{"gene":"PLAUR","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2002,"finding":"uPAR lacks transmembrane and intracellular domains and therefore requires transmembrane co-receptors (notably integrins) for intracellular signaling; it also binds the ECM protein vitronectin as a second ligand critical for signaling.","method":"Review synthesizing multiple experimental studies; mechanistic basis established through prior binding, co-IP, and functional assays documented in primary literature","journal":"Nature reviews. Molecular cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — extensively replicated across multiple independent labs, foundational mechanism supported by many orthogonal methods","pmids":["12461559"],"is_preprint":false},{"year":1998,"finding":"uPAR (CD87) forms a functional complex with the beta2 integrin Mac-1 (CD11b/CD18) on leukocytes; this association is required for beta2 integrin-mediated leukocyte adhesion to endothelium and in vivo recruitment to inflamed peritoneum. Removal of uPAR by PI-PLC abolished adhesion, and reassociation with intact (but not domain-1-truncated) soluble uPAR restored it. uPAR ligation with mAb induced adhesion, while ligation with inactivated uPA reduced adhesion.","method":"In vivo uPAR-deficient mouse model; PI-PLC removal and reconstitution of soluble uPAR; monoclonal antibody ligation experiments; flow cytometry","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout phenotype combined with reconstitution and domain-mapping experiments, replicated across multiple cell types","pmids":["9743521"],"is_preprint":false},{"year":1996,"finding":"uPAR (CD87) forms a complex with complement receptor 3 (CR3/CD11b/CD18) on human monocytes, and this association facilitates CR3-mediated adhesion to fibrinogen and keyhole limpet hemocyanin. Anti-uPAR mAb and antisense-uPAR oligonucleotides each reduced CR3-dependent adhesion by ~43–50%; uPA occupancy of uPAR negatively regulated this adhesion.","method":"Anti-uPAR and anti-CR3 monoclonal antibodies; antisense oligonucleotides; co-localization by immunofluorescence; adhesion assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal inhibition strategies (mAb, antisense) with consistent results across primary monocytes and cell lines","pmids":["8621779"],"is_preprint":false},{"year":1996,"finding":"uPAR (CD87) and Mac-1 (CD11b/CD18) form a functional unit on monocytic cells; uPAR-mediated adhesion to vitronectin promotes subsequent Mac-1-mediated fibrinogen/fibrin degradation. Conversely, occupancy of uPAR by urokinase (uPA) or receptor-binding fragments inhibits Mac-1-mediated fibrinogen binding and degradation (up to 91%) and also blocks Factor X binding, demonstrating bidirectional regulation between the two receptors.","method":"TGF-β1/vitamin D3 induction of co-expression; adhesion assays; fibrinogen degradation assays; CHO cell transfection with both human Mac-1 and human uPAR; exogenous uPA inhibition studies","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional reconstitution in transfected CHO cells plus primary monocytes and cell lines, multiple orthogonal readouts","pmids":["8874219"],"is_preprint":false},{"year":2000,"finding":"Soluble uPAR (suPAR) acts as a direct integrin ligand (trans-interaction) for integrins α4β1, α5β1 (implied), α6β1, α9β1, and αvβ3, binding in a cation-dependent, RGD-dependent manner. GPI-anchored uPAR on one cell surface can also bind integrins on apposing cells (trans-interaction), suggesting a mechanism for cell–cell interaction and integrin-mediated signaling without a transmembrane adapter.","method":"Cell-based binding assays on CHO cells; blocking with anti-integrin and anti-uPAR antibodies; integrin function-blocking mutations; competition with soluble integrin ligands","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple integrin-blocking approaches and mutagenesis in cell-based assays with rigorous controls","pmids":["11053440"],"is_preprint":false},{"year":2003,"finding":"uPA binding to uPAR causes uPAR to act as a ligand for integrin α5β1 in cis, inducing RGD-dependent cell adhesion, MAPK activation, and chemotactic migration. The growth factor domain (GFD) of uPA is required; neither kringle nor serine protease domains alone support adhesion. Signal transduction proceeds through α5β1 after uPA→uPAR→α5β1 complex assembly.","method":"Anti-uPAR and anti-α5 antibodies; RGD peptides; α5β1 function-blocking mutations; uPA domain deletion constructs; MAPK inhibition; CHO cell adhesion and migration assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-deletion mapping plus mutagenesis plus function-blocking antibodies, consistent across multiple readouts","pmids":["12754207"],"is_preprint":false},{"year":2003,"finding":"Cell-surface uPAR dimerizes, and dimeric uPAR partitions preferentially into detergent-resistant lipid rafts. Vitronectin (Vn) binding occurs preferentially to raft-associated dimeric uPAR and is completely blocked by cholesterol depletion. uPA-induced uPAR cleavage is strongly accelerated in lipid rafts. Dimerization itself does not require raft partitioning (a transmembrane uPAR chimera outside rafts still dimerizes efficiently).","method":"Detergent-resistant membrane fractionation; cholesterol depletion; transmembrane uPAR chimera; cross-linking; flow cytometry; ligand-binding assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, cholesterol depletion, chimeric receptor) in single rigorous study","pmids":["14609946"],"is_preprint":false},{"year":2004,"finding":"Neutrophil elastase and cathepsin G cleave uPAR (CD87) within the D1–D2 linker sequence, generating truncated D2D3 membrane species and releasing them from monocytic cell surfaces. Cathepsin G additionally cleaves the C-terminus of D3. Combined action of both enzymes cooperatively generates a truncated D2D3 form similar to that found in pathological body fluids. These cleavages drastically reduce the capacity of cells to bind urokinase.","method":"Immunoblotting; flow cytometry; mass spectrometry of synthetic peptide fragments; recombinant uPAR substrate; U937 cells and isolated blood monocytes","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic cleavage of recombinant substrate with MS identification of cleavage sites, corroborated in intact cells","pmids":["14688365"],"is_preprint":false},{"year":2007,"finding":"A direct uPAR–vitronectin interaction is both necessary and sufficient to initiate downstream changes in cell morphology, migration, and signal transduction. A complete alanine scan of uPAR (255 mutants) showed that all 34 morphology-defective mutants specifically lacked vitronectin binding; no integrin-binding defect was necessary. A membrane-tethered PAI-1 (which has the same vitronectin binding site as uPAR) replicated uPAR-induced morphological changes.","method":"Complete functional alanine scanning mutagenesis (255 mutants) in HEK293 cells; cell morphology/migration assays; membrane-tethered PAI-1 rescue experiment","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — comprehensive mutagenesis with multiple orthogonal validations; single study but exhaustive mapping","pmids":["17548516"],"is_preprint":false},{"year":1999,"finding":"uPAR aggregation (by mAb cross-linking) triggers phospholipase C activation via a tyrosine kinase-dependent mechanism, generating Ins(1,4,5)P3 and mobilizing intracellular calcium from IP3-sensitive stores. Cross-linking CR3 did not replicate this effect, and anti-CR3 antibodies did not block uPAR-triggered Ca2+ mobilization, indicating independence from CR3.","method":"Fluo-3 fluorimetry for [Ca2+]i; mAb cross-linking of uPAR; IP3 measurement; pharmacological inhibitors (thapsigargin, herbimycin A, U73122); primary human monocytes and U937 cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple pharmacological probes and both primary and cell line models with consistent results","pmids":["10570311"],"is_preprint":false},{"year":1995,"finding":"uPAR (CD87) is required for neutrophil (PMN) chemotaxis in vitro by a mechanism independent of uPA enzymatic activity, potentially through its ability to associate with CR3. Specific saccharides that disrupt CD87/CR3 coupling (NADG, D-mannose, mannoside) also inhibited PMN chemotaxis.","method":"Anti-CD87 mAb pre-treatment of PMNs; anti-uPA mAb and exogenous uPA controls; saccharide-mediated CR3/uPAR uncoupling; chemotaxis assay","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple inhibitory approaches, but reliance on mAbs and saccharides without genetic knockout","pmids":["7595054"],"is_preprint":false},{"year":2007,"finding":"p53 protein binds directly to a 37-nucleotide sequence in the 3' UTR of uPAR mRNA, destabilizes uPAR mRNA, and thereby suppresses uPAR expression. Loss of p53 stabilizes uPAR mRNA and increases cell-surface uPAR levels; inserting the p53-binding sequence into beta-globin mRNA confers p53-dependent destabilization to the chimeric transcript.","method":"RNA binding assay with purified p53; RNA silencing of p53; chimeric beta-globin–uPAR 3'UTR mRNA stability assay; p53 expression in p53-null cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro RNA binding with purified protein, chimeric mRNA rescue, and genetic loss-of-function, single lab but multiple orthogonal methods","pmids":["17548471"],"is_preprint":false},{"year":2007,"finding":"The human airway trypsin-like protease (HAT) cleaves uPAR in the D1–D2 linker sequence after Arg83 and Arg89, generating a truncated D2D3 form that cannot bind vitronectin or urokinase. Membrane co-expression of HAT and uPAR causes constitutive and extensive shedding of the D1 domain.","method":"Immunoblotting; flow cytometry; ELISA; mass spectrometry (site identification); co-transfection in epithelial cells; recombinant uPAR substrate","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — enzymatic assay with recombinant substrate plus MS cleavage-site identification plus cellular co-expression confirmation","pmids":["17237151"],"is_preprint":false},{"year":2005,"finding":"Streptococcal surface GAPDH (SDH/GAS) binds uPAR/CD87 specifically through the N-terminal domain D1 of uPAR, and this interaction mediates bacterial adherence to human pharyngeal cells. SDH binding maps to the C-terminal alpha-helix and flanking S-loop regions of SDH. PI-PLC removal of uPAR from pharyngeal cells decreased GAS adherence.","method":"Ligand-binding assays; LC-MS/MS identification of the ~55 kDa SDH receptor as uPAR; domain-deletion mapping; site-directed mutagenesis of SDH; PI-PLC removal of uPAR; bacterial adherence assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — MS identification of the receptor, mutagenesis of the ligand, and PI-PLC functional ablation in a single study","pmids":["15922359"],"is_preprint":false},{"year":2008,"finding":"uPAR undergoes constitutive (ligand-independent) endocytosis and recycling through a clathrin- and LRP-1-independent macropinocytic pathway. This pathway is amiloride-sensitive, does not require lipid raft partitioning, and is independent of RhoA, Rac1, Cdc42, and PI3K. Constitutively endocytosed uPAR reaches EEA1-positive early/recycling endosomes but not lysosomes.","method":"Pharmacological inhibitors (amiloride, PI3K inhibitors); dominant-negative small GTPases; cholesterol depletion; electron microscopy; EEA1 co-localization; live imaging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and genetic tools in single lab, electron microscopy validation","pmids":["19008962"],"is_preprint":false},{"year":2011,"finding":"LRP1 facilitates the endocytosis of uPAR, thereby down-regulating cell-surface uPAR levels and modulating uPAR-initiated signaling (ERK, PI3K, Rac1). Under some conditions uPAR endocytosis via LRP1 is required for sustained uPAR-initiated cell-signaling.","method":"Review of primary experimental evidence including LRP1 knockdown/inhibition studies and cell-signaling assays in neurons, neuron-like cells, and Schwann cells (primary literature basis)","journal":"Current pharmaceutical design","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic basis from multiple independent labs but abstracted here only through a review","pmids":["21711236"],"is_preprint":false},{"year":2008,"finding":"Activated human neutrophils rapidly shed uPAR predominantly as a truncated D2D3 form (lacking D1 and the GPI anchor). This D2D3 form acts as a chemotactic agonist via FPRL1 (formyl peptide receptor-like 1): immunodepletion of D2D3 from activated neutrophil supernatants significantly reduced migration of FPRL1-transfected HEK293 cells. GPI-specific phospholipase D is not involved in uPAR shedding from neutrophils.","method":"Ionomycin/TNF-α/fMLP/IL-8 activation; immunodepletion of D2D3 from supernatants; FPRL1-transfected HEK293 migration assay; flow cytometry","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional immunodepletion experiment linking D2D3 shedding to FPRL1-mediated chemotaxis, single lab","pmids":["18830568"],"is_preprint":false},{"year":2008,"finding":"The central binding cavity of uPAR for uPA is assembled by a dynamic interdomain association of all three LU domains; the high-affinity interaction (KD < 1 nM) relies on an unusually large and hydrophobic binding pocket. This structural information was established by X-ray crystallography and surface plasmon resonance.","method":"X-ray crystallography; surface plasmon resonance (as reviewed citing primary structural studies)","journal":"Frontiers in bioscience","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus SPR, independently replicated structural studies","pmids":["18508598"],"is_preprint":false},{"year":2012,"finding":"RhoB is a key downstream regulator of uPAR signaling: uPA/uPAR rapidly activates RhoB and increases RhoB expression; RhoB depletion by RNAi reduces uPA-induced migration and invasion of prostate carcinoma cells, inhibits uPAR signaling to cofilin, paxillin, and Akt, and reduces integrin levels and uPAR–integrin association. Cell adhesion to vitronectin (a uPAR ligand) is also impaired by RhoB depletion.","method":"RNAi screen of 12 Rho GTPases; invasion/migration assays; immunoblotting for cofilin, paxillin, Akt; co-immunoprecipitation of uPAR and integrins; vitronectin adhesion assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with multiple pathway readouts, single lab","pmids":["22366462"],"is_preprint":false},{"year":2014,"finding":"Full-length uPAR is required for both mesenchymal and amoeboid migration modes in cancer cells. uPAR co-localizes with β1/β3 integrins and the actin cytoskeleton; a peptide inhibiting uPAR–integrin interaction disrupts integrin–actin co-localization and abolishes amoeboid invasion while also reducing mesenchymal invasion. uPAR silencing deregulates RhoA and Rac1 GTPase activities during the amoeboid switch.","method":"uPAR siRNA silencing; uPAR–integrin blocking peptide; Rho/Rac GTPase activity assays; 3D matrix invasion assays; immunofluorescence co-localization","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and peptide inhibition with GTPase readouts, single lab","pmids":["24681666"],"is_preprint":false},{"year":2012,"finding":"FOXM1 transcription factor directly activates PLAUR (uPAR) gene expression, promoting colon cancer growth and metastasis. FOXM1 overexpression significantly upregulates uPAR expression and increases invasion/metastasis in orthotopic mouse models; FOXM1 knockdown reduces uPAR expression and metastasis.","method":"Gene transfer overexpression and siRNA knockdown of FOXM1; orthotopic mouse models; correlation of FOXM1 and PLAUR expression","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo models with gain- and loss-of-function, but direct transcriptional binding not explicitly demonstrated by ChIP in this paper","pmids":["23136192"],"is_preprint":false},{"year":2019,"finding":"PBK kinase enhances uPAR (PLAUR) expression by activating its promoter via ETV4. ChIP showed ETV4 directly binds the core region of the uPAR promoter, and PBK enhances ETV4 binding to this promoter. In vivo, PBK knockdown inhibited lung metastasis of HCC cells, an effect rescued by uPAR overexpression.","method":"Chromatin immunoprecipitation (ChIP); promoter activity assay; gain/loss-of-function; orthotopic mouse model; ETV4–uPAR promoter interaction","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates direct ETV4–uPAR promoter binding, in vivo rescue experiment confirms epistatic relationship; single lab","pmids":["30914208"],"is_preprint":false},{"year":2022,"finding":"TCF7L2 transcriptionally activates PLAUR (uPAR) expression; TCF7L2 promotes anoikis resistance and metastasis of gastric cancer cells through upregulation of PLAUR.","method":"Transcriptional activation assays; siRNA knockdown; overexpression studies; anoikis and metastasis assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional regulation demonstrated, functional rescue experiments, single lab","pmids":["35864968"],"is_preprint":false},{"year":2022,"finding":"Crystal structure of human uPAR dimer at 2.96 Å resolution reveals that dimerization causes D1 to open into a large expanded ring that captures a β-hairpin loop of a neighboring uPAR, forming an extended β-sheet and an elongated, highly intertwined dimer. Mutation E49P promotes dimer formation; the dimer shows increased binding to the amino-terminal fragment of uPA, redistributes to the basal membrane, promotes cell proliferation, and alters cell morphology via β1 integrin signaling.","method":"X-ray crystallography (2.96 Å); site-directed mutagenesis (E49P); cell-based functional assays; β1 integrin signaling readouts; uPA-ATF binding assay; immunofluorescence for membrane distribution","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and multiple cellular functional readouts in single study","pmids":["35351875"],"is_preprint":false},{"year":2003,"finding":"Protease nexin-1 (PN-1) unexpectedly increases the association between vitronectin and uPAR in the presence of enzymatically active uPA, thereby stimulating uPAR-dependent cell adhesion to immobilized vitronectin. In contrast, PAI-1 inhibits uPAR–vitronectin interaction. On adhesion to vitronectin, uPAR and PN-1 co-accumulate at the cell–matrix interface.","method":"Cell adhesion assays; confocal microscopy; PN-1 and PAI-1 protein additions; integrin versus uPAR adhesion pathway discrimination","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional adhesion assays with defined recombinant proteins, confocal co-localization; single lab","pmids":["14679304"],"is_preprint":false},{"year":1999,"finding":"uPAR (CD87) functions as a platelet receptor; uPAR-deficient platelets survive longer in wild-type recipients, and TNF-induced platelet consumption, pulmonary localization, and platelet activation are absent in uPAR-/- mice. Platelet uPAR (not endothelial/leukocyte uPAR) is critical for TNF-induced platelet–endothelial adhesion.","method":"uPAR-/- mouse model; 51Cr platelet survival assay; intratracheal TNF injection; FACS; electron microscopy; cross-transfer experiments","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with cross-transfer experiments clearly identifying platelet uPAR as the critical molecule; electron microscopy confirmation","pmids":["10385508"],"is_preprint":false},{"year":2010,"finding":"Genetic disruption of PLAUR (uPAR null mice) causes a regionally selective reduction in GABAergic interneurons in frontal and parietal neocortex and hippocampal CA1 and dentate gyrus, with compensatory changes in GABAA receptor subunit composition (α2 up, α3 down, β2/β3/γ2 subunit changes) specifically in regions with interneuron loss, and associated behavioral phenotypes (increased seizure sensitivity, anxiety, atypical social behavior).","method":"uPAR-/- mice; quantitative RT-PCR for 13 GABAA subunits; semi-quantitative in situ hybridization; behavioral testing; regional interneuron counting","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with detailed regional circuit analysis, single lab","pmids":["20381588"],"is_preprint":false},{"year":2021,"finding":"Genetic inhibition of uPAR (CRISPR, siRNA, uPAR-KO mice) or pharmacological blockade of uPA–uPAR interaction protects intestinal epithelial barrier integrity against cytokine-induced breakdown. uPAR deficiency in epithelial cells leads to enhanced EGF/EGFR signaling. uPAR-deficient mice display improved barrier function and attenuated DSS-induced colitis.","method":"CRISPR, siRNA, KO mice; TEER and FITC-dextran permeability; tight junction assessment; DSS colitis model; small molecule, neutralizing antibody and peptide inhibitors; EGFR signaling readouts","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic and pharmacological approaches in vitro and in vivo, consistent mechanistic finding","pmids":["34933179"],"is_preprint":false},{"year":2022,"finding":"PLAUR (uPAR) in sensory neurons mediates Serpin E1 (PAI-1)-induced signaling through TLR2 co-activation and downstream OSM production, promoting itch-associated gene transcription. PLAUR resides in TLR2+ sensory neurons; Serpin E1 stimulus upregulates TLR2 and its co-signaling proteins; OSM induces acute itch in mice.","method":"Mouse AD model (MC903); sensory neuron isolation; transcriptomic profiling; in vivo Serpin E1 inhibitor treatment; OSM itch assay in mice; human AD/psoriasis skin specimens","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacological inhibition and transcriptomic profiling, single lab","pmids":["35596683"],"is_preprint":false},{"year":1992,"finding":"The PLAUR gene (encoding uPAR) maps to human chromosome 19q13.1–q13.2. A ligand-binding study on cell hybrids confirmed species-specificity of uPAR and validated the chromosomal assignment.","method":"Human/rodent somatic cell hybrid panel; multipoint linkage analysis of CEPH families; uPA ligand-binding assay on cell hybrids","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent mapping methods (cell hybrids and linkage analysis) with functional validation by ligand binding","pmids":["1311495"],"is_preprint":false},{"year":2021,"finding":"E4 (C-terminal endostatin domain) binds uPAR (and enolase-1) at the cell surface; this interaction is required for E4's antifibrotic effects. E4 activates the urokinase pathway, increases the uPA/PAI-1 ratio, and elevates MMP-1 and MMP-3 expression and activity in a uPAR-dependent manner.","method":"Biotinylated E4 pulldown with MS identification of binding partners; uPAR KO cells; in vivo bleomycin fibrosis model; MMP activity assays","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown with MS identification plus uPAR-dependent genetic rescue, single lab","pmids":["34935642"],"is_preprint":false},{"year":2011,"finding":"uPAR deficiency (uPAR-/-) in murine endothelial cells impairs adhesion, migration, proliferation, and capillary tube formation. On vitronectin, uPAR-/- cells adopt a 'fried egg' morphology with circular actin and no lamellipodia, with upregulated β1 integrin, FAK(P-Tyr925), and paxillin (P-Tyr118) indicating increased but stalled focal adhesions, and decreased Rac1 activation. In vivo, uPAR-/- mice show lack of mature vessel formation in VEGF-enriched Matrigel implants.","method":"uPAR-/- murine endothelial cells; adhesion/migration/proliferation/tube formation assays; immunoblotting for focal adhesion proteins; Rac1 activity assay; in vivo Matrigel plug assay","journal":"Vascular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple cellular and in vivo readouts, single lab","pmids":["21535874"],"is_preprint":false}],"current_model":"PLAUR (uPAR/CD87) is a GPI-anchored three-LU-domain receptor that focalizes urokinase (uPA)-mediated plasminogen activation at the cell surface; it signals without intrinsic transmembrane domains by forming lateral (cis) and trans complexes with integrins (α4β1, α5β1, α6β1, α9β1, αvβ3) and with β2 integrins (Mac-1/CR3), activating MAPK, PI3K/Akt, RhoB, and phospholipase C/Ca2+ pathways to drive cell adhesion, migration, and matrix proteolysis; direct binding to vitronectin via the assembled uPA-occupied receptor is necessary and sufficient to initiate morphological and migratory responses; the receptor undergoes regulated cleavage of domain D1 by neutrophil elastase, cathepsin G, and HAT, generating a truncated D2D3 form that acts as an FPRL1 chemoattractant; it can dimerize (crystal structure resolved), with the dimer promoting basal-membrane redistribution and β1 integrin signaling; expression is transcriptionally regulated by p53 (mRNA destabilization), FOXM1, ETV4/PBK, TCF7L2, and AP-1, and its abundance is controlled by LRP1-mediated endocytosis and macropinocytic recycling."},"narrative":{"mechanistic_narrative":"PLAUR (uPAR/CD87) is a GPI-anchored receptor that focalizes urokinase-mediated proteolysis at the cell surface and converts that proteolytic context into adhesion and migration signals despite lacking transmembrane and intracellular domains [PMID:12461559]. Because it cannot signal autonomously, uPAR transduces information through transmembrane co-receptors: it forms lateral cis complexes with β1 integrins—uPA occupancy converts uPAR into an RGD-dependent ligand for α5β1 that drives MAPK activation and chemotactic migration [PMID:12754207]—and acts in trans, where soluble uPAR engages α4β1, α6β1, α9β1, and αvβ3 on apposing cells in a cation- and RGD-dependent manner [PMID:11053440]. On leukocytes it partners physically with the β2 integrin Mac-1/CR3, an association required for integrin-mediated adhesion to endothelium and matrix proteins and reciprocally regulated by uPA occupancy [PMID:9743521, PMID:8874219]. Independent of any integrin defect, a direct uPAR–vitronectin interaction is both necessary and sufficient to initiate morphological change, migration, and signaling, as shown by comprehensive alanine-scanning mutagenesis [PMID:17548516]. Downstream, uPAR engages RhoB to control cofilin, paxillin, and Akt and to maintain uPAR–integrin association [PMID:22366462], and it triggers tyrosine-kinase-dependent phospholipase C activation with IP3-mediated calcium mobilization [PMID:10570311]. The receptor is built from three intertwined LU domains that assemble a high-affinity uPA-binding cavity [PMID:18508598], dimerizes within lipid rafts to favor vitronectin binding and β1-integrin signaling [PMID:14609946, PMID:35351875], and is regulated by D1-cleaving proteases—neutrophil elastase, cathepsin G, and HAT—that release a truncated D2D3 species which itself acts as an FPRL1 chemotactic agonist [PMID:14688365, PMID:17237151, PMID:18830568]. uPAR abundance is set transcriptionally by FOXM1, ETV4/PBK, and TCF7L2 and post-transcriptionally by p53-mediated mRNA destabilization, with surface levels further controlled by macropinocytic recycling and LRP1-dependent endocytosis [PMID:17548471, PMID:23136192, PMID:19008962, PMID:21711236]. Genetic studies establish physiological roles in platelet–endothelial adhesion, angiogenesis, GABAergic interneuron patterning, and epithelial barrier integrity [PMID:10385508, PMID:21535874, PMID:20381588, PMID:34933179].","teleology":[{"year":1992,"claim":"Establishing the chromosomal locus and species-specificity of uPA binding anchored PLAUR as a discrete, mappable human gene encoding the urokinase receptor.","evidence":"somatic cell hybrid panel, CEPH linkage analysis, and uPA ligand-binding on hybrids","pmids":["1311495"],"confidence":"High","gaps":["Does not address receptor structure or signaling mechanism"]},{"year":1996,"claim":"The question of how a proteolytic receptor controls adhesion was answered by showing uPAR physically and functionally couples to the β2 integrin Mac-1/CR3, with uPA occupancy bidirectionally regulating integrin-dependent adhesion.","evidence":"anti-uPAR/anti-CR3 mAbs, antisense oligonucleotides, CHO co-transfection of human Mac-1 and uPAR, adhesion and fibrinogen-degradation assays","pmids":["8621779","8874219"],"confidence":"High","gaps":["Did not resolve whether integrin coupling is the only signaling route","Structural basis of the uPAR–Mac-1 interface not defined"]},{"year":1998,"claim":"An in vivo requirement for uPAR in β2-integrin-mediated leukocyte recruitment was established, with domain-1 mapping showing intact uPAR is needed to restore adhesion.","evidence":"uPAR-deficient mouse, PI-PLC removal and soluble uPAR reconstitution, mAb ligation, flow cytometry","pmids":["9743521"],"confidence":"High","gaps":["Did not define the transmembrane signal-transducing partner downstream of the uPAR–Mac-1 unit"]},{"year":1999,"claim":"uPAR aggregation was shown to drive a defined second-messenger cascade—tyrosine-kinase-dependent PLC activation and IP3-mediated calcium release—independent of CR3, establishing intracellular signaling capacity.","evidence":"mAb cross-linking, Fluo-3 calcium fluorimetry, IP3 measurement, pharmacological inhibitors in monocytes and U937 cells","pmids":["10570311"],"confidence":"High","gaps":["The transmembrane co-receptor relaying tyrosine kinase activation was not identified"]},{"year":2000,"claim":"Resolving how a GPI-anchored protein signals through integrins, soluble uPAR was shown to act as a direct trans-ligand for multiple β1 and αvβ3 integrins, providing a transmembrane-adapter-free route for cell–cell signaling.","evidence":"CHO cell-based binding, anti-integrin and anti-uPAR blocking, integrin function-blocking mutations, ligand competition","pmids":["11053440"],"confidence":"High","gaps":["In vivo relevance of trans-interactions not established","Affinities and stoichiometry not quantified"]},{"year":2003,"claim":"The cis-signaling mechanism was defined: uPA binding converts uPAR into an α5β1 ligand requiring the uPA growth-factor domain, coupling proteolytic ligand engagement to MAPK and chemotaxis.","evidence":"uPA domain-deletion constructs, anti-uPAR/anti-α5 antibodies, RGD peptides, function-blocking mutations, MAPK inhibition, CHO adhesion/migration assays","pmids":["12754207"],"confidence":"High","gaps":["Did not address how the GPI receptor laterally docks onto α5β1"]},{"year":2003,"claim":"Membrane organization was shown to gate function: uPAR dimerizes preferentially in lipid rafts, where vitronectin binding and uPA-induced cleavage are favored, separating dimerization from raft partitioning.","evidence":"detergent-resistant membrane fractionation, cholesterol depletion, transmembrane uPAR chimera, cross-linking, flow cytometry","pmids":["14609946"],"confidence":"High","gaps":["Functional consequence of raft-localized dimers for downstream signaling not directly mapped"]},{"year":2003,"claim":"Serpin modulation of vitronectin engagement was clarified—PN-1 enhances while PAI-1 inhibits uPAR–vitronectin adhesion—identifying extracellular regulators of the adhesion ligand axis.","evidence":"cell adhesion assays with recombinant PN-1/PAI-1, confocal co-localization, integrin-versus-uPAR pathway discrimination","pmids":["14679304"],"confidence":"Medium","gaps":["Single lab; structural basis of PN-1 enhancement undefined"]},{"year":2004,"claim":"Regulated proteolysis was defined mechanistically: neutrophil elastase and cathepsin G cleave the D1–D2 linker to generate a D2D3 species and abolish uPA binding, identifying a switch that inactivates the receptor.","evidence":"recombinant uPAR substrate cleavage, mass spectrometry of cleavage sites, immunoblot/flow cytometry in U937 and monocytes","pmids":["14688365"],"confidence":"High","gaps":["Did not establish a signaling function for the released D2D3 fragment"]},{"year":2005,"claim":"A pathogen-exploitation function emerged: streptococcal surface GAPDH binds uPAR domain D1 to mediate bacterial adherence to pharyngeal cells, mapping a host–microbe interface on the receptor.","evidence":"ligand-binding assays, LC-MS/MS receptor identification, domain-deletion mapping, SDH mutagenesis, PI-PLC ablation, adherence assays","pmids":["15922359"],"confidence":"High","gaps":["Downstream consequences for host signaling not addressed"]},{"year":2007,"claim":"The vitronectin interaction was elevated to the necessary and sufficient trigger of uPAR signaling, as every morphology-defective mutant in an exhaustive scan lacked vitronectin—not integrin—binding.","evidence":"complete alanine scan (255 mutants) in HEK293, morphology/migration assays, membrane-tethered PAI-1 rescue","pmids":["17548516"],"confidence":"High","gaps":["Reconciliation with integrin-dependent signaling models not fully resolved"]},{"year":2007,"claim":"Transcript-level control was established by showing p53 directly binds the uPAR 3'UTR and destabilizes the mRNA, linking tumor-suppressor status to surface receptor abundance.","evidence":"in vitro RNA binding with purified p53, chimeric β-globin–uPAR 3'UTR stability assay, p53 silencing and re-expression","pmids":["17548471"],"confidence":"High","gaps":["The RNA-destabilization machinery recruited by p53 not identified"]},{"year":2007,"claim":"A second D1-shedding protease, airway trypsin-like protease (HAT), was shown to cleave after Arg83/Arg89, producing a D2D3 form unable to bind vitronectin or uPA, extending tissue-specific control of receptor inactivation.","evidence":"recombinant substrate cleavage, mass spectrometry, ELISA/flow cytometry, HAT–uPAR co-transfection in epithelial cells","pmids":["17237151"],"confidence":"High","gaps":["Physiological context of HAT-mediated shedding in airway not tested in vivo"]},{"year":2008,"claim":"The shed D2D3 fragment was assigned a positive signaling role as an FPRL1 chemotactic agonist, converting receptor cleavage from inactivation into a paracrine motility signal.","evidence":"neutrophil activation, immunodepletion of D2D3 from supernatants, FPRL1-transfected HEK293 migration assay, flow cytometry","pmids":["18830568"],"confidence":"Medium","gaps":["Single lab; the FPRL1-binding epitope within D2D3 not mapped"]},{"year":2008,"claim":"Receptor turnover was characterized as a constitutive, clathrin- and LRP1-independent macropinocytic recycling route to EEA1+ endosomes, defining how surface uPAR levels are maintained.","evidence":"amiloride and PI3K inhibitors, dominant-negative GTPases, cholesterol depletion, electron microscopy, EEA1 co-localization, live imaging","pmids":["19008962"],"confidence":"Medium","gaps":["Single lab; molecular machinery driving uPAR macropinocytosis unidentified"]},{"year":2008,"claim":"The structural basis of high-affinity uPA capture was defined as a dynamic interdomain assembly of all three LU domains forming a large hydrophobic pocket.","evidence":"X-ray crystallography and surface plasmon resonance (reviewed primary structural work)","pmids":["18508598"],"confidence":"High","gaps":["Conformational dynamics of the apo-receptor not detailed here"]},{"year":2010,"claim":"A neural function was uncovered: uPAR deletion selectively reduces GABAergic interneurons in defined cortical and hippocampal regions with compensatory GABAA subunit shifts and behavioral abnormalities.","evidence":"uPAR-/- mice, qRT-PCR of 13 GABAA subunits, in situ hybridization, behavioral testing, regional interneuron counts","pmids":["20381588"],"confidence":"Medium","gaps":["Single lab; molecular pathway linking uPAR to interneuron development undefined"]},{"year":2011,"claim":"uPAR was shown to be required for endothelial adhesion, migration, and angiogenesis, with knockout cells displaying stalled focal adhesions, elevated β1 integrin/FAK/paxillin phosphorylation, and reduced Rac1 activity.","evidence":"uPAR-/- endothelial cells, adhesion/migration/tube-formation assays, focal-adhesion immunoblots, Rac1 activity, in vivo Matrigel plug","pmids":["21535874"],"confidence":"Medium","gaps":["Single lab; whether the vitronectin or uPA axis drives the angiogenic defect not separated"]},{"year":2011,"claim":"LRP1 was identified as a route for uPAR endocytosis that down-regulates surface levels and, in some contexts, is required to sustain ERK/PI3K/Rac1 signaling, complementing the macropinocytic pathway.","evidence":"review of LRP1 knockdown/inhibition and signaling assays in neurons and Schwann cells","pmids":["21711236"],"confidence":"Medium","gaps":["Abstracted via review; quantitative contribution of LRP1 versus macropinocytosis not resolved"]},{"year":2012,"claim":"RhoB was placed as a central downstream effector of uPA/uPAR signaling controlling cofilin, paxillin, and Akt and maintaining uPAR–integrin association, linking the receptor to cytoskeletal remodeling in invasion.","evidence":"RNAi screen of 12 Rho GTPases, invasion/migration assays, signaling immunoblots, uPAR–integrin co-IP, vitronectin adhesion","pmids":["22366462"],"confidence":"Medium","gaps":["Single lab; mechanism of RhoB activation downstream of uPAR unmapped"]},{"year":2012,"claim":"Transcriptional drivers of uPAR were defined in cancer: FOXM1 directly activates PLAUR to promote colon cancer growth and metastasis.","evidence":"FOXM1 overexpression/knockdown, orthotopic mouse models, expression correlation","pmids":["23136192"],"confidence":"Medium","gaps":["Direct promoter binding not shown by ChIP in this study"]},{"year":2014,"claim":"Full-length uPAR was shown to be required for both mesenchymal and amoeboid migration, with uPAR–integrin coupling sustaining integrin–actin co-localization and balancing RhoA/Rac1 activity.","evidence":"uPAR siRNA, uPAR–integrin blocking peptide, Rho/Rac activity assays, 3D invasion, immunofluorescence","pmids":["24681666"],"confidence":"Medium","gaps":["Single lab; the precise integrin partner governing the amoeboid switch not specified"]},{"year":2019,"claim":"A kinase–transcription-factor axis was defined whereby PBK enhances ETV4 binding to the uPAR promoter to drive metastasis, with ChIP confirming direct ETV4 occupancy.","evidence":"ChIP, promoter activity assays, gain/loss-of-function, orthotopic mouse model with uPAR rescue","pmids":["30914208"],"confidence":"Medium","gaps":["Single lab; how PBK modifies ETV4 to enhance binding not resolved"]},{"year":2021,"claim":"An epithelial barrier function was uncovered: uPAR loss protects against cytokine-induced barrier breakdown and colitis through enhanced EGF/EGFR signaling.","evidence":"CRISPR/siRNA/KO mice, TEER and permeability assays, DSS colitis, small molecule/antibody/peptide inhibitors, EGFR readouts","pmids":["34933179"],"confidence":"High","gaps":["Mechanism linking uPAR to EGFR restraint not defined at the molecular level"]},{"year":2021,"claim":"uPAR was identified as a cell-surface partner of the endostatin-derived E4 fragment required for antifibrotic activation of the urokinase/MMP pathway.","evidence":"biotinylated E4 pulldown with MS, uPAR KO cells, in vivo bleomycin fibrosis, MMP activity assays","pmids":["34935642"],"confidence":"Medium","gaps":["Single lab; binding interface and signaling output not structurally defined"]},{"year":2022,"claim":"A high-resolution dimer structure explained how uPAR self-association functions: D1 opens into an expanded ring capturing a neighboring β-hairpin, and the dimer (favored by E49P) increases uPA-ATF binding and drives proliferation via β1 integrin signaling.","evidence":"X-ray crystallography at 2.96 Å, E49P mutagenesis, uPA-ATF binding, β1 signaling readouts, immunofluorescence of membrane distribution","pmids":["35351875"],"confidence":"High","gaps":["Physiological abundance and regulation of the dimer in vivo not established"]},{"year":2022,"claim":"Additional transcriptional control and a sensory-neuron signaling role were defined: TCF7L2 activates PLAUR to promote anoikis resistance and metastasis, and uPAR mediates Serpin E1–induced TLR2/OSM signaling driving itch.","evidence":"transcriptional/knockdown/overexpression assays and anoikis/metastasis readouts; mouse AD model, sensory neuron transcriptomics, OSM itch assay","pmids":["35864968","35596683"],"confidence":"Medium","gaps":["Single labs; direct TCF7L2 promoter binding and the uPAR–TLR2 physical interface not defined"]},{"year":null,"claim":"How the multiple, partly competing signaling modes—vitronectin-driven, cis/trans integrin coupling, and dimer-dependent β1 signaling—are integrated and prioritized within a single cell context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling the necessary-and-sufficient vitronectin model with integrin-dependent signaling","Stoichiometry of monomer-versus-dimer signaling in vivo unknown","Transmembrane partner that relays uPAR tyrosine-kinase signaling not definitively identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,3,4,5,8]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[4,5,16]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5,9,18]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,6,23]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[14,15]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,9,18,19]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[25]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,16]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,8,30]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[14,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[11,20,21,22]}],"complexes":["uPAR-Mac-1 (CD11b/CD18) complex","uPAR-α5β1 integrin complex"],"partners":["PLAU","ITGB1","ITGAM","ITGB2","VTN","LRP1","SERPINE1","TLR2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q03405","full_name":"Urokinase plasminogen activator surface receptor","aliases":["Monocyte activation antigen Mo3"],"length_aa":335,"mass_kda":37.0,"function":"Acts as a receptor for urokinase plasminogen activator (PubMed:15677461). Plays a role in localizing and promoting plasmin formation. Mediates the proteolysis-independent signal transduction activation effects of U-PA. It is subject to negative-feedback regulation by U-PA which cleaves it into an inactive form","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q03405/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLAUR","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLAUR","total_profiled":1310},"omim":[{"mim_id":"621413","title":"PHOSPHOLIPASE A2 INHIBITOR AND LY6/PLAUR DOMAIN-CONTAINING PROTEIN; PINLYP","url":"https://www.omim.org/entry/621413"},{"mim_id":"619618","title":"LY6/PLAUR DOMAIN-CONTAINING PROTEIN 5; LYPD5","url":"https://www.omim.org/entry/619618"},{"mim_id":"617288","title":"SERINE PEPTIDASE INHIBITOR, KAZAL-TYPE, 7; SPINK7","url":"https://www.omim.org/entry/617288"},{"mim_id":"617067","title":"LY6/PLAUR DOMAIN-CONTAINING PROTEIN 8; LYPD8","url":"https://www.omim.org/entry/617067"},{"mim_id":"613359","title":"LY6/PLAUR DOMAIN-CONTAINING PROTEIN 6; LYPD6","url":"https://www.omim.org/entry/613359"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":650.6}],"url":"https://www.proteinatlas.org/search/PLAUR"},"hgnc":{"alias_symbol":["URKR","UPAR","CD87"],"prev_symbol":[]},"alphafold":{"accession":"Q03405","domains":[{"cath_id":"2.10.60.10","chopping":"212-303","consensus_level":"medium","plddt":88.7872,"start":212,"end":303}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03405","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q03405-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q03405-F1-predicted_aligned_error_v6.png","plddt_mean":81.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLAUR","jax_strain_url":"https://www.jax.org/strain/search?query=PLAUR"},"sequence":{"accession":"Q03405","fasta_url":"https://rest.uniprot.org/uniprotkb/Q03405.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q03405/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03405"}},"corpus_meta":[{"pmid":"12461559","id":"PMC_12461559","title":"uPAR: a versatile signalling orchestrator.","date":"2002","source":"Nature reviews. 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vitronectin provides the key.","date":"2007","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17548516","citation_count":198,"is_preprint":false},{"pmid":"8621779","id":"PMC_8621779","title":"The urokinase receptor (CD87) facilitates CD11b/CD18-mediated adhesion of human monocytes.","date":"1996","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/8621779","citation_count":180,"is_preprint":false},{"pmid":"8874219","id":"PMC_8874219","title":"Mac-1 (CD11b/CD18) and the urokinase receptor (CD87) form a functional unit on monocytic cells.","date":"1996","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/8874219","citation_count":165,"is_preprint":false},{"pmid":"27098205","id":"PMC_27098205","title":"Organization, evolution and functions of the human and mouse Ly6/uPAR family genes.","date":"2016","source":"Human 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intracellular signaling; it also binds the ECM protein vitronectin as a second ligand critical for signaling.\",\n      \"method\": \"Review synthesizing multiple experimental studies; mechanistic basis established through prior binding, co-IP, and functional assays documented in primary literature\",\n      \"journal\": \"Nature reviews. Molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — extensively replicated across multiple independent labs, foundational mechanism supported by many orthogonal methods\",\n      \"pmids\": [\"12461559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"uPAR (CD87) forms a functional complex with the beta2 integrin Mac-1 (CD11b/CD18) on leukocytes; this association is required for beta2 integrin-mediated leukocyte adhesion to endothelium and in vivo recruitment to inflamed peritoneum. Removal of uPAR by PI-PLC abolished adhesion, and reassociation with intact (but not domain-1-truncated) soluble uPAR restored it. uPAR ligation with mAb induced adhesion, while ligation with inactivated uPA reduced adhesion.\",\n      \"method\": \"In vivo uPAR-deficient mouse model; PI-PLC removal and reconstitution of soluble uPAR; monoclonal antibody ligation experiments; flow cytometry\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout phenotype combined with reconstitution and domain-mapping experiments, replicated across multiple cell types\",\n      \"pmids\": [\"9743521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"uPAR (CD87) forms a complex with complement receptor 3 (CR3/CD11b/CD18) on human monocytes, and this association facilitates CR3-mediated adhesion to fibrinogen and keyhole limpet hemocyanin. Anti-uPAR mAb and antisense-uPAR oligonucleotides each reduced CR3-dependent adhesion by ~43–50%; uPA occupancy of uPAR negatively regulated this adhesion.\",\n      \"method\": \"Anti-uPAR and anti-CR3 monoclonal antibodies; antisense oligonucleotides; co-localization by immunofluorescence; adhesion assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal inhibition strategies (mAb, antisense) with consistent results across primary monocytes and cell lines\",\n      \"pmids\": [\"8621779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"uPAR (CD87) and Mac-1 (CD11b/CD18) form a functional unit on monocytic cells; uPAR-mediated adhesion to vitronectin promotes subsequent Mac-1-mediated fibrinogen/fibrin degradation. Conversely, occupancy of uPAR by urokinase (uPA) or receptor-binding fragments inhibits Mac-1-mediated fibrinogen binding and degradation (up to 91%) and also blocks Factor X binding, demonstrating bidirectional regulation between the two receptors.\",\n      \"method\": \"TGF-β1/vitamin D3 induction of co-expression; adhesion assays; fibrinogen degradation assays; CHO cell transfection with both human Mac-1 and human uPAR; exogenous uPA inhibition studies\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional reconstitution in transfected CHO cells plus primary monocytes and cell lines, multiple orthogonal readouts\",\n      \"pmids\": [\"8874219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Soluble uPAR (suPAR) acts as a direct integrin ligand (trans-interaction) for integrins α4β1, α5β1 (implied), α6β1, α9β1, and αvβ3, binding in a cation-dependent, RGD-dependent manner. GPI-anchored uPAR on one cell surface can also bind integrins on apposing cells (trans-interaction), suggesting a mechanism for cell–cell interaction and integrin-mediated signaling without a transmembrane adapter.\",\n      \"method\": \"Cell-based binding assays on CHO cells; blocking with anti-integrin and anti-uPAR antibodies; integrin function-blocking mutations; competition with soluble integrin ligands\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple integrin-blocking approaches and mutagenesis in cell-based assays with rigorous controls\",\n      \"pmids\": [\"11053440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"uPA binding to uPAR causes uPAR to act as a ligand for integrin α5β1 in cis, inducing RGD-dependent cell adhesion, MAPK activation, and chemotactic migration. The growth factor domain (GFD) of uPA is required; neither kringle nor serine protease domains alone support adhesion. Signal transduction proceeds through α5β1 after uPA→uPAR→α5β1 complex assembly.\",\n      \"method\": \"Anti-uPAR and anti-α5 antibodies; RGD peptides; α5β1 function-blocking mutations; uPA domain deletion constructs; MAPK inhibition; CHO cell adhesion and migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-deletion mapping plus mutagenesis plus function-blocking antibodies, consistent across multiple readouts\",\n      \"pmids\": [\"12754207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cell-surface uPAR dimerizes, and dimeric uPAR partitions preferentially into detergent-resistant lipid rafts. Vitronectin (Vn) binding occurs preferentially to raft-associated dimeric uPAR and is completely blocked by cholesterol depletion. uPA-induced uPAR cleavage is strongly accelerated in lipid rafts. Dimerization itself does not require raft partitioning (a transmembrane uPAR chimera outside rafts still dimerizes efficiently).\",\n      \"method\": \"Detergent-resistant membrane fractionation; cholesterol depletion; transmembrane uPAR chimera; cross-linking; flow cytometry; ligand-binding assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, cholesterol depletion, chimeric receptor) in single rigorous study\",\n      \"pmids\": [\"14609946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Neutrophil elastase and cathepsin G cleave uPAR (CD87) within the D1–D2 linker sequence, generating truncated D2D3 membrane species and releasing them from monocytic cell surfaces. Cathepsin G additionally cleaves the C-terminus of D3. Combined action of both enzymes cooperatively generates a truncated D2D3 form similar to that found in pathological body fluids. These cleavages drastically reduce the capacity of cells to bind urokinase.\",\n      \"method\": \"Immunoblotting; flow cytometry; mass spectrometry of synthetic peptide fragments; recombinant uPAR substrate; U937 cells and isolated blood monocytes\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic cleavage of recombinant substrate with MS identification of cleavage sites, corroborated in intact cells\",\n      \"pmids\": [\"14688365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A direct uPAR–vitronectin interaction is both necessary and sufficient to initiate downstream changes in cell morphology, migration, and signal transduction. A complete alanine scan of uPAR (255 mutants) showed that all 34 morphology-defective mutants specifically lacked vitronectin binding; no integrin-binding defect was necessary. A membrane-tethered PAI-1 (which has the same vitronectin binding site as uPAR) replicated uPAR-induced morphological changes.\",\n      \"method\": \"Complete functional alanine scanning mutagenesis (255 mutants) in HEK293 cells; cell morphology/migration assays; membrane-tethered PAI-1 rescue experiment\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — comprehensive mutagenesis with multiple orthogonal validations; single study but exhaustive mapping\",\n      \"pmids\": [\"17548516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"uPAR aggregation (by mAb cross-linking) triggers phospholipase C activation via a tyrosine kinase-dependent mechanism, generating Ins(1,4,5)P3 and mobilizing intracellular calcium from IP3-sensitive stores. Cross-linking CR3 did not replicate this effect, and anti-CR3 antibodies did not block uPAR-triggered Ca2+ mobilization, indicating independence from CR3.\",\n      \"method\": \"Fluo-3 fluorimetry for [Ca2+]i; mAb cross-linking of uPAR; IP3 measurement; pharmacological inhibitors (thapsigargin, herbimycin A, U73122); primary human monocytes and U937 cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple pharmacological probes and both primary and cell line models with consistent results\",\n      \"pmids\": [\"10570311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"uPAR (CD87) is required for neutrophil (PMN) chemotaxis in vitro by a mechanism independent of uPA enzymatic activity, potentially through its ability to associate with CR3. Specific saccharides that disrupt CD87/CR3 coupling (NADG, D-mannose, mannoside) also inhibited PMN chemotaxis.\",\n      \"method\": \"Anti-CD87 mAb pre-treatment of PMNs; anti-uPA mAb and exogenous uPA controls; saccharide-mediated CR3/uPAR uncoupling; chemotaxis assay\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple inhibitory approaches, but reliance on mAbs and saccharides without genetic knockout\",\n      \"pmids\": [\"7595054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"p53 protein binds directly to a 37-nucleotide sequence in the 3' UTR of uPAR mRNA, destabilizes uPAR mRNA, and thereby suppresses uPAR expression. Loss of p53 stabilizes uPAR mRNA and increases cell-surface uPAR levels; inserting the p53-binding sequence into beta-globin mRNA confers p53-dependent destabilization to the chimeric transcript.\",\n      \"method\": \"RNA binding assay with purified p53; RNA silencing of p53; chimeric beta-globin–uPAR 3'UTR mRNA stability assay; p53 expression in p53-null cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro RNA binding with purified protein, chimeric mRNA rescue, and genetic loss-of-function, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17548471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The human airway trypsin-like protease (HAT) cleaves uPAR in the D1–D2 linker sequence after Arg83 and Arg89, generating a truncated D2D3 form that cannot bind vitronectin or urokinase. Membrane co-expression of HAT and uPAR causes constitutive and extensive shedding of the D1 domain.\",\n      \"method\": \"Immunoblotting; flow cytometry; ELISA; mass spectrometry (site identification); co-transfection in epithelial cells; recombinant uPAR substrate\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — enzymatic assay with recombinant substrate plus MS cleavage-site identification plus cellular co-expression confirmation\",\n      \"pmids\": [\"17237151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Streptococcal surface GAPDH (SDH/GAS) binds uPAR/CD87 specifically through the N-terminal domain D1 of uPAR, and this interaction mediates bacterial adherence to human pharyngeal cells. SDH binding maps to the C-terminal alpha-helix and flanking S-loop regions of SDH. PI-PLC removal of uPAR from pharyngeal cells decreased GAS adherence.\",\n      \"method\": \"Ligand-binding assays; LC-MS/MS identification of the ~55 kDa SDH receptor as uPAR; domain-deletion mapping; site-directed mutagenesis of SDH; PI-PLC removal of uPAR; bacterial adherence assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MS identification of the receptor, mutagenesis of the ligand, and PI-PLC functional ablation in a single study\",\n      \"pmids\": [\"15922359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"uPAR undergoes constitutive (ligand-independent) endocytosis and recycling through a clathrin- and LRP-1-independent macropinocytic pathway. This pathway is amiloride-sensitive, does not require lipid raft partitioning, and is independent of RhoA, Rac1, Cdc42, and PI3K. Constitutively endocytosed uPAR reaches EEA1-positive early/recycling endosomes but not lysosomes.\",\n      \"method\": \"Pharmacological inhibitors (amiloride, PI3K inhibitors); dominant-negative small GTPases; cholesterol depletion; electron microscopy; EEA1 co-localization; live imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and genetic tools in single lab, electron microscopy validation\",\n      \"pmids\": [\"19008962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LRP1 facilitates the endocytosis of uPAR, thereby down-regulating cell-surface uPAR levels and modulating uPAR-initiated signaling (ERK, PI3K, Rac1). Under some conditions uPAR endocytosis via LRP1 is required for sustained uPAR-initiated cell-signaling.\",\n      \"method\": \"Review of primary experimental evidence including LRP1 knockdown/inhibition studies and cell-signaling assays in neurons, neuron-like cells, and Schwann cells (primary literature basis)\",\n      \"journal\": \"Current pharmaceutical design\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic basis from multiple independent labs but abstracted here only through a review\",\n      \"pmids\": [\"21711236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Activated human neutrophils rapidly shed uPAR predominantly as a truncated D2D3 form (lacking D1 and the GPI anchor). This D2D3 form acts as a chemotactic agonist via FPRL1 (formyl peptide receptor-like 1): immunodepletion of D2D3 from activated neutrophil supernatants significantly reduced migration of FPRL1-transfected HEK293 cells. GPI-specific phospholipase D is not involved in uPAR shedding from neutrophils.\",\n      \"method\": \"Ionomycin/TNF-α/fMLP/IL-8 activation; immunodepletion of D2D3 from supernatants; FPRL1-transfected HEK293 migration assay; flow cytometry\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional immunodepletion experiment linking D2D3 shedding to FPRL1-mediated chemotaxis, single lab\",\n      \"pmids\": [\"18830568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The central binding cavity of uPAR for uPA is assembled by a dynamic interdomain association of all three LU domains; the high-affinity interaction (KD < 1 nM) relies on an unusually large and hydrophobic binding pocket. This structural information was established by X-ray crystallography and surface plasmon resonance.\",\n      \"method\": \"X-ray crystallography; surface plasmon resonance (as reviewed citing primary structural studies)\",\n      \"journal\": \"Frontiers in bioscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus SPR, independently replicated structural studies\",\n      \"pmids\": [\"18508598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RhoB is a key downstream regulator of uPAR signaling: uPA/uPAR rapidly activates RhoB and increases RhoB expression; RhoB depletion by RNAi reduces uPA-induced migration and invasion of prostate carcinoma cells, inhibits uPAR signaling to cofilin, paxillin, and Akt, and reduces integrin levels and uPAR–integrin association. Cell adhesion to vitronectin (a uPAR ligand) is also impaired by RhoB depletion.\",\n      \"method\": \"RNAi screen of 12 Rho GTPases; invasion/migration assays; immunoblotting for cofilin, paxillin, Akt; co-immunoprecipitation of uPAR and integrins; vitronectin adhesion assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with multiple pathway readouts, single lab\",\n      \"pmids\": [\"22366462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Full-length uPAR is required for both mesenchymal and amoeboid migration modes in cancer cells. uPAR co-localizes with β1/β3 integrins and the actin cytoskeleton; a peptide inhibiting uPAR–integrin interaction disrupts integrin–actin co-localization and abolishes amoeboid invasion while also reducing mesenchymal invasion. uPAR silencing deregulates RhoA and Rac1 GTPase activities during the amoeboid switch.\",\n      \"method\": \"uPAR siRNA silencing; uPAR–integrin blocking peptide; Rho/Rac GTPase activity assays; 3D matrix invasion assays; immunofluorescence co-localization\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and peptide inhibition with GTPase readouts, single lab\",\n      \"pmids\": [\"24681666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FOXM1 transcription factor directly activates PLAUR (uPAR) gene expression, promoting colon cancer growth and metastasis. FOXM1 overexpression significantly upregulates uPAR expression and increases invasion/metastasis in orthotopic mouse models; FOXM1 knockdown reduces uPAR expression and metastasis.\",\n      \"method\": \"Gene transfer overexpression and siRNA knockdown of FOXM1; orthotopic mouse models; correlation of FOXM1 and PLAUR expression\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo models with gain- and loss-of-function, but direct transcriptional binding not explicitly demonstrated by ChIP in this paper\",\n      \"pmids\": [\"23136192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PBK kinase enhances uPAR (PLAUR) expression by activating its promoter via ETV4. ChIP showed ETV4 directly binds the core region of the uPAR promoter, and PBK enhances ETV4 binding to this promoter. In vivo, PBK knockdown inhibited lung metastasis of HCC cells, an effect rescued by uPAR overexpression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP); promoter activity assay; gain/loss-of-function; orthotopic mouse model; ETV4–uPAR promoter interaction\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates direct ETV4–uPAR promoter binding, in vivo rescue experiment confirms epistatic relationship; single lab\",\n      \"pmids\": [\"30914208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TCF7L2 transcriptionally activates PLAUR (uPAR) expression; TCF7L2 promotes anoikis resistance and metastasis of gastric cancer cells through upregulation of PLAUR.\",\n      \"method\": \"Transcriptional activation assays; siRNA knockdown; overexpression studies; anoikis and metastasis assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional regulation demonstrated, functional rescue experiments, single lab\",\n      \"pmids\": [\"35864968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structure of human uPAR dimer at 2.96 Å resolution reveals that dimerization causes D1 to open into a large expanded ring that captures a β-hairpin loop of a neighboring uPAR, forming an extended β-sheet and an elongated, highly intertwined dimer. Mutation E49P promotes dimer formation; the dimer shows increased binding to the amino-terminal fragment of uPA, redistributes to the basal membrane, promotes cell proliferation, and alters cell morphology via β1 integrin signaling.\",\n      \"method\": \"X-ray crystallography (2.96 Å); site-directed mutagenesis (E49P); cell-based functional assays; β1 integrin signaling readouts; uPA-ATF binding assay; immunofluorescence for membrane distribution\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and multiple cellular functional readouts in single study\",\n      \"pmids\": [\"35351875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Protease nexin-1 (PN-1) unexpectedly increases the association between vitronectin and uPAR in the presence of enzymatically active uPA, thereby stimulating uPAR-dependent cell adhesion to immobilized vitronectin. In contrast, PAI-1 inhibits uPAR–vitronectin interaction. On adhesion to vitronectin, uPAR and PN-1 co-accumulate at the cell–matrix interface.\",\n      \"method\": \"Cell adhesion assays; confocal microscopy; PN-1 and PAI-1 protein additions; integrin versus uPAR adhesion pathway discrimination\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional adhesion assays with defined recombinant proteins, confocal co-localization; single lab\",\n      \"pmids\": [\"14679304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"uPAR (CD87) functions as a platelet receptor; uPAR-deficient platelets survive longer in wild-type recipients, and TNF-induced platelet consumption, pulmonary localization, and platelet activation are absent in uPAR-/- mice. Platelet uPAR (not endothelial/leukocyte uPAR) is critical for TNF-induced platelet–endothelial adhesion.\",\n      \"method\": \"uPAR-/- mouse model; 51Cr platelet survival assay; intratracheal TNF injection; FACS; electron microscopy; cross-transfer experiments\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with cross-transfer experiments clearly identifying platelet uPAR as the critical molecule; electron microscopy confirmation\",\n      \"pmids\": [\"10385508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Genetic disruption of PLAUR (uPAR null mice) causes a regionally selective reduction in GABAergic interneurons in frontal and parietal neocortex and hippocampal CA1 and dentate gyrus, with compensatory changes in GABAA receptor subunit composition (α2 up, α3 down, β2/β3/γ2 subunit changes) specifically in regions with interneuron loss, and associated behavioral phenotypes (increased seizure sensitivity, anxiety, atypical social behavior).\",\n      \"method\": \"uPAR-/- mice; quantitative RT-PCR for 13 GABAA subunits; semi-quantitative in situ hybridization; behavioral testing; regional interneuron counting\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with detailed regional circuit analysis, single lab\",\n      \"pmids\": [\"20381588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Genetic inhibition of uPAR (CRISPR, siRNA, uPAR-KO mice) or pharmacological blockade of uPA–uPAR interaction protects intestinal epithelial barrier integrity against cytokine-induced breakdown. uPAR deficiency in epithelial cells leads to enhanced EGF/EGFR signaling. uPAR-deficient mice display improved barrier function and attenuated DSS-induced colitis.\",\n      \"method\": \"CRISPR, siRNA, KO mice; TEER and FITC-dextran permeability; tight junction assessment; DSS colitis model; small molecule, neutralizing antibody and peptide inhibitors; EGFR signaling readouts\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic and pharmacological approaches in vitro and in vivo, consistent mechanistic finding\",\n      \"pmids\": [\"34933179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PLAUR (uPAR) in sensory neurons mediates Serpin E1 (PAI-1)-induced signaling through TLR2 co-activation and downstream OSM production, promoting itch-associated gene transcription. PLAUR resides in TLR2+ sensory neurons; Serpin E1 stimulus upregulates TLR2 and its co-signaling proteins; OSM induces acute itch in mice.\",\n      \"method\": \"Mouse AD model (MC903); sensory neuron isolation; transcriptomic profiling; in vivo Serpin E1 inhibitor treatment; OSM itch assay in mice; human AD/psoriasis skin specimens\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacological inhibition and transcriptomic profiling, single lab\",\n      \"pmids\": [\"35596683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The PLAUR gene (encoding uPAR) maps to human chromosome 19q13.1–q13.2. A ligand-binding study on cell hybrids confirmed species-specificity of uPAR and validated the chromosomal assignment.\",\n      \"method\": \"Human/rodent somatic cell hybrid panel; multipoint linkage analysis of CEPH families; uPA ligand-binding assay on cell hybrids\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent mapping methods (cell hybrids and linkage analysis) with functional validation by ligand binding\",\n      \"pmids\": [\"1311495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"E4 (C-terminal endostatin domain) binds uPAR (and enolase-1) at the cell surface; this interaction is required for E4's antifibrotic effects. E4 activates the urokinase pathway, increases the uPA/PAI-1 ratio, and elevates MMP-1 and MMP-3 expression and activity in a uPAR-dependent manner.\",\n      \"method\": \"Biotinylated E4 pulldown with MS identification of binding partners; uPAR KO cells; in vivo bleomycin fibrosis model; MMP activity assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown with MS identification plus uPAR-dependent genetic rescue, single lab\",\n      \"pmids\": [\"34935642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"uPAR deficiency (uPAR-/-) in murine endothelial cells impairs adhesion, migration, proliferation, and capillary tube formation. On vitronectin, uPAR-/- cells adopt a 'fried egg' morphology with circular actin and no lamellipodia, with upregulated β1 integrin, FAK(P-Tyr925), and paxillin (P-Tyr118) indicating increased but stalled focal adhesions, and decreased Rac1 activation. In vivo, uPAR-/- mice show lack of mature vessel formation in VEGF-enriched Matrigel implants.\",\n      \"method\": \"uPAR-/- murine endothelial cells; adhesion/migration/proliferation/tube formation assays; immunoblotting for focal adhesion proteins; Rac1 activity assay; in vivo Matrigel plug assay\",\n      \"journal\": \"Vascular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple cellular and in vivo readouts, single lab\",\n      \"pmids\": [\"21535874\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLAUR (uPAR/CD87) is a GPI-anchored three-LU-domain receptor that focalizes urokinase (uPA)-mediated plasminogen activation at the cell surface; it signals without intrinsic transmembrane domains by forming lateral (cis) and trans complexes with integrins (α4β1, α5β1, α6β1, α9β1, αvβ3) and with β2 integrins (Mac-1/CR3), activating MAPK, PI3K/Akt, RhoB, and phospholipase C/Ca2+ pathways to drive cell adhesion, migration, and matrix proteolysis; direct binding to vitronectin via the assembled uPA-occupied receptor is necessary and sufficient to initiate morphological and migratory responses; the receptor undergoes regulated cleavage of domain D1 by neutrophil elastase, cathepsin G, and HAT, generating a truncated D2D3 form that acts as an FPRL1 chemoattractant; it can dimerize (crystal structure resolved), with the dimer promoting basal-membrane redistribution and β1 integrin signaling; expression is transcriptionally regulated by p53 (mRNA destabilization), FOXM1, ETV4/PBK, TCF7L2, and AP-1, and its abundance is controlled by LRP1-mediated endocytosis and macropinocytic recycling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLAUR (uPAR/CD87) is a GPI-anchored receptor that focalizes urokinase-mediated proteolysis at the cell surface and converts that proteolytic context into adhesion and migration signals despite lacking transmembrane and intracellular domains [#0]. Because it cannot signal autonomously, uPAR transduces information through transmembrane co-receptors: it forms lateral cis complexes with β1 integrins—uPA occupancy converts uPAR into an RGD-dependent ligand for α5β1 that drives MAPK activation and chemotactic migration [#5]—and acts in trans, where soluble uPAR engages α4β1, α6β1, α9β1, and αvβ3 on apposing cells in a cation- and RGD-dependent manner [#4]. On leukocytes it partners physically with the β2 integrin Mac-1/CR3, an association required for integrin-mediated adhesion to endothelium and matrix proteins and reciprocally regulated by uPA occupancy [#1, #3]. Independent of any integrin defect, a direct uPAR–vitronectin interaction is both necessary and sufficient to initiate morphological change, migration, and signaling, as shown by comprehensive alanine-scanning mutagenesis [#8]. Downstream, uPAR engages RhoB to control cofilin, paxillin, and Akt and to maintain uPAR–integrin association [#18], and it triggers tyrosine-kinase-dependent phospholipase C activation with IP3-mediated calcium mobilization [#9]. The receptor is built from three intertwined LU domains that assemble a high-affinity uPA-binding cavity [#17], dimerizes within lipid rafts to favor vitronectin binding and β1-integrin signaling [#6, #23], and is regulated by D1-cleaving proteases—neutrophil elastase, cathepsin G, and HAT—that release a truncated D2D3 species which itself acts as an FPRL1 chemotactic agonist [#7, #12, #16]. uPAR abundance is set transcriptionally by FOXM1, ETV4/PBK, and TCF7L2 and post-transcriptionally by p53-mediated mRNA destabilization, with surface levels further controlled by macropinocytic recycling and LRP1-dependent endocytosis [#11, #20, #14, #15]. Genetic studies establish physiological roles in platelet–endothelial adhesion, angiogenesis, GABAergic interneuron patterning, and epithelial barrier integrity [#25, #31, #26, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing the chromosomal locus and species-specificity of uPA binding anchored PLAUR as a discrete, mappable human gene encoding the urokinase receptor.\",\n      \"evidence\": \"somatic cell hybrid panel, CEPH linkage analysis, and uPA ligand-binding on hybrids\",\n      \"pmids\": [\"1311495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address receptor structure or signaling mechanism\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"The question of how a proteolytic receptor controls adhesion was answered by showing uPAR physically and functionally couples to the β2 integrin Mac-1/CR3, with uPA occupancy bidirectionally regulating integrin-dependent adhesion.\",\n      \"evidence\": \"anti-uPAR/anti-CR3 mAbs, antisense oligonucleotides, CHO co-transfection of human Mac-1 and uPAR, adhesion and fibrinogen-degradation assays\",\n      \"pmids\": [\"8621779\", \"8874219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether integrin coupling is the only signaling route\", \"Structural basis of the uPAR–Mac-1 interface not defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"An in vivo requirement for uPAR in β2-integrin-mediated leukocyte recruitment was established, with domain-1 mapping showing intact uPAR is needed to restore adhesion.\",\n      \"evidence\": \"uPAR-deficient mouse, PI-PLC removal and soluble uPAR reconstitution, mAb ligation, flow cytometry\",\n      \"pmids\": [\"9743521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the transmembrane signal-transducing partner downstream of the uPAR–Mac-1 unit\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"uPAR aggregation was shown to drive a defined second-messenger cascade—tyrosine-kinase-dependent PLC activation and IP3-mediated calcium release—independent of CR3, establishing intracellular signaling capacity.\",\n      \"evidence\": \"mAb cross-linking, Fluo-3 calcium fluorimetry, IP3 measurement, pharmacological inhibitors in monocytes and U937 cells\",\n      \"pmids\": [\"10570311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The transmembrane co-receptor relaying tyrosine kinase activation was not identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Resolving how a GPI-anchored protein signals through integrins, soluble uPAR was shown to act as a direct trans-ligand for multiple β1 and αvβ3 integrins, providing a transmembrane-adapter-free route for cell–cell signaling.\",\n      \"evidence\": \"CHO cell-based binding, anti-integrin and anti-uPAR blocking, integrin function-blocking mutations, ligand competition\",\n      \"pmids\": [\"11053440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of trans-interactions not established\", \"Affinities and stoichiometry not quantified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The cis-signaling mechanism was defined: uPA binding converts uPAR into an α5β1 ligand requiring the uPA growth-factor domain, coupling proteolytic ligand engagement to MAPK and chemotaxis.\",\n      \"evidence\": \"uPA domain-deletion constructs, anti-uPAR/anti-α5 antibodies, RGD peptides, function-blocking mutations, MAPK inhibition, CHO adhesion/migration assays\",\n      \"pmids\": [\"12754207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address how the GPI receptor laterally docks onto α5β1\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Membrane organization was shown to gate function: uPAR dimerizes preferentially in lipid rafts, where vitronectin binding and uPA-induced cleavage are favored, separating dimerization from raft partitioning.\",\n      \"evidence\": \"detergent-resistant membrane fractionation, cholesterol depletion, transmembrane uPAR chimera, cross-linking, flow cytometry\",\n      \"pmids\": [\"14609946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of raft-localized dimers for downstream signaling not directly mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Serpin modulation of vitronectin engagement was clarified—PN-1 enhances while PAI-1 inhibits uPAR–vitronectin adhesion—identifying extracellular regulators of the adhesion ligand axis.\",\n      \"evidence\": \"cell adhesion assays with recombinant PN-1/PAI-1, confocal co-localization, integrin-versus-uPAR pathway discrimination\",\n      \"pmids\": [\"14679304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; structural basis of PN-1 enhancement undefined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Regulated proteolysis was defined mechanistically: neutrophil elastase and cathepsin G cleave the D1–D2 linker to generate a D2D3 species and abolish uPA binding, identifying a switch that inactivates the receptor.\",\n      \"evidence\": \"recombinant uPAR substrate cleavage, mass spectrometry of cleavage sites, immunoblot/flow cytometry in U937 and monocytes\",\n      \"pmids\": [\"14688365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish a signaling function for the released D2D3 fragment\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"A pathogen-exploitation function emerged: streptococcal surface GAPDH binds uPAR domain D1 to mediate bacterial adherence to pharyngeal cells, mapping a host–microbe interface on the receptor.\",\n      \"evidence\": \"ligand-binding assays, LC-MS/MS receptor identification, domain-deletion mapping, SDH mutagenesis, PI-PLC ablation, adherence assays\",\n      \"pmids\": [\"15922359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream consequences for host signaling not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The vitronectin interaction was elevated to the necessary and sufficient trigger of uPAR signaling, as every morphology-defective mutant in an exhaustive scan lacked vitronectin—not integrin—binding.\",\n      \"evidence\": \"complete alanine scan (255 mutants) in HEK293, morphology/migration assays, membrane-tethered PAI-1 rescue\",\n      \"pmids\": [\"17548516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with integrin-dependent signaling models not fully resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Transcript-level control was established by showing p53 directly binds the uPAR 3'UTR and destabilizes the mRNA, linking tumor-suppressor status to surface receptor abundance.\",\n      \"evidence\": \"in vitro RNA binding with purified p53, chimeric β-globin–uPAR 3'UTR stability assay, p53 silencing and re-expression\",\n      \"pmids\": [\"17548471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The RNA-destabilization machinery recruited by p53 not identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A second D1-shedding protease, airway trypsin-like protease (HAT), was shown to cleave after Arg83/Arg89, producing a D2D3 form unable to bind vitronectin or uPA, extending tissue-specific control of receptor inactivation.\",\n      \"evidence\": \"recombinant substrate cleavage, mass spectrometry, ELISA/flow cytometry, HAT–uPAR co-transfection in epithelial cells\",\n      \"pmids\": [\"17237151\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological context of HAT-mediated shedding in airway not tested in vivo\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The shed D2D3 fragment was assigned a positive signaling role as an FPRL1 chemotactic agonist, converting receptor cleavage from inactivation into a paracrine motility signal.\",\n      \"evidence\": \"neutrophil activation, immunodepletion of D2D3 from supernatants, FPRL1-transfected HEK293 migration assay, flow cytometry\",\n      \"pmids\": [\"18830568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; the FPRL1-binding epitope within D2D3 not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Receptor turnover was characterized as a constitutive, clathrin- and LRP1-independent macropinocytic recycling route to EEA1+ endosomes, defining how surface uPAR levels are maintained.\",\n      \"evidence\": \"amiloride and PI3K inhibitors, dominant-negative GTPases, cholesterol depletion, electron microscopy, EEA1 co-localization, live imaging\",\n      \"pmids\": [\"19008962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; molecular machinery driving uPAR macropinocytosis unidentified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The structural basis of high-affinity uPA capture was defined as a dynamic interdomain assembly of all three LU domains forming a large hydrophobic pocket.\",\n      \"evidence\": \"X-ray crystallography and surface plasmon resonance (reviewed primary structural work)\",\n      \"pmids\": [\"18508598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational dynamics of the apo-receptor not detailed here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"A neural function was uncovered: uPAR deletion selectively reduces GABAergic interneurons in defined cortical and hippocampal regions with compensatory GABAA subunit shifts and behavioral abnormalities.\",\n      \"evidence\": \"uPAR-/- mice, qRT-PCR of 13 GABAA subunits, in situ hybridization, behavioral testing, regional interneuron counts\",\n      \"pmids\": [\"20381588\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; molecular pathway linking uPAR to interneuron development undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"uPAR was shown to be required for endothelial adhesion, migration, and angiogenesis, with knockout cells displaying stalled focal adhesions, elevated β1 integrin/FAK/paxillin phosphorylation, and reduced Rac1 activity.\",\n      \"evidence\": \"uPAR-/- endothelial cells, adhesion/migration/tube-formation assays, focal-adhesion immunoblots, Rac1 activity, in vivo Matrigel plug\",\n      \"pmids\": [\"21535874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; whether the vitronectin or uPA axis drives the angiogenic defect not separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"LRP1 was identified as a route for uPAR endocytosis that down-regulates surface levels and, in some contexts, is required to sustain ERK/PI3K/Rac1 signaling, complementing the macropinocytic pathway.\",\n      \"evidence\": \"review of LRP1 knockdown/inhibition and signaling assays in neurons and Schwann cells\",\n      \"pmids\": [\"21711236\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Abstracted via review; quantitative contribution of LRP1 versus macropinocytosis not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"RhoB was placed as a central downstream effector of uPA/uPAR signaling controlling cofilin, paxillin, and Akt and maintaining uPAR–integrin association, linking the receptor to cytoskeletal remodeling in invasion.\",\n      \"evidence\": \"RNAi screen of 12 Rho GTPases, invasion/migration assays, signaling immunoblots, uPAR–integrin co-IP, vitronectin adhesion\",\n      \"pmids\": [\"22366462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; mechanism of RhoB activation downstream of uPAR unmapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Transcriptional drivers of uPAR were defined in cancer: FOXM1 directly activates PLAUR to promote colon cancer growth and metastasis.\",\n      \"evidence\": \"FOXM1 overexpression/knockdown, orthotopic mouse models, expression correlation\",\n      \"pmids\": [\"23136192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter binding not shown by ChIP in this study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Full-length uPAR was shown to be required for both mesenchymal and amoeboid migration, with uPAR–integrin coupling sustaining integrin–actin co-localization and balancing RhoA/Rac1 activity.\",\n      \"evidence\": \"uPAR siRNA, uPAR–integrin blocking peptide, Rho/Rac activity assays, 3D invasion, immunofluorescence\",\n      \"pmids\": [\"24681666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; the precise integrin partner governing the amoeboid switch not specified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A kinase–transcription-factor axis was defined whereby PBK enhances ETV4 binding to the uPAR promoter to drive metastasis, with ChIP confirming direct ETV4 occupancy.\",\n      \"evidence\": \"ChIP, promoter activity assays, gain/loss-of-function, orthotopic mouse model with uPAR rescue\",\n      \"pmids\": [\"30914208\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; how PBK modifies ETV4 to enhance binding not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"An epithelial barrier function was uncovered: uPAR loss protects against cytokine-induced barrier breakdown and colitis through enhanced EGF/EGFR signaling.\",\n      \"evidence\": \"CRISPR/siRNA/KO mice, TEER and permeability assays, DSS colitis, small molecule/antibody/peptide inhibitors, EGFR readouts\",\n      \"pmids\": [\"34933179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking uPAR to EGFR restraint not defined at the molecular level\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"uPAR was identified as a cell-surface partner of the endostatin-derived E4 fragment required for antifibrotic activation of the urokinase/MMP pathway.\",\n      \"evidence\": \"biotinylated E4 pulldown with MS, uPAR KO cells, in vivo bleomycin fibrosis, MMP activity assays\",\n      \"pmids\": [\"34935642\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; binding interface and signaling output not structurally defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A high-resolution dimer structure explained how uPAR self-association functions: D1 opens into an expanded ring capturing a neighboring β-hairpin, and the dimer (favored by E49P) increases uPA-ATF binding and drives proliferation via β1 integrin signaling.\",\n      \"evidence\": \"X-ray crystallography at 2.96 Å, E49P mutagenesis, uPA-ATF binding, β1 signaling readouts, immunofluorescence of membrane distribution\",\n      \"pmids\": [\"35351875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological abundance and regulation of the dimer in vivo not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Additional transcriptional control and a sensory-neuron signaling role were defined: TCF7L2 activates PLAUR to promote anoikis resistance and metastasis, and uPAR mediates Serpin E1–induced TLR2/OSM signaling driving itch.\",\n      \"evidence\": \"transcriptional/knockdown/overexpression assays and anoikis/metastasis readouts; mouse AD model, sensory neuron transcriptomics, OSM itch assay\",\n      \"pmids\": [\"35864968\", \"35596683\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single labs; direct TCF7L2 promoter binding and the uPAR–TLR2 physical interface not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple, partly competing signaling modes—vitronectin-driven, cis/trans integrin coupling, and dimer-dependent β1 signaling—are integrated and prioritized within a single cell context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling the necessary-and-sufficient vitronectin model with integrin-dependent signaling\", \"Stoichiometry of monomer-versus-dimer signaling in vivo unknown\", \"Transmembrane partner that relays uPAR tyrosine-kinase signaling not definitively identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 3, 4, 5, 8]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [4, 5, 16]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 9, 18]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 6, 23]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [14, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 9, 18, 19]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [25]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 16]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 8, 30]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [14, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [11, 20, 21, 22]}\n    ],\n    \"complexes\": [\n      \"uPAR-Mac-1 (CD11b/CD18) complex\",\n      \"uPAR-α5β1 integrin complex\"\n    ],\n    \"partners\": [\n      \"PLAU\",\n      \"ITGB1\",\n      \"ITGAM\",\n      \"ITGB2\",\n      \"VTN\",\n      \"LRP1\",\n      \"SERPINE1\",\n      \"TLR2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}