{"gene":"PLAU","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2011,"finding":"miR-193a directly targets the 3' UTR of PLAU to suppress its expression; this suppression controls invasive growth (distinct from anchorage-independent growth, which is controlled via K-Ras). The transcription factors Max and RXRα bind directly to the miR-193a promoter and inhibit miR-193a expression, thereby de-repressing PLAU during cellular transformation.","method":"3' UTR luciferase reporter assay, ChIP, RNAi, soft-agar and invasion assays in isogenic breast epithelial and fibroblast transformation models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct 3'UTR reporter validation plus ChIP and functional rescue experiments; multiple orthogonal methods in a single rigorous study","pmids":["21670079"],"is_preprint":false},{"year":2009,"finding":"Quebec platelet disorder (QPD) is caused by a tandem duplication of a 78-kb genomic segment on chromosome 10q that includes PLAU; this duplication increases urokinase plasminogen activator mRNA levels specifically during megakaryocyte differentiation, causing >100-fold elevation of uPA in platelets without systemic fibrinolysis.","method":"Copy number variation analysis (Southern blotting, quantitative PCR), genetic linkage, allele-specific expression analysis in primary megakaryocytes","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutation identified by multiple methods (Southern blot, qPCR, sequencing) and replicated across 38 QPD subjects and multiple control cohorts","pmids":["20007542","18988861"],"is_preprint":false},{"year":2017,"finding":"The QPD PLAU duplication dysregulates PLAU in a megakaryocyte-specific manner: QPD megakaryocytes overexpress normal PLAU transcripts predominantly from the disease chromosome, whereas QPD leukocytes show only a ~3.9-fold increase consistent with gene dosage. C10orf55 (co-duplicated gene) is not overexpressed in QPD megakaryocytes or platelets. QPD megakaryocytes also show global down-regulation of the interferon type 1 pathway.","method":"RNA-seq, quantitative RT-PCR, allele-specific expression analysis, protein expression analysis in primary cells and cultured megakaryocytes from QPD donors","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNA-seq, qPCR, protein analysis) in primary human cells; confirms and extends QPD mechanism","pmids":["28301587"],"is_preprint":false},{"year":2012,"finding":"PLAU (urokinase plasminogen activator) is a critical gene for the suppressor function of human FOXP3+CD25+CD4+ regulatory T cells (Tregs). PLAU mediates Treg suppressor function via STAT5 and ERK signaling pathways, and is particularly important for memory Tregs.","method":"Inferred from high-time-resolution transcriptome correlation network; validated by functional knockdown/loss-of-function experiments in human and murine Tregs with suppressor function readout, STAT5/ERK pathway analysis","journal":"Molecular systems biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional knockdown validated in human and murine Tregs with defined suppressor readout and pathway confirmation; single lab","pmids":["23169000"],"is_preprint":false},{"year":2014,"finding":"Fra-1/AP-1 controls transcription of PLAU (uPA) in aggressive breast cancer (MDA-MB231) through two AP-1 enhancers located -1.9 kb (ABR-1.9) and -4.1 kb (ABR-4.1) upstream of the Plau-001 transcription start site. RNA Pol II is recruited not only to the Plau-001 TSS but also to these upstream enhancers, where it transcribes short unstable RNAs that track toward the TSS before converting to productive Plau-001 mRNA. A minority of Pol II molecules transcribes a low-abundance mRNA (Plau-004) from the ABR-1.9 domain, whose expression is tempered by Fra-1.","method":"ChIP, pharmacological inhibition, RNAi, promoter-enhancer dissection in MDA-MB231 cells","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and RNAi with multiple orthogonal approaches; single lab","pmids":["25200076"],"is_preprint":false},{"year":2022,"finding":"STING pathway activation inhibits PLAU translation via the STING-PERK-eIF2α signaling axis. Suppression of PLAU by STING activation inhibits cancer cell migration and invasion.","method":"Quantitative proteomics of secretory proteins, mechanistic analysis of STING-PERK-eIF2α pathway, functional migration/invasion assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus mechanistic pathway dissection; single lab with multiple orthogonal methods","pmids":["36496076"],"is_preprint":false},{"year":2021,"finding":"PLAU secreted by ESCC tumor cells promotes conversion of normal fibroblasts to inflammatory cancer-associated fibroblasts (CAFs) via the uPAR/Akt/NF-κB pathway, leading to upregulation and secretion of IL-8. IL-8 secreted by CAFs in turn promotes high PLAU expression in tumor cells, creating a positive feedback loop. PLAU also promotes ESCC cell proliferation via the MAPK pathway and migration via upregulation of Slug and MMP9.","method":"Loss-of-function and gain-of-function experiments, RNA sequencing, cytokine detection, RT-qPCR, pharmacological inhibition (U0126), co-culture assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNA-seq, cytokine assays, pharmacological rescue); single lab","pmids":["33574243"],"is_preprint":false},{"year":2022,"finding":"METTL3 upregulates PLAU mRNA in an m6A-dependent manner, stabilizing PLAU mRNA to promote angiogenesis and metastasis via the MAPK/ERK pathway in colorectal cancer.","method":"m6A methylation assays, mRNA stability assays, functional in vitro and in vivo metastasis assays, MAPK/ERK pathway analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — m6A modification and mRNA stability confirmed by multiple methods; single lab","pmids":["35567945"],"is_preprint":false},{"year":2023,"finding":"WTAP mediates m6A modification of PLAU mRNA to stabilize it and increase PLAU expression in laryngeal squamous cell carcinoma, promoting cell migration, invasion, and proliferation.","method":"Luciferase reporter assay, methylated-RNA immunoprecipitation (Me-RIP), qRT-PCR, Western blotting, CCK-8/EdU/Transwell functional assays","journal":"Annals of clinical and laboratory science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Me-RIP and reporter assay confirm m6A modification of PLAU; single lab","pmids":["37094860"],"is_preprint":false},{"year":2022,"finding":"The transcription factor YY1 regulates PLAU mRNA expression by binding to the core PLAU promoter in cervical cancer cells.","method":"Core promoter mapping, transcription factor binding assay, RT-qPCR, functional knockdown assays for migration and invasion","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — promoter characterization and TF binding confirmed; single lab","pmids":["36524374"],"is_preprint":false},{"year":2024,"finding":"GATA6 transcriptionally represses PLAU expression in lung squamous cell carcinoma cells. PLAU promotes LUSC cell proliferation and migration.","method":"Dual-luciferase reporter assay, RT-PCR, immunoblotting, EdU incorporation, Transwell assays, RNA-seq","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter-reporter assay and transcriptional regulation confirmed by multiple methods; single lab","pmids":["38702016"],"is_preprint":false},{"year":2024,"finding":"PLAU interacts with TM4SF1 to promote activation of Akt signaling, conferring growth, survival, and cisplatin resistance to ARID1A-depleted NSCLC cells. Anti-TM4SF1 neutralizing antibody reversed these effects.","method":"Co-immunoprecipitation (interaction), overexpression and knockdown studies, Akt signaling analysis, in vivo xenograft models, neutralizing antibody treatment","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — protein interaction by Co-IP plus functional rescue and in vivo validation; single lab","pmids":["38229120"],"is_preprint":false},{"year":2022,"finding":"CRISPR-dCas9-mediated downregulation of PLAU in high-expressing MDA-MB-231 breast cancer cells (using DNMT3A/3L-KRAB) decreased cell proliferation, while CRISPR-dCas9-VP64-mediated upregulation in low-expressing MCF-7 cells significantly increased aggressiveness and invasion, functionally validating PLAU as an oncogene in breast cancer.","method":"CRISPR-dCas9 epigenetic modulation (transcriptional activation and repression), cell proliferation and invasion assays","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional CRISPR-dCas9 modulation with functional readouts; single lab, two orthogonal approaches","pmids":["36672610"],"is_preprint":false},{"year":2023,"finding":"PLAU activates the AKT/NF-κB signaling pathway; miR-181b targets PLAU to inhibit this axis and reduce pro-inflammatory cytokine (IL-1β, IL-6, TNF-α) expression in dental pulp cells. PLAU knockdown reversed the pro-inflammatory effect of miR-181b inhibition, and PLAU overexpression prevented the anti-inflammatory effects of miR-181b mimics.","method":"Dual-luciferase gene reporter assay (miR-181b→PLAU targeting), RNA sequencing, Western blotting, qRT-PCR, in vivo rat pulpitis model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct target validation by reporter assay plus pathway confirmation; single lab","pmids":["38154211"],"is_preprint":false},{"year":2021,"finding":"PLAU promotes proliferation via the MAPK pathway and promotes EMT progression (supported by Western blot evidence) in pancreatic ductal adenocarcinoma cells.","method":"In vitro cell proliferation/migration assays, Western blot for EMT markers, shRNA knockdown, immunohistochemistry in patient samples","journal":"European journal of pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, MAPK pathway inference by Western blot without detailed mechanistic dissection","pmids":["32464191"],"is_preprint":false},{"year":2024,"finding":"PLAU promotes head and neck cancer cell proliferation and metastasis via the JAK-STAT3 signaling pathway; pharmacological inhibition of STAT3 (S3I-201) reversed the effects of ectopic PLAU expression.","method":"RNA-seq pathway identification, Western blotting, STAT3 inhibitor rescue assay, xenograft models","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RNA-seq pathway identification confirmed by Western blot and pharmacological rescue; single lab","pmids":["38663475"],"is_preprint":false},{"year":2021,"finding":"Functional loss of PLAU (plau) in zebrafish synergistically impairs intersegmental vessel formation with loss of EP300 (ep300a), resulting in vascular occlusion phenotype, establishing PLAU's role in vascular development.","method":"Zebrafish morpholino/CRISPR loss-of-function, vascular phenotype assessment (intersegmental vessel formation)","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — zebrafish model, single lab, phenotypic readout without detailed mechanistic pathway dissection","pmids":["34354133"],"is_preprint":false},{"year":2022,"finding":"AQR promotes endothelial cell senescence and upregulates PLAU as a downstream effector; PLAU knockdown rescues senescence-related phenotypes, endothelial cell activation, and inflammation in models induced by AQR overexpression or TNF-α, establishing AQR/PLAU as a signaling axis in hyperglycemia-induced endothelial senescence.","method":"AQR overexpression/knockdown transcriptomic analyses, PLAU knockdown, senescence-associated β-galactosidase staining, CDKN1A/P21 measurement, colony formation, cell cycle analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — transcriptomics plus functional rescue validation; single lab, multiple phenotypic readouts","pmids":["35270021"],"is_preprint":false},{"year":2023,"finding":"PLAU activates the NF-κB signaling pathway in cholangiocarcinoma cells to drive malignant phenotypes; PLAU knockdown suppressed NF-κB activation and inhibited proliferation, migration, and tumor growth in vitro and in vivo.","method":"PLAU siRNA knockdown, NF-κB pathway analysis, proliferation/migration/apoptosis assays, in vivo mouse tumor model","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional knockdown with pathway analysis; single lab, limited mechanistic detail in abstract","pmids":["37067236"],"is_preprint":false},{"year":2021,"finding":"PLAU promotes nucleus pulposus chondrocyte apoptosis in intervertebral disc degeneration through activation of the HIPPO signaling pathway, increasing phosphorylation levels of MST1/2, LATS1/2, and YAP.","method":"In vitro and in vivo experiments, phosphorylation analysis of HIPPO pathway components, apoptosis assays","journal":"Pathology, research and practice","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, phosphorylation analysis without detailed mechanistic dissection or rescue","pmids":["40700932"],"is_preprint":false},{"year":2025,"finding":"In hypoxia-associated lung adenocarcinoma, HIF1A recruits the mitophagy protein NIX for a non-canonical nuclear role: under hypoxia, NIX translocates to the nucleus, interacts with the PLAU transcription factor YY1, and enhances YY1 binding to the PLAU promoter, thereby upregulating PLAU. PLAU then activates Hippo-YAP signaling upon binding to PLAUR on lung fibroblasts, driving CAF activation.","method":"CUT&RUN, mass spectrometry, immunofluorescence, co-immunoprecipitation, Western blotting, ELISA, in vivo studies","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (CUT&RUN, MS, Co-IP) establishing NIX-YY1-PLAU mechanism; single lab","pmids":["40639051"],"is_preprint":false},{"year":2025,"finding":"FOSL1 (delivered by CAF-derived exosomes) transcriptionally activates PLAU expression in hepatocellular carcinoma cells, as validated by ChIP and luciferase assays. PLAU depletion suppressed HCC malignant phenotypes and decreased pro-tumorigenic M2 macrophage polarization.","method":"ChIP assay, luciferase reporter assay, exosome co-culture, functional migration/proliferation/invasion assays, macrophage polarization assays","journal":"Applied biochemistry and biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay confirm FOSL1 transcriptional activation of PLAU; single lab","pmids":["41264215"],"is_preprint":false},{"year":2025,"finding":"Apolipoprotein E protein interacts with PLAU as a high-affinity interactor (identified by SPIDER technology and surface plasmon resonance), and apoE suppresses TGF-β/Smad-driven fibroblast activation via dual LRP1/PLAU co-engagement, attenuating α-SMA, collagen 1, and fibronectin expression.","method":"SPIDER technology, surface plasmon resonance (SPR), single-cell transcriptomics, TGF-β/Smad pathway analysis, Apoe-/- mouse models, recombinant protein rescue","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — SPR confirms direct protein interaction; multiple orthogonal methods and cross-species validation; single lab","pmids":["41475664"],"is_preprint":false},{"year":2025,"finding":"PLAU activates the Hippo-YAP signaling pathway upon binding to its receptor PLAUR on lung fibroblasts, promoting CAF activation in collagenic lung adenocarcinoma.","method":"Western blotting, immunohistochemistry, co-culture systems, in vivo studies, Upamostat treatment","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway activation shown by Western blot; mechanistic detail is limited in abstract; single lab","pmids":["40639051"],"is_preprint":false},{"year":2025,"finding":"Plau D277N mutation (impairing catalytic activity of uPA) in mice causes autism spectrum disorder-like traits including high anxiety, impaired social behavior, slowed spatial memory learning, and impaired stress adaptation, demonstrating that uPA proteolytic activity is required for adequate positioning of cellular components in the developing nervous system.","method":"CRISPR/Cas9 knock-in mouse model (D277N), behavioral assays (social activity, anxiety, memory, problem-solving), brain histology","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR knock-in with defined catalytic mutation, multiple behavioral and histological readouts; single lab","pmids":["42170179"],"is_preprint":false},{"year":2018,"finding":"Plau is a direct YAP/TEAD target gene in mouse skin keratinocytes; YAP2-5SA-ΔC overexpression upregulates Plau (with TEAD binding motifs in its 3' UTR), and Plau promotes keratinocyte proliferation in epidermal stem/progenitor cell populations.","method":"RNA-seq from YAP2-5SA-ΔC transgenic mouse skin, TEAD binding motif analysis, functional validation assays for proliferation","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptomic identification with partial functional validation; single lab","pmids":["30382077"],"is_preprint":false},{"year":2025,"finding":"siRNA knockdown of PLAU decreased in vitro TNBC-endothelial cell interactions and ex vivo extravasation of MDA-MB231 mono-clusters, establishing a direct role for uPA/PLAU in breast cancer cell extravasation from capillary venules.","method":"siRNA knockdown, in vitro endothelial binding assay, ex vivo lung extravasation assay, single-cell RNA-seq","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2-3 / Weak — functional knockdown with extravasation readout; preprint, not peer-reviewed; single lab","pmids":["bio_10.1101_2025.06.11.659108"],"is_preprint":true},{"year":2025,"finding":"OSBPL3 interacts with transcription factor NFE2L2, promoting its nuclear translocation and enhancing transcriptional activation of PLAU. PLAU upregulation then stimulates glycolytic enzyme expression through PI3K/AKT pathway activation, driving aerobic glycolysis and LUAD progression.","method":"Co-immunoprecipitation (OSBPL3-NFE2L2), nuclear fractionation, PLAU knockdown, AKT inhibition, metabolic assays (glucose consumption, lactate secretion), in vivo tumor models","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms protein interaction, pathway validated by genetic and pharmacological approaches; single lab","pmids":["41687403"],"is_preprint":false},{"year":2025,"finding":"PLAU activates Cox-2 expression in neuronal cells, leading to cellular senescence. Suppression of Plau in AD mice (via adeno-associated virus) reduced disease progression. Vilazodone, identified as a Plau inhibitor, triggers autophagy in senescent cells and eliminates them.","method":"AAV-mediated Plau knockdown in AD mice, cognitive function assays, Cox-2 pathway analysis, autophagy assays","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vivo AAV knockdown with cognitive readout; Cox-2 mechanistic link limited to abstract description; single lab","pmids":["40690806"],"is_preprint":false},{"year":2025,"finding":"ZC3H13-mediated m6A modification increases PLAU mRNA stability and expression in oral squamous cell carcinoma; ZC3H13 overexpression rescued the suppressive effects of PLAU silencing on OSCC cells.","method":"MeRIP, RIP, mRNA stability assays, qRT-PCR, immunoblotting, rescue experiments","journal":"Cytotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP confirms m6A modification; mRNA stability assay and rescue experiments; single lab","pmids":["41377025"],"is_preprint":false},{"year":2025,"finding":"In ESCC, EVA1A promotes glycolysis and lactate production; lactate drives histone H4K12 lactylation at the PLAU locus, enhancing PLAU expression. Elevated PLAU then suppresses CD8+ T cell anti-tumor activity. PLAU overexpression reversed CD8+ T cell activation induced by EVA1A silencing.","method":"Chromatin immunoprecipitation (ChIP) for H4K12la at PLAU locus, flow cytometry, qRT-PCR, ELISA, LDH assays, xenograft models, co-culture with CD8+ T cells","journal":"Expert review of clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms histone lactylation at PLAU locus; functional rescue experiments; single lab","pmids":["40826503"],"is_preprint":false}],"current_model":"PLAU encodes urokinase-type plasminogen activator (uPA), a secreted serine protease whose expression is transcriptionally controlled by multiple factors (Fra-1/AP-1 through enhancers, YY1, GATA6, FOSL1, Max/RXRα via miR-193a suppression) and post-transcriptionally stabilized by m6A writers (METTL3, WTAP, ZC3H13); PLAU promotes cell migration/invasion, EMT, and proliferation via signaling through its receptor PLAUR/uPAR activating downstream pathways including MAPK/ERK, Akt/NF-κB, JAK-STAT3, and Hippo-YAP; PLAU expression is negatively regulated at the translational level by the STING-PERK-eIF2α axis; in the immune system, PLAU mediates regulatory T cell suppressor function via STAT5 and ERK; PLAU's role in Quebec platelet disorder is mechanistically established as a tandem duplication that specifically dysregulates PLAU transcription in megakaryocytes through disruption of cis-regulatory elements; and emerging evidence places PLAU at the interface of epigenetic regulation (histone lactylation, m6A modification), tumor microenvironment remodeling (CAF conversion via uPAR/Akt/NF-κB), and vascular/neural development."},"narrative":{"mechanistic_narrative":"PLAU encodes urokinase-type plasminogen activator (uPA), a secreted serine protease that functions through its receptor PLAUR/uPAR to drive cell proliferation, migration, invasion, and EMT across diverse cancers and to remodel the tumor microenvironment [PMID:33574243, PMID:32464191, PMID:36672610]. Upon binding PLAUR, PLAU activates multiple downstream signaling cascades—MAPK/ERK [PMID:33574243, PMID:35567945], Akt/NF-κB [PMID:33574243, PMID:38229120, PMID:37067236], JAK-STAT3 [PMID:38663475], and Hippo-YAP [PMID:40639051]—and in esophageal and lung cancers it converts normal fibroblasts into cancer-associated fibroblasts, establishing pro-tumorigenic feedback loops via IL-8 and macrophage polarization [PMID:33574243, PMID:41264215, PMID:40639051]. PLAU expression is controlled at multiple regulatory layers: transcriptionally by activating factors (Fra-1/AP-1 enhancers, YY1, FOSL1, NFE2L2/OSBPL3, the NIX-YY1 axis) and repressors (GATA6, miR-193a via Max/RXRα) [PMID:25200076, PMID:36524374, PMID:41264215, PMID:41687403, PMID:40639051, PMID:38702016, PMID:21670079]; post-transcriptionally by m6A writers METTL3, WTAP, and ZC3H13 that stabilize PLAU mRNA [PMID:35567945, PMID:37094860, PMID:41377025]; epigenetically through histone H4K12 lactylation at the PLAU locus, which links tumor metabolism to PLAU-mediated CD8+ T cell suppression [PMID:40826503]; and translationally through repression by the STING-PERK-eIF2α axis [PMID:36496076]. Beyond cancer, PLAU supports the suppressor function of regulatory T cells via STAT5 and ERK [PMID:23169000], and its catalytic activity is required for proper nervous-system development, since a catalytic-dead Plau D277N mutation produces autism-like behavioral deficits in mice [PMID:42170179]. PLAU dysregulation causes Quebec platelet disorder, in which a 78-kb tandem duplication on chromosome 10q drives megakaryocyte-specific PLAU overexpression and >100-fold elevation of uPA in platelets [PMID:20007542, PMID:18988861, PMID:28301587].","teleology":[{"year":2009,"claim":"Established that a defined genomic lesion at the PLAU locus causes human disease, linking PLAU dosage and tissue-specific transcriptional control to a bleeding phenotype.","evidence":"Copy number, linkage, and allele-specific expression analysis of a 78-kb tandem duplication in Quebec platelet disorder megakaryocytes","pmids":["20007542","18988861"],"confidence":"High","gaps":["The cis-regulatory elements within the duplication responsible for megakaryocyte-specific dysregulation were not fully mapped","Mechanism of tissue specificity unresolved at this stage"]},{"year":2011,"claim":"Identified a microRNA-transcription factor circuit controlling PLAU during transformation, showing PLAU is a direct effector of invasive growth distinct from anchorage-independent growth.","evidence":"3'UTR luciferase reporter, ChIP, RNAi, and invasion assays in isogenic breast epithelial and fibroblast transformation models","pmids":["21670079"],"confidence":"High","gaps":["Did not address whether miR-193a regulation operates in established tumors in vivo","Downstream proteolytic substrates of de-repressed PLAU not defined"]},{"year":2012,"claim":"Extended PLAU function beyond cancer to immune regulation, showing it is required for regulatory T cell suppressor activity.","evidence":"Transcriptome correlation network with functional knockdown in human and murine Tregs and STAT5/ERK pathway analysis","pmids":["23169000"],"confidence":"Medium","gaps":["Whether secreted protease activity or receptor signaling mediates the Treg effect not dissected","Single lab"]},{"year":2014,"claim":"Resolved the transcriptional architecture of the PLAU promoter, defining AP-1 enhancers and enhancer-derived transcription that feed productive Plau-001 mRNA in aggressive breast cancer.","evidence":"ChIP, pharmacological inhibition, RNAi, and promoter-enhancer dissection in MDA-MB231 cells","pmids":["25200076"],"confidence":"Medium","gaps":["Function of enhancer-derived unstable RNAs not established","Generality beyond MDA-MB231 untested"]},{"year":2017,"claim":"Refined the QPD mechanism by demonstrating megakaryocyte-specific overexpression from the disease chromosome rather than simple gene-dosage effects, excluding the co-duplicated gene C10orf55.","evidence":"RNA-seq, allele-specific expression, and protein analysis in primary QPD megakaryocytes and platelets","pmids":["28301587"],"confidence":"High","gaps":["Causal driver of type I interferon pathway down-regulation in QPD megakaryocytes unknown","Specific disrupted cis-elements still uncharacterized"]},{"year":2021,"claim":"Defined PLAU as a tumor-microenvironment remodeling factor that drives fibroblast-to-CAF conversion and reciprocal feedback, and confirmed pro-proliferative/EMT roles across cancers.","evidence":"Gain/loss-of-function, RNA-seq, cytokine assays, co-culture and pharmacological rescue in ESCC and PDAC; zebrafish vascular loss-of-function","pmids":["33574243","32464191","34354133"],"confidence":"Medium","gaps":["uPAR/Akt/NF-κB feedback loop validated in single tumor type","Vascular and EMT roles rely on phenotypic readouts without deep pathway dissection"]},{"year":2022,"claim":"Established multilayered post-transcriptional and translational control of PLAU, identifying m6A-dependent mRNA stabilization and STING-mediated translational repression as opposing inputs.","evidence":"m6A/Me-RIP and mRNA stability assays (METTL3), secretory proteomics and pathway dissection (STING-PERK-eIF2α), promoter binding (YY1), and CRISPR-dCas9 bidirectional modulation","pmids":["35567945","36496076","36524374","36672610","35270021"],"confidence":"Medium","gaps":["Which m6A readers decode PLAU methylation not identified","Crosstalk between transcriptional and translational control not integrated"]},{"year":2023,"claim":"Broadened the regulatory and signaling map of PLAU, adding further m6A writers and connecting PLAU to AKT/NF-κB-driven inflammation beyond cancer.","evidence":"Me-RIP/reporter assays (WTAP), miR-181b 3'UTR targeting with in vivo pulpitis model, and siRNA knockdown with NF-κB analysis in cholangiocarcinoma","pmids":["37094860","38154211","37067236"],"confidence":"Medium","gaps":["Redundancy among m6A writers (METTL3/WTAP/ZC3H13) on PLAU not compared","Cholangiocarcinoma link is low-confidence with limited mechanistic detail"]},{"year":2024,"claim":"Expanded the PLAU signaling repertoire to JAK-STAT3 and identified protein partners (TM4SF1) and transcriptional repressors (GATA6) governing PLAU output.","evidence":"RNA-seq, Co-IP, STAT3 inhibitor and neutralizing-antibody rescue, and dual-luciferase promoter assays across head/neck and lung cancers","pmids":["38663475","38229120","38702016"],"confidence":"Medium","gaps":["Whether TM4SF1 acts on secreted uPA or intracellular PLAU unclear","Each pathway demonstrated in a single tumor context"]},{"year":2025,"claim":"Integrated PLAU into metabolic-epigenetic and immune-evasion axes and established a causal requirement for uPA catalytic activity in nervous-system development.","evidence":"ChIP for H4K12 lactylation, CUT&RUN/MS/Co-IP (NIX-YY1), SPR (ApoE interaction), FOSL1 exosome ChIP/reporter, OSBPL3-NFE2L2 Co-IP, and a CRISPR D277N catalytic-dead knock-in mouse with behavioral phenotyping","pmids":["40826503","40639051","41475664","41264215","41687403","42170179"],"confidence":"Medium","gaps":["Whether protease activity versus receptor signaling underlies each new role is largely unresolved","Neuronal substrate(s) of uPA proteolysis in development not identified","Many axes shown in single-lab single-context studies"]},{"year":null,"claim":"It remains unresolved how PLAU's catalytic protease activity versus its receptor-mediated (PLAUR) signaling is partitioned across its many reported roles, and which downstream proteolytic substrates execute its effects in each context.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No comprehensive substrate inventory tied to specific phenotypes","Relative contributions of transcriptional, m6A, lactylation, and translational control not integrated into one quantitative model","Most signaling axes lack independent cross-context replication"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[24]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[24]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[6,23]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[6,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,15,20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,30]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,9,10,21]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[7,8,29]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,24]}],"complexes":[],"partners":["PLAUR","TM4SF1","APOE","LRP1","YY1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P00749","full_name":"Urokinase-type plasminogen activator","aliases":[],"length_aa":431,"mass_kda":48.5,"function":"Specifically cleaves the zymogen plasminogen to form the active enzyme 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Huafengdan Inhibits Glioblastoma Cell Growth and Mobility by Acting on PLAU and CAV1 Targets. 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The transcription factors Max and RXRα bind directly to the miR-193a promoter and inhibit miR-193a expression, thereby de-repressing PLAU during cellular transformation.\",\n      \"method\": \"3' UTR luciferase reporter assay, ChIP, RNAi, soft-agar and invasion assays in isogenic breast epithelial and fibroblast transformation models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct 3'UTR reporter validation plus ChIP and functional rescue experiments; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"21670079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Quebec platelet disorder (QPD) is caused by a tandem duplication of a 78-kb genomic segment on chromosome 10q that includes PLAU; this duplication increases urokinase plasminogen activator mRNA levels specifically during megakaryocyte differentiation, causing >100-fold elevation of uPA in platelets without systemic fibrinolysis.\",\n      \"method\": \"Copy number variation analysis (Southern blotting, quantitative PCR), genetic linkage, allele-specific expression analysis in primary megakaryocytes\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutation identified by multiple methods (Southern blot, qPCR, sequencing) and replicated across 38 QPD subjects and multiple control cohorts\",\n      \"pmids\": [\"20007542\", \"18988861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The QPD PLAU duplication dysregulates PLAU in a megakaryocyte-specific manner: QPD megakaryocytes overexpress normal PLAU transcripts predominantly from the disease chromosome, whereas QPD leukocytes show only a ~3.9-fold increase consistent with gene dosage. C10orf55 (co-duplicated gene) is not overexpressed in QPD megakaryocytes or platelets. QPD megakaryocytes also show global down-regulation of the interferon type 1 pathway.\",\n      \"method\": \"RNA-seq, quantitative RT-PCR, allele-specific expression analysis, protein expression analysis in primary cells and cultured megakaryocytes from QPD donors\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNA-seq, qPCR, protein analysis) in primary human cells; confirms and extends QPD mechanism\",\n      \"pmids\": [\"28301587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PLAU (urokinase plasminogen activator) is a critical gene for the suppressor function of human FOXP3+CD25+CD4+ regulatory T cells (Tregs). PLAU mediates Treg suppressor function via STAT5 and ERK signaling pathways, and is particularly important for memory Tregs.\",\n      \"method\": \"Inferred from high-time-resolution transcriptome correlation network; validated by functional knockdown/loss-of-function experiments in human and murine Tregs with suppressor function readout, STAT5/ERK pathway analysis\",\n      \"journal\": \"Molecular systems biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional knockdown validated in human and murine Tregs with defined suppressor readout and pathway confirmation; single lab\",\n      \"pmids\": [\"23169000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Fra-1/AP-1 controls transcription of PLAU (uPA) in aggressive breast cancer (MDA-MB231) through two AP-1 enhancers located -1.9 kb (ABR-1.9) and -4.1 kb (ABR-4.1) upstream of the Plau-001 transcription start site. RNA Pol II is recruited not only to the Plau-001 TSS but also to these upstream enhancers, where it transcribes short unstable RNAs that track toward the TSS before converting to productive Plau-001 mRNA. A minority of Pol II molecules transcribes a low-abundance mRNA (Plau-004) from the ABR-1.9 domain, whose expression is tempered by Fra-1.\",\n      \"method\": \"ChIP, pharmacological inhibition, RNAi, promoter-enhancer dissection in MDA-MB231 cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and RNAi with multiple orthogonal approaches; single lab\",\n      \"pmids\": [\"25200076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STING pathway activation inhibits PLAU translation via the STING-PERK-eIF2α signaling axis. Suppression of PLAU by STING activation inhibits cancer cell migration and invasion.\",\n      \"method\": \"Quantitative proteomics of secretory proteins, mechanistic analysis of STING-PERK-eIF2α pathway, functional migration/invasion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus mechanistic pathway dissection; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36496076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PLAU secreted by ESCC tumor cells promotes conversion of normal fibroblasts to inflammatory cancer-associated fibroblasts (CAFs) via the uPAR/Akt/NF-κB pathway, leading to upregulation and secretion of IL-8. IL-8 secreted by CAFs in turn promotes high PLAU expression in tumor cells, creating a positive feedback loop. PLAU also promotes ESCC cell proliferation via the MAPK pathway and migration via upregulation of Slug and MMP9.\",\n      \"method\": \"Loss-of-function and gain-of-function experiments, RNA sequencing, cytokine detection, RT-qPCR, pharmacological inhibition (U0126), co-culture assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNA-seq, cytokine assays, pharmacological rescue); single lab\",\n      \"pmids\": [\"33574243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL3 upregulates PLAU mRNA in an m6A-dependent manner, stabilizing PLAU mRNA to promote angiogenesis and metastasis via the MAPK/ERK pathway in colorectal cancer.\",\n      \"method\": \"m6A methylation assays, mRNA stability assays, functional in vitro and in vivo metastasis assays, MAPK/ERK pathway analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — m6A modification and mRNA stability confirmed by multiple methods; single lab\",\n      \"pmids\": [\"35567945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WTAP mediates m6A modification of PLAU mRNA to stabilize it and increase PLAU expression in laryngeal squamous cell carcinoma, promoting cell migration, invasion, and proliferation.\",\n      \"method\": \"Luciferase reporter assay, methylated-RNA immunoprecipitation (Me-RIP), qRT-PCR, Western blotting, CCK-8/EdU/Transwell functional assays\",\n      \"journal\": \"Annals of clinical and laboratory science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Me-RIP and reporter assay confirm m6A modification of PLAU; single lab\",\n      \"pmids\": [\"37094860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The transcription factor YY1 regulates PLAU mRNA expression by binding to the core PLAU promoter in cervical cancer cells.\",\n      \"method\": \"Core promoter mapping, transcription factor binding assay, RT-qPCR, functional knockdown assays for migration and invasion\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — promoter characterization and TF binding confirmed; single lab\",\n      \"pmids\": [\"36524374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GATA6 transcriptionally represses PLAU expression in lung squamous cell carcinoma cells. PLAU promotes LUSC cell proliferation and migration.\",\n      \"method\": \"Dual-luciferase reporter assay, RT-PCR, immunoblotting, EdU incorporation, Transwell assays, RNA-seq\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter-reporter assay and transcriptional regulation confirmed by multiple methods; single lab\",\n      \"pmids\": [\"38702016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PLAU interacts with TM4SF1 to promote activation of Akt signaling, conferring growth, survival, and cisplatin resistance to ARID1A-depleted NSCLC cells. Anti-TM4SF1 neutralizing antibody reversed these effects.\",\n      \"method\": \"Co-immunoprecipitation (interaction), overexpression and knockdown studies, Akt signaling analysis, in vivo xenograft models, neutralizing antibody treatment\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — protein interaction by Co-IP plus functional rescue and in vivo validation; single lab\",\n      \"pmids\": [\"38229120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPR-dCas9-mediated downregulation of PLAU in high-expressing MDA-MB-231 breast cancer cells (using DNMT3A/3L-KRAB) decreased cell proliferation, while CRISPR-dCas9-VP64-mediated upregulation in low-expressing MCF-7 cells significantly increased aggressiveness and invasion, functionally validating PLAU as an oncogene in breast cancer.\",\n      \"method\": \"CRISPR-dCas9 epigenetic modulation (transcriptional activation and repression), cell proliferation and invasion assays\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional CRISPR-dCas9 modulation with functional readouts; single lab, two orthogonal approaches\",\n      \"pmids\": [\"36672610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PLAU activates the AKT/NF-κB signaling pathway; miR-181b targets PLAU to inhibit this axis and reduce pro-inflammatory cytokine (IL-1β, IL-6, TNF-α) expression in dental pulp cells. PLAU knockdown reversed the pro-inflammatory effect of miR-181b inhibition, and PLAU overexpression prevented the anti-inflammatory effects of miR-181b mimics.\",\n      \"method\": \"Dual-luciferase gene reporter assay (miR-181b→PLAU targeting), RNA sequencing, Western blotting, qRT-PCR, in vivo rat pulpitis model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct target validation by reporter assay plus pathway confirmation; single lab\",\n      \"pmids\": [\"38154211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PLAU promotes proliferation via the MAPK pathway and promotes EMT progression (supported by Western blot evidence) in pancreatic ductal adenocarcinoma cells.\",\n      \"method\": \"In vitro cell proliferation/migration assays, Western blot for EMT markers, shRNA knockdown, immunohistochemistry in patient samples\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, MAPK pathway inference by Western blot without detailed mechanistic dissection\",\n      \"pmids\": [\"32464191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PLAU promotes head and neck cancer cell proliferation and metastasis via the JAK-STAT3 signaling pathway; pharmacological inhibition of STAT3 (S3I-201) reversed the effects of ectopic PLAU expression.\",\n      \"method\": \"RNA-seq pathway identification, Western blotting, STAT3 inhibitor rescue assay, xenograft models\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RNA-seq pathway identification confirmed by Western blot and pharmacological rescue; single lab\",\n      \"pmids\": [\"38663475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Functional loss of PLAU (plau) in zebrafish synergistically impairs intersegmental vessel formation with loss of EP300 (ep300a), resulting in vascular occlusion phenotype, establishing PLAU's role in vascular development.\",\n      \"method\": \"Zebrafish morpholino/CRISPR loss-of-function, vascular phenotype assessment (intersegmental vessel formation)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — zebrafish model, single lab, phenotypic readout without detailed mechanistic pathway dissection\",\n      \"pmids\": [\"34354133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AQR promotes endothelial cell senescence and upregulates PLAU as a downstream effector; PLAU knockdown rescues senescence-related phenotypes, endothelial cell activation, and inflammation in models induced by AQR overexpression or TNF-α, establishing AQR/PLAU as a signaling axis in hyperglycemia-induced endothelial senescence.\",\n      \"method\": \"AQR overexpression/knockdown transcriptomic analyses, PLAU knockdown, senescence-associated β-galactosidase staining, CDKN1A/P21 measurement, colony formation, cell cycle analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — transcriptomics plus functional rescue validation; single lab, multiple phenotypic readouts\",\n      \"pmids\": [\"35270021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PLAU activates the NF-κB signaling pathway in cholangiocarcinoma cells to drive malignant phenotypes; PLAU knockdown suppressed NF-κB activation and inhibited proliferation, migration, and tumor growth in vitro and in vivo.\",\n      \"method\": \"PLAU siRNA knockdown, NF-κB pathway analysis, proliferation/migration/apoptosis assays, in vivo mouse tumor model\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional knockdown with pathway analysis; single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"37067236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PLAU promotes nucleus pulposus chondrocyte apoptosis in intervertebral disc degeneration through activation of the HIPPO signaling pathway, increasing phosphorylation levels of MST1/2, LATS1/2, and YAP.\",\n      \"method\": \"In vitro and in vivo experiments, phosphorylation analysis of HIPPO pathway components, apoptosis assays\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, phosphorylation analysis without detailed mechanistic dissection or rescue\",\n      \"pmids\": [\"40700932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In hypoxia-associated lung adenocarcinoma, HIF1A recruits the mitophagy protein NIX for a non-canonical nuclear role: under hypoxia, NIX translocates to the nucleus, interacts with the PLAU transcription factor YY1, and enhances YY1 binding to the PLAU promoter, thereby upregulating PLAU. PLAU then activates Hippo-YAP signaling upon binding to PLAUR on lung fibroblasts, driving CAF activation.\",\n      \"method\": \"CUT&RUN, mass spectrometry, immunofluorescence, co-immunoprecipitation, Western blotting, ELISA, in vivo studies\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (CUT&RUN, MS, Co-IP) establishing NIX-YY1-PLAU mechanism; single lab\",\n      \"pmids\": [\"40639051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FOSL1 (delivered by CAF-derived exosomes) transcriptionally activates PLAU expression in hepatocellular carcinoma cells, as validated by ChIP and luciferase assays. PLAU depletion suppressed HCC malignant phenotypes and decreased pro-tumorigenic M2 macrophage polarization.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, exosome co-culture, functional migration/proliferation/invasion assays, macrophage polarization assays\",\n      \"journal\": \"Applied biochemistry and biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay confirm FOSL1 transcriptional activation of PLAU; single lab\",\n      \"pmids\": [\"41264215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Apolipoprotein E protein interacts with PLAU as a high-affinity interactor (identified by SPIDER technology and surface plasmon resonance), and apoE suppresses TGF-β/Smad-driven fibroblast activation via dual LRP1/PLAU co-engagement, attenuating α-SMA, collagen 1, and fibronectin expression.\",\n      \"method\": \"SPIDER technology, surface plasmon resonance (SPR), single-cell transcriptomics, TGF-β/Smad pathway analysis, Apoe-/- mouse models, recombinant protein rescue\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — SPR confirms direct protein interaction; multiple orthogonal methods and cross-species validation; single lab\",\n      \"pmids\": [\"41475664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PLAU activates the Hippo-YAP signaling pathway upon binding to its receptor PLAUR on lung fibroblasts, promoting CAF activation in collagenic lung adenocarcinoma.\",\n      \"method\": \"Western blotting, immunohistochemistry, co-culture systems, in vivo studies, Upamostat treatment\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway activation shown by Western blot; mechanistic detail is limited in abstract; single lab\",\n      \"pmids\": [\"40639051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Plau D277N mutation (impairing catalytic activity of uPA) in mice causes autism spectrum disorder-like traits including high anxiety, impaired social behavior, slowed spatial memory learning, and impaired stress adaptation, demonstrating that uPA proteolytic activity is required for adequate positioning of cellular components in the developing nervous system.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse model (D277N), behavioral assays (social activity, anxiety, memory, problem-solving), brain histology\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR knock-in with defined catalytic mutation, multiple behavioral and histological readouts; single lab\",\n      \"pmids\": [\"42170179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Plau is a direct YAP/TEAD target gene in mouse skin keratinocytes; YAP2-5SA-ΔC overexpression upregulates Plau (with TEAD binding motifs in its 3' UTR), and Plau promotes keratinocyte proliferation in epidermal stem/progenitor cell populations.\",\n      \"method\": \"RNA-seq from YAP2-5SA-ΔC transgenic mouse skin, TEAD binding motif analysis, functional validation assays for proliferation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptomic identification with partial functional validation; single lab\",\n      \"pmids\": [\"30382077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"siRNA knockdown of PLAU decreased in vitro TNBC-endothelial cell interactions and ex vivo extravasation of MDA-MB231 mono-clusters, establishing a direct role for uPA/PLAU in breast cancer cell extravasation from capillary venules.\",\n      \"method\": \"siRNA knockdown, in vitro endothelial binding assay, ex vivo lung extravasation assay, single-cell RNA-seq\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — functional knockdown with extravasation readout; preprint, not peer-reviewed; single lab\",\n      \"pmids\": [\"bio_10.1101_2025.06.11.659108\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OSBPL3 interacts with transcription factor NFE2L2, promoting its nuclear translocation and enhancing transcriptional activation of PLAU. PLAU upregulation then stimulates glycolytic enzyme expression through PI3K/AKT pathway activation, driving aerobic glycolysis and LUAD progression.\",\n      \"method\": \"Co-immunoprecipitation (OSBPL3-NFE2L2), nuclear fractionation, PLAU knockdown, AKT inhibition, metabolic assays (glucose consumption, lactate secretion), in vivo tumor models\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms protein interaction, pathway validated by genetic and pharmacological approaches; single lab\",\n      \"pmids\": [\"41687403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PLAU activates Cox-2 expression in neuronal cells, leading to cellular senescence. Suppression of Plau in AD mice (via adeno-associated virus) reduced disease progression. Vilazodone, identified as a Plau inhibitor, triggers autophagy in senescent cells and eliminates them.\",\n      \"method\": \"AAV-mediated Plau knockdown in AD mice, cognitive function assays, Cox-2 pathway analysis, autophagy assays\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vivo AAV knockdown with cognitive readout; Cox-2 mechanistic link limited to abstract description; single lab\",\n      \"pmids\": [\"40690806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZC3H13-mediated m6A modification increases PLAU mRNA stability and expression in oral squamous cell carcinoma; ZC3H13 overexpression rescued the suppressive effects of PLAU silencing on OSCC cells.\",\n      \"method\": \"MeRIP, RIP, mRNA stability assays, qRT-PCR, immunoblotting, rescue experiments\",\n      \"journal\": \"Cytotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP confirms m6A modification; mRNA stability assay and rescue experiments; single lab\",\n      \"pmids\": [\"41377025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In ESCC, EVA1A promotes glycolysis and lactate production; lactate drives histone H4K12 lactylation at the PLAU locus, enhancing PLAU expression. Elevated PLAU then suppresses CD8+ T cell anti-tumor activity. PLAU overexpression reversed CD8+ T cell activation induced by EVA1A silencing.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for H4K12la at PLAU locus, flow cytometry, qRT-PCR, ELISA, LDH assays, xenograft models, co-culture with CD8+ T cells\",\n      \"journal\": \"Expert review of clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms histone lactylation at PLAU locus; functional rescue experiments; single lab\",\n      \"pmids\": [\"40826503\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLAU encodes urokinase-type plasminogen activator (uPA), a secreted serine protease whose expression is transcriptionally controlled by multiple factors (Fra-1/AP-1 through enhancers, YY1, GATA6, FOSL1, Max/RXRα via miR-193a suppression) and post-transcriptionally stabilized by m6A writers (METTL3, WTAP, ZC3H13); PLAU promotes cell migration/invasion, EMT, and proliferation via signaling through its receptor PLAUR/uPAR activating downstream pathways including MAPK/ERK, Akt/NF-κB, JAK-STAT3, and Hippo-YAP; PLAU expression is negatively regulated at the translational level by the STING-PERK-eIF2α axis; in the immune system, PLAU mediates regulatory T cell suppressor function via STAT5 and ERK; PLAU's role in Quebec platelet disorder is mechanistically established as a tandem duplication that specifically dysregulates PLAU transcription in megakaryocytes through disruption of cis-regulatory elements; and emerging evidence places PLAU at the interface of epigenetic regulation (histone lactylation, m6A modification), tumor microenvironment remodeling (CAF conversion via uPAR/Akt/NF-κB), and vascular/neural development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLAU encodes urokinase-type plasminogen activator (uPA), a secreted serine protease that functions through its receptor PLAUR/uPAR to drive cell proliferation, migration, invasion, and EMT across diverse cancers and to remodel the tumor microenvironment [#6, #14, #12]. Upon binding PLAUR, PLAU activates multiple downstream signaling cascades—MAPK/ERK [#6, #7], Akt/NF-\\u03baB [#6, #11, #18], JAK-STAT3 [#15], and Hippo-YAP [#20, #23]—and in esophageal and lung cancers it converts normal fibroblasts into cancer-associated fibroblasts, establishing pro-tumorigenic feedback loops via IL-8 and macrophage polarization [#6, #21, #23]. PLAU expression is controlled at multiple regulatory layers: transcriptionally by activating factors (Fra-1/AP-1 enhancers, YY1, FOSL1, NFE2L2/OSBPL3, the NIX-YY1 axis) and repressors (GATA6, miR-193a via Max/RXR\\u03b1) [#4, #9, #21, #27, #20, #10, #0]; post-transcriptionally by m6A writers METTL3, WTAP, and ZC3H13 that stabilize PLAU mRNA [#7, #8, #29]; epigenetically through histone H4K12 lactylation at the PLAU locus, which links tumor metabolism to PLAU-mediated CD8+ T cell suppression [#30]; and translationally through repression by the STING-PERK-eIF2\\u03b1 axis [#5]. Beyond cancer, PLAU supports the suppressor function of regulatory T cells via STAT5 and ERK [#3], and its catalytic activity is required for proper nervous-system development, since a catalytic-dead Plau D277N mutation produces autism-like behavioral deficits in mice [#24]. PLAU dysregulation causes Quebec platelet disorder, in which a 78-kb tandem duplication on chromosome 10q drives megakaryocyte-specific PLAU overexpression and >100-fold elevation of uPA in platelets [#1, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that a defined genomic lesion at the PLAU locus causes human disease, linking PLAU dosage and tissue-specific transcriptional control to a bleeding phenotype.\",\n      \"evidence\": \"Copy number, linkage, and allele-specific expression analysis of a 78-kb tandem duplication in Quebec platelet disorder megakaryocytes\",\n      \"pmids\": [\"20007542\", \"18988861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The cis-regulatory elements within the duplication responsible for megakaryocyte-specific dysregulation were not fully mapped\", \"Mechanism of tissue specificity unresolved at this stage\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified a microRNA-transcription factor circuit controlling PLAU during transformation, showing PLAU is a direct effector of invasive growth distinct from anchorage-independent growth.\",\n      \"evidence\": \"3'UTR luciferase reporter, ChIP, RNAi, and invasion assays in isogenic breast epithelial and fibroblast transformation models\",\n      \"pmids\": [\"21670079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether miR-193a regulation operates in established tumors in vivo\", \"Downstream proteolytic substrates of de-repressed PLAU not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended PLAU function beyond cancer to immune regulation, showing it is required for regulatory T cell suppressor activity.\",\n      \"evidence\": \"Transcriptome correlation network with functional knockdown in human and murine Tregs and STAT5/ERK pathway analysis\",\n      \"pmids\": [\"23169000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether secreted protease activity or receptor signaling mediates the Treg effect not dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the transcriptional architecture of the PLAU promoter, defining AP-1 enhancers and enhancer-derived transcription that feed productive Plau-001 mRNA in aggressive breast cancer.\",\n      \"evidence\": \"ChIP, pharmacological inhibition, RNAi, and promoter-enhancer dissection in MDA-MB231 cells\",\n      \"pmids\": [\"25200076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of enhancer-derived unstable RNAs not established\", \"Generality beyond MDA-MB231 untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Refined the QPD mechanism by demonstrating megakaryocyte-specific overexpression from the disease chromosome rather than simple gene-dosage effects, excluding the co-duplicated gene C10orf55.\",\n      \"evidence\": \"RNA-seq, allele-specific expression, and protein analysis in primary QPD megakaryocytes and platelets\",\n      \"pmids\": [\"28301587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal driver of type I interferon pathway down-regulation in QPD megakaryocytes unknown\", \"Specific disrupted cis-elements still uncharacterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined PLAU as a tumor-microenvironment remodeling factor that drives fibroblast-to-CAF conversion and reciprocal feedback, and confirmed pro-proliferative/EMT roles across cancers.\",\n      \"evidence\": \"Gain/loss-of-function, RNA-seq, cytokine assays, co-culture and pharmacological rescue in ESCC and PDAC; zebrafish vascular loss-of-function\",\n      \"pmids\": [\"33574243\", \"32464191\", \"34354133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"uPAR/Akt/NF-\\u03baB feedback loop validated in single tumor type\", \"Vascular and EMT roles rely on phenotypic readouts without deep pathway dissection\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established multilayered post-transcriptional and translational control of PLAU, identifying m6A-dependent mRNA stabilization and STING-mediated translational repression as opposing inputs.\",\n      \"evidence\": \"m6A/Me-RIP and mRNA stability assays (METTL3), secretory proteomics and pathway dissection (STING-PERK-eIF2\\u03b1), promoter binding (YY1), and CRISPR-dCas9 bidirectional modulation\",\n      \"pmids\": [\"35567945\", \"36496076\", \"36524374\", \"36672610\", \"35270021\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which m6A readers decode PLAU methylation not identified\", \"Crosstalk between transcriptional and translational control not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened the regulatory and signaling map of PLAU, adding further m6A writers and connecting PLAU to AKT/NF-\\u03baB-driven inflammation beyond cancer.\",\n      \"evidence\": \"Me-RIP/reporter assays (WTAP), miR-181b 3'UTR targeting with in vivo pulpitis model, and siRNA knockdown with NF-\\u03baB analysis in cholangiocarcinoma\",\n      \"pmids\": [\"37094860\", \"38154211\", \"37067236\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Redundancy among m6A writers (METTL3/WTAP/ZC3H13) on PLAU not compared\", \"Cholangiocarcinoma link is low-confidence with limited mechanistic detail\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded the PLAU signaling repertoire to JAK-STAT3 and identified protein partners (TM4SF1) and transcriptional repressors (GATA6) governing PLAU output.\",\n      \"evidence\": \"RNA-seq, Co-IP, STAT3 inhibitor and neutralizing-antibody rescue, and dual-luciferase promoter assays across head/neck and lung cancers\",\n      \"pmids\": [\"38663475\", \"38229120\", \"38702016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TM4SF1 acts on secreted uPA or intracellular PLAU unclear\", \"Each pathway demonstrated in a single tumor context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Integrated PLAU into metabolic-epigenetic and immune-evasion axes and established a causal requirement for uPA catalytic activity in nervous-system development.\",\n      \"evidence\": \"ChIP for H4K12 lactylation, CUT&RUN/MS/Co-IP (NIX-YY1), SPR (ApoE interaction), FOSL1 exosome ChIP/reporter, OSBPL3-NFE2L2 Co-IP, and a CRISPR D277N catalytic-dead knock-in mouse with behavioral phenotyping\",\n      \"pmids\": [\"40826503\", \"40639051\", \"41475664\", \"41264215\", \"41687403\", \"42170179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether protease activity versus receptor signaling underlies each new role is largely unresolved\", \"Neuronal substrate(s) of uPA proteolysis in development not identified\", \"Many axes shown in single-lab single-context studies\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how PLAU's catalytic protease activity versus its receptor-mediated (PLAUR) signaling is partitioned across its many reported roles, and which downstream proteolytic substrates execute its effects in each context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No comprehensive substrate inventory tied to specific phenotypes\", \"Relative contributions of transcriptional, m6A, lactylation, and translational control not integrated into one quantitative model\", \"Most signaling axes lack independent cross-context replication\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [6, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [6, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 15, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 30]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 9, 10, 21]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7, 8, 29]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PLAUR\", \"TM4SF1\", \"APOE\", \"LRP1\", \"YY1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}