed cell death through Erk1/2 activation (preprint confirmation of peer-reviewed findings above); tPA interacts with Alk kinase as an upstream regulator of Erk1/2.\",\n      \"method\": \"Transcriptomics, Plat knockdown, Erk1/2 pathway assays, exogenous tPA rescue in vitro\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — corroborates peer-reviewed paper with similar methods; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mechanical stimulation induces osteoblastic Wnt1 expression, which upregulates Plat expression via β-Catenin activation; Plat in turn promotes expression of osteogenic markers Runx2 and Sp7. Plat depletion by siRNA prevents mechanically induced osteogenic marker upregulation, placing Plat downstream of Wnt1/β-Catenin in the mechanosensitive osteogenic signaling pathway.\",\n      \"method\": \"Mechanical stimulation of osteoblasts, siRNA knockdown of Wnt1 and Plat, RNAseq, western blot, β-Catenin activation assays, OVX and aged mouse models\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with defined phenotypic readout and pathway placement (Wnt1/β-Catenin/Plat axis), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38407813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PLAT knockdown in gefitinib-resistant NSCLC cells restores gefitinib sensitivity by affecting mitochondrial function, causing caspase activation, cell cycle arrest, and activation of TNF-α signaling, leading to apoptosis; PLAT normally reduces apoptosis in these resistant cells.\",\n      \"method\": \"Lentivirus-based RNA silencing of PLAT in resistant PC9 cells, flow cytometry, JC-1 mitochondrial membrane potential assay, cDNA arrays, in vivo nude mouse xenograft model\",\n      \"journal\": \"Journal of thoracic disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype and in vivo validation, multiple readouts; single lab\",\n      \"pmids\": [\"32274137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PLAT promotes migration and invasion of gefitinib-resistant NSCLC cells through the PLAT/FAK/AKT signaling pathway; ADI treatment downregulates PLAT, TNC, ITGB3, p-AKT, p-PI3K, and p-FAK, inhibiting these processes.\",\n      \"method\": \"Whole-transcriptome sequencing, bioinformatics, western blot for pathway components (FAK, AKT, PI3K), in vitro migration/invasion assays, in vivo NSG mouse model\",\n      \"journal\": \"Chinese medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement by expression and inhibition without direct mechanistic reconstitution of PLAT's role in FAK activation; single lab\",\n      \"pmids\": [\"39754146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ADAM9 upregulates PLAT (tissue plasminogen activator) expression in lung cancer cells, promoting angiogenesis and vascular remodeling; ADAM9 silencing suppresses PLAT expression and decreases angiogenesis and tumor growth in vivo.\",\n      \"method\": \"Microarray gene expression, ADAM9 siRNA silencing, in vivo tumor growth assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — PLAT placed downstream of ADAM9 by expression analysis and knockdown, but no direct biochemical mechanism of regulation established; single lab\",\n      \"pmids\": [\"29118335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hypermethylation of CpG sites in the proximal PLAT promoter (at -618, -121, and -105 relative to the transcription initiation site) is negatively correlated with PLAT gene expression in nasal polyp tissue, indicating that DNA methylation of the proximal promoter downregulates PLAT transcription.\",\n      \"method\": \"Bisulfite pyrosequencing of CpG sites, quantitative RT-PCR of PLAT expression, paired tissue samples (nasal polyp vs. inferior turbinate)\",\n      \"journal\": \"American journal of rhinology & allergy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlation between methylation and expression in tissue samples, no functional reporter or methyltransferase experiments; single lab\",\n      \"pmids\": [\"29962211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"The human tissue-type plasminogen activator gene (PLAT) was assigned to chromosome 8 using somatic cell hybrid analysis.\",\n      \"method\": \"Somatic cell hybrid panel with Southern blotting using a 1.2 kb 3'-terminal PstI fragment of full-length tPA cDNA\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct chromosomal assignment by somatic cell hybrid analysis, replicated in subsequent studies mapping to 8p12\",\n      \"pmids\": [\"3002960\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLAT encodes tissue-type plasminogen activator (tPA), a serine protease localized to chromosome 8p12 that cleaves IGFBP3 to increase free IGF1 bioavailability and activate IGF1R/PI3K-AKT-MTOR signaling (suppressing deleterious autophagy after ischemia), activates Erk1/2 via interaction with Alk kinase to protect aged oocytes from apoptosis and ferroptosis, and functions downstream of Wnt1/β-Catenin signaling to promote osteoblast differentiation in response to mechanical stimulation; its expression is regulated by ADAM9 upstream in tumor angiogenesis and by promoter CpG methylation in epithelial tissue.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLAT encodes tissue-type plasminogen activator (tPA), a serine protease whose proteolytic and signaling activities couple it to growth-factor and survival pathways across multiple tissues [#0, #1]. In the context of cerebral ischemia, tPA degrades IGFBP3 to increase free IGF1 bioavailability, activating the IGF1R tyrosine kinase receptor and the downstream PI3K-AKT-MTOR axis to suppress deleterious autophagy and confer neuroprotection [#0]. tPA also acts as an upstream signaling molecule that activates Erk1/2, in part through interaction with the kinase Alk, protecting maternally aged oocytes from apoptosis and ferroptosis [#1]. In bone, PLAT functions downstream of mechanically induced Wnt1/\\u03b2-Catenin signaling, where it is required for upregulation of the osteogenic markers Runx2 and Sp7 [#3]. In gefitinib-resistant non-small-cell lung cancer cells, PLAT limits apoptosis and supports survival by preserving mitochondrial function [#4]. PLAT expression is itself regulated upstream by ADAM9 in tumor angiogenesis and by proximal-promoter CpG methylation, which negatively correlates with its transcription [#6, #7]. The PLAT gene maps to chromosome 8 [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Establishing the chromosomal location of the human tPA gene was the first step in defining PLAT as a discrete genetic locus.\",\n      \"evidence\": \"Somatic cell hybrid panel with Southern blotting using a tPA cDNA fragment\",\n      \"pmids\": [\"3002960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address gene structure, regulation, or protein function\", \"No fine-scale mapping or expression analysis at this stage\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Whether PLAT acts within a defined oncogenic regulatory cascade was unknown; placing it downstream of ADAM9 connected its expression to tumor angiogenesis.\",\n      \"evidence\": \"Microarray expression and ADAM9 siRNA silencing in lung cancer cells with in vivo tumor growth assays\",\n      \"pmids\": [\"29118335\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical mechanism linking ADAM9 to PLAT transcription\", \"Regulation inferred from expression and knockdown correlation only\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"How PLAT transcription is controlled epigenetically was unaddressed; promoter methylation analysis identified specific CpG sites whose hypermethylation suppresses expression.\",\n      \"evidence\": \"Bisulfite pyrosequencing of proximal-promoter CpG sites with RT-PCR in paired nasal polyp tissue\",\n      \"pmids\": [\"29962211\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlation only, no functional reporter or methyltransferase manipulation\", \"Causal direction between methylation and expression not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The role of PLAT in drug-resistant cancer cell survival was unclear; knockdown showed it normally restrains apoptosis by preserving mitochondrial function.\",\n      \"evidence\": \"Lentiviral PLAT silencing in resistant PC9 cells with mitochondrial membrane potential, flow cytometry, cDNA arrays, and xenografts\",\n      \"pmids\": [\"32274137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between PLAT and mitochondrial function not resolved\", \"Whether protease activity is required is not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The mechanism of tPA neuroprotection beyond thrombolysis was unknown; tPA was shown to degrade IGFBP3, freeing IGF1 to activate IGF1R/PI3K-AKT-MTOR and suppress autophagy.\",\n      \"evidence\": \"In vitro hypoxia-reperfusion and in vivo thromboembolic stroke models with pathway inhibitors and human stroke samples\",\n      \"pmids\": [\"34520334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic cleavage of IGFBP3 by tPA not biochemically reconstituted\", \"Contribution of plasmin-independent activity not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether PLAT participates in mechanosensitive bone signaling was unknown; it was placed downstream of Wnt1/\\u03b2-Catenin as a required mediator of osteogenic marker induction.\",\n      \"evidence\": \"Mechanical stimulation of osteoblasts with Wnt1/Plat siRNA, RNAseq, \\u03b2-Catenin assays, and OVX/aged mouse models\",\n      \"pmids\": [\"38407813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Plat promotes Runx2/Sp7 expression not defined\", \"Direct molecular targets of Plat in osteoblasts unidentified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether tPA has a survival role in aging gametes was unknown; it was shown to activate Erk1/2 via interaction with Alk to protect aged oocytes from apoptosis and ferroptosis.\",\n      \"evidence\": \"Single-oocyte transcriptomics, Plat siRNA knockdown, Erk1/2 pathway assays, exogenous tPA rescue, and Alk co-interaction analysis\",\n      \"pmids\": [\"41252074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nature of the tPA-Alk interaction not structurally characterized\", \"Whether protease activity is required for Erk1/2 activation unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extending the cancer survival role, PLAT was linked to migration and invasion of resistant NSCLC cells via a PLAT/FAK/AKT axis.\",\n      \"evidence\": \"Whole-transcriptome sequencing, pathway western blots, migration/invasion assays, and an in vivo NSG model with ADI treatment\",\n      \"pmids\": [\"39754146\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"PLAT's direct role in FAK activation not reconstituted\", \"Pathway placement inferred from expression and inhibition only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether PLAT's diverse tissue functions depend on its protease activity versus non-proteolytic receptor interactions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No catalytic-dead mutant comparison across the reported pathways\", \"Direct substrates and binding partners not biochemically reconstituted\", \"Unifying mechanism across stroke, oocyte, bone, and cancer contexts undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ALK\", \"IGFBP3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}