Affinage

PLAU

Urokinase-type plasminogen activator · UniProt P00749

Round 2 corrected
Length
431 aa
Mass
48.5 kDa
Annotated
2026-04-28
130 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PLAU encodes urokinase-type plasminogen activator (uPA), a secreted serine protease that is produced as inactive single-chain pro-uPA and activated extracellularly by plasmin, cathepsin B, matriptase, or TMPRSS4 through cleavage at Lys158–Ile159, yielding a two-chain enzyme whose primary function is conversion of plasminogen to plasmin at the cell surface (PMID:1829461, PMID:1900515, PMID:10962009, PMID:24434139). Binding of uPA to its GPI-anchored receptor uPAR via the amino-terminal growth factor domain lowers the Km for plasminogen activation ~40-fold, focuses pericellular proteolysis to the leading edge of migrating cells, and triggers non-proteolytic signaling through Ras/MEK/ERK/MLCK, PI3K/Akt, and LRP1/β1-integrin/Rac1 cascades that drive cell migration, survival, axonal regeneration, and angiogenesis (PMID:2166055, PMID:10402467, PMID:27986809, PMID:16456079). uPA also cleaves pro-HGF/SF to its active heterodimer, degrades extracellular matrix in 3D tumour models, and its kringle domain independently engages αVβ3 integrin to promote migration (PMID:1334458, PMID:38020586, PMID:16525582). Tandem duplication of the PLAU locus causes Quebec platelet disorder, a dominant bleeding disorder driven by megakaryocyte-specific >100-fold overexpression of uPA (PMID:20007542, PMID:28301587).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1982 High

    Determination of the complete primary structure of the uPA A-chain revealed a modular architecture — growth factor, kringle, and connecting peptide domains — establishing the domain logic that underlies all subsequent functional mapping.

    Evidence Edman degradation and multiple fragmentation strategies on purified high-MW urokinase

    PMID:6754569

    Open questions at the time
    • No structure–function assignments for individual domains yet
    • Receptor identity unknown
  2. 1984 High

    Isolation and sequencing of the PLAU gene (6.4 kb, 11 exons) showed that intron–exon boundaries separate functional domains, providing the genomic framework for understanding splicing, transcriptional regulation, and evolutionary relationships.

    Evidence Gene cloning, nucleotide sequencing, S1 mapping, primer extension, cDNA analysis

    PMID:2987867 PMID:6589620

    Open questions at the time
    • Promoter regulatory elements beyond CAAT/TATA not yet defined
    • No information on tissue-specific regulation
  3. 1987 High

    Mapping of the receptor-binding determinant to the growth factor module (residues 12–32) answered how uPA engages the cell surface and showed the catalytic domain is dispensable for receptor binding.

    Evidence Synthetic peptide competition binding assays with ¹²⁵I-ATF on intact cells

    PMID:3031025

    Open questions at the time
    • Receptor identity still uncloned
    • Three-dimensional basis of binding unknown
  4. 1990 High

    Cloning of uPAR as a 313-aa GPI-anchored protein and demonstration that receptor-bound uPA localizes to the leading edge of migrating cells established the paradigm of receptor-focused pericellular proteolysis.

    Evidence cDNA cloning with heterologous reconstitution; immunofluorescence on chemotactically migrating monocytes; kinetic inhibition studies with PAI-1/PAI-2

    PMID:1689240 PMID:2161846 PMID:2166055

    Open questions at the time
    • Structural basis of uPA–uPAR interaction unknown
    • Intracellular signaling consequences not addressed
  5. 1991 High

    Quantitative enzymology revealed that uPAR binding drops the Km for plasminogen activation 40-fold (to 0.67 µM, below physiological [plasminogen]) and protects product plasmin from α2-antiplasmin, explaining why cell-surface localization matters for in vivo fibrinolysis and invasion.

    Evidence Kinetic analysis on U937 cells and purified isolated uPAR

    PMID:1829461

    Open questions at the time
    • Structural explanation for kinetic enhancement unknown
    • Relative contribution of plasminogen co-receptors not resolved
  6. 1991 High

    Identification of cathepsin B as a pro-uPA activator cleaving the same Lys158–Ile159 bond as plasmin revealed that tumor-derived cysteine proteases can initiate the uPA activation cascade independently of plasmin feedback.

    Evidence In vitro cleavage with purified cathepsin B, N-terminal sequencing, E-64 inhibitor control

    PMID:1900515

    Open questions at the time
    • In vivo relevance of cathepsin B activation vs. plasmin autoactivation not determined
  7. 1992 High

    Discovery that uPA converts pro-HGF/SF to active HGF/SF expanded the substrate repertoire beyond plasminogen, linking uPA to receptor tyrosine kinase signaling (c-Met) and cell scattering.

    Evidence In vitro cleavage of purified pro-HGF/SF with functional scatter and Met phosphorylation readouts

    PMID:1334458

    Open questions at the time
    • Relative in vivo contribution of uPA vs. other HGF activases (e.g., HGFA) unresolved
  8. 1996 High

    Demonstration that PAI-1 blocks migration by competing with αVβ3 integrin for vitronectin — independent of its protease-inhibitory activity — revealed a non-canonical regulatory mechanism where serpin–protease complex formation restores migration by lowering PAI-1 affinity for vitronectin.

    Evidence SMC migration assays with PAI-1 mutants, integrin blocking antibodies

    PMID:8837777

    Open questions at the time
    • Structural basis of PAI-1–vitronectin–integrin competition not resolved at atomic level
  9. 1997 High

    Elucidation of composite PEA3/AP-1 enhancer elements at −2.4 kb and −6.9 kb, combined with later JNK/AP-1 pathway mapping and Fra-1 studies, defined the transcriptional logic driving PLAU induction in response to growth factors and genotoxic stress.

    Evidence DNase I hypersensitivity, deletion reporters, EMSA, dominant-negative kinases; ChIP and RNAi of Fra-1

    PMID:10942386 PMID:25200076 PMID:9409785

    Open questions at the time
    • Chromatin remodeling steps at the PLAU locus incompletely mapped
    • Megakaryocyte-specific regulatory elements not identified
  10. 1997 High

    Discovery that uPAR is recycled back to the cell surface after LRP-mediated endocytosis of uPA:serpin complexes explained how cells maintain receptor availability for successive rounds of pericellular proteolysis.

    Evidence Surface biotinylation recycling assay, PI-PLC sensitivity, immunoelectron microscopy

    PMID:9184208

    Open questions at the time
    • Sorting signals directing uPAR recycling vs. LRP degradation not identified
  11. 1999 High

    Genetic epistasis with dominant-negative Ras/MEK and MLCK inhibitors established the first complete intracellular signaling cascade (Ras→MEK→ERK→MLCK→myosin II) downstream of uPA–uPAR ligation driving cell migration, demonstrating that uPA is a bona fide signaling ligand beyond its protease role.

    Evidence Dominant-negative constructs, pharmacological inhibitors, migration assays on vitronectin with integrin blocking antibodies

    PMID:10402467

    Open questions at the time
    • Proximal signaling link between GPI-anchored uPAR and cytoplasmic Ras not identified
    • Lipid raft requirement not yet established
  12. 2006 High

    The 1.9 Å crystal structure of the uPA–uPAR complex revealed uPAR's three-domain concave architecture with a central cone-shaped cavity accommodating the uPA amino-terminal fragment, providing the atomic framework for understanding receptor engagement and enabling structure-based drug design.

    Evidence X-ray crystallography of uPA:uPAR:antibody ternary complex

    PMID:16456079

    Open questions at the time
    • Full-length uPA structure in complex not determined
    • Conformational dynamics upon uPAR engagement not characterized
  13. 2006 High

    The uPA kringle domain was shown to bind αVβ3 integrin directly and independently of uPAR, identifying a second cell-surface tethering mechanism that enhances plasminogen activation on uPAR-negative cells and promotes integrin-dependent migration.

    Evidence Binding assays on uPAR-depleted CHO cells and purified αVβ3, blocking antibodies

    PMID:16525582

    Open questions at the time
    • Structural basis of kringle–integrin interaction unknown
    • Physiological context where this uPAR-independent mechanism dominates not defined
  14. 2007 Medium

    Demonstration that uPA binding drives uPAR into lipid rafts — independently of catalytic activity — and that raft disruption abolishes ERK signaling provided a mechanistic link between GPI-anchored uPAR and cytoplasmic signaling.

    Evidence Sucrose gradient DRM fractionation, methyl-β-cyclodextrin treatment, ERK phosphorylation assays

    PMID:17963689

    Open questions at the time
    • Identity of the raft-resident transmembrane partner transducing the signal not determined
    • Single lab observation
  15. 2009 High

    Identification of a 78-kb tandem duplication encompassing PLAU as the cause of Quebec platelet disorder — with megakaryocyte-specific >100-fold overexpression — established uPA gene dosage as a Mendelian disease mechanism and revealed cell-type-specific regulatory vulnerability.

    Evidence Array CGH, FISH in 38 QPD subjects and 425 controls; RNA-seq and allele-specific transcript analysis in megakaryocytes

    PMID:20007542 PMID:28301587

    Open questions at the time
    • Regulatory element within the duplication conferring megakaryocyte specificity not mapped
    • Therapeutic strategy to normalize uPA in megakaryocytes not developed
  16. 2016 High

    uPA–uPAR signaling was shown to promote CNS axonal regeneration through a plasminogen-independent, LRP1/β1-integrin/Rac1 pathway, expanding uPA function from proteolysis and migration to neural repair.

    Evidence In vitro axonal injury and in vivo CNS injury models with LRP1 inhibition, β1-integrin blocking, Rac1 activity assays

    PMID:27986809

    Open questions at the time
    • Whether this pathway operates in peripheral nerve injury not tested
    • LRP1 binding determinants on uPA for this non-proteolytic function not mapped
  17. 2022 Medium

    Discovery that METTL3 stabilizes PLAU mRNA through m6A modification introduced an epitranscriptomic layer of uPA regulation, linking RNA methylation to metastatic potential via MAPK/ERK signaling.

    Evidence m6A-seq, METTL3 overexpression/knockdown, RNA stability assays, in vivo tumour models

    PMID:35567945

    Open questions at the time
    • Specific m6A site(s) on PLAU mRNA not mapped at single-nucleotide resolution
    • m6A reader(s) responsible for stabilization not identified
  18. 2023 High

    CRISPR knockout of PLAU completely abolished matrix remodeling and invasion in 3D tumouroid models, confirming with genetic precision that uPA enzymatic activity is the dominant driver of ECM degradation during cancer cell invasion.

    Evidence CRISPR-Cas9 KO, AFM stiffness measurements, pharmacological inhibitor UK-371,801, 3D tumouroid culture

    PMID:38020586

    Open questions at the time
    • Redundancy with tPA or other MMPs in different tumour types not assessed
    • In vivo metastasis suppression by PLAU KO not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the transmembrane co-receptor that couples GPI-anchored uPAR to intracellular kinase cascades, the structural basis for the kringle–αVβ3 interaction, the megakaryocyte-specific regulatory element disrupted in QPD, and whether therapeutic targeting of the uPA–uPAR interface can achieve anti-metastatic efficacy in vivo.
  • Transmembrane signaling partner of uPAR not conclusively identified
  • No in vivo efficacy data for uPA–uPAR PPI inhibitors in metastasis models
  • Full-length active uPA crystal structure still lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 4 GO:0048018 receptor ligand activity 3
Localization
GO:0005576 extracellular region 4 GO:0005886 plasma membrane 3 GO:0031012 extracellular matrix 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-109582 Hemostasis 3 R-HSA-1643685 Disease 3 R-HSA-1474244 Extracellular matrix organization 1
Partners
HGFITGAVITGB3LRP1PLAURSERPINE1ST14TM4SF1

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 The human urokinase-type plasminogen activator (uPA/PLAU) gene was isolated and its complete nucleotide sequence determined. The gene is 6.4 kb long, organized in 11 exons, and contains a functional promoter region with GGCGGG repeats between CAAT and TATA boxes. The 5' end of uPA mRNA was mapped by S1 and primer extension. Gene cloning, nucleotide sequencing, S1 mapping, primer extension, CAT reporter transfection Nucleic acids research High 2987867
1984 A partially spliced polyadenylated precursor to urokinase mRNA was identified; the introns separate functionally different domains of the enzyme, establishing the domain organization of PLAU. cDNA cloning, nucleotide sequencing, RNA blot Proceedings of the National Academy of Sciences of the United States of America High 6589620
1982 Complete primary structure of the A chain (157 amino acids) of high molecular mass urokinase was determined, revealing three domains: a growth factor domain (homologous to EGF), a kringle domain (homologous to plasminogen kringles), and a connecting peptide domain. Protein sequencing by Edman degradation, cyanogen bromide cleavage, endoproteinase Lys-C fragmentation, carboxypeptidase treatment Hoppe-Seyler's Zeitschrift fur physiologische Chemie High 6754569
1987 The receptor-binding domain of uPA was mapped to the growth factor module (residues ~12–32), specifically amino acids 20–30 confer receptor binding specificity while residues 13–19 provide proper conformation. Synthetic peptides corresponding to uPA-(12-32) inhibited receptor binding of 125I-ATF with 50% inhibition at 100 nM. Synthetic peptide competition binding assays with 125I-labeled amino-terminal fragment (ATF) The Journal of biological chemistry High 3031025
1990 The cDNA for the human uPA receptor (uPAR) was cloned and sequenced, encoding a 313 amino acid protein with a signal peptide and GPI-anchor signal. Expression of uPAR cDNA in mouse cells confirmed it is a functional uPA-binding protein that localizes to the cell surface and facilitates uPA-catalyzed plasminogen activation. cDNA cloning, sequencing, heterologous expression in mouse LB6 cells, cross-linking, direct binding, caseinolytic plaque assay, immunofluorescence The EMBO journal High 1689240
1990 uPA receptor localizes uPA to the leading edge of migrating monocytes in a chemotactic gradient, focusing extracellular proteolysis at the front of migrating cells. Receptor-bound uPA/PAI-2 complexes are rapidly cleared by cell-surface cleavage followed by endocytosis and degradation. Immunofluorescence on migrating monocytes, kinetic studies of PAI-2 inhibition of receptor-bound vs. free uPA, endocytosis assays The Journal of cell biology High 2166055
1990 Receptor-bound uPA retains susceptibility to inhibition by PAI-1 and PAI-2, but with association rate constants ~40% lower than free uPA. PMA stimulation of U937 cells further reduces receptor-bound uPA inhibition by PAI-1 and PAI-2. Kinetic inhibition assays on receptor-bound uPA on U937 cells; second-order rate constant measurements The Journal of biological chemistry High 2161846
1991 Binding of uPA to its cellular receptor on U937 cells dramatically increases the efficiency of plasminogen activation: Km drops 40-fold to 0.67 µM (below physiological plasminogen concentration of 2 µM), and plasmin generated at the cell surface is protected from α2-antiplasmin. Cell-surface binding of plasminogen is critical for this high-affinity activation. Kinetic analysis of plasminogen activation on U937 cells and with purified isolated uPAR; Km and kcat measurements; plasmin inhibitor protection assays The Journal of biological chemistry High 1829461
1991 Cathepsin B cleaves pro-uPA at the Lys158-Ile159 bond (same site as plasmin/kallikrein) to generate enzymatically active two-chain uPA. This activation occurs both for soluble and tumor cell receptor-bound pro-uPA; the receptor-binding growth factor domain remains intact after cathepsin B cleavage. In vitro cleavage assay with purified cathepsin B and pro-uPA, SDS-PAGE, Western blot, N-terminal sequencing, receptor binding assays on U937 cells, E-64 inhibitor control The Journal of biological chemistry High 1900515
1992 uPA (urokinase) is a pro-HGF/SF convertase: it cleaves the single-chain biologically inactive precursor of hepatocyte growth factor/scatter factor (pro-HGF/SF) at a single site, generating the active mature α–β heterodimer. This activation is blocked by PAI-1, protease nexin-1, and anti-uPA catalytic domain antibodies. In vitro cleavage of purified pro-HGF/SF by pure urokinase at nanomolar concentrations; functional assays (MDCK scatter, Met phosphorylation); inhibitor studies The EMBO journal High 1334458
1996 PAI-1, the endogenous inhibitor of uPA, blocks cell migration by occupying the αVβ3 integrin binding site on vitronectin, thereby preventing integrin-mediated adhesion. This anti-migratory effect requires high-affinity PAI-1 binding to vitronectin and is independent of PAI-1's ability to inhibit plasminogen activators. Formation of PAI-1/plasminogen activator complexes reduces PAI-1 affinity for vitronectin and restores migration. SMC migration assays on vitronectin, blocking antibodies against αVβ3, active vs. latent PAI-1 competition, PAI-1 mutants Nature High 8837777
1997 uPAR is internalized with uPA:serpin complexes via α2-macroglobulin receptor/LRP, then recycled back to the cell surface. Surface biotinylation experiments demonstrated that internalized biotinylated uPAR reappears at the plasma membrane in a PI-PLC-sensitive form, confirming true recycling rather than redistribution of intracellular pools. FACScan, immunofluorescence, immunoelectron microscopy, surface biotinylation recycling assay, PI-PLC sensitivity assay The EMBO journal High 9184208
1997 Two PEA3/AP-1 composite elements at −2.4 kb and −6.9 kb upstream of the transcription start site cooperate synergistically to confer full TPA- and FGF-2-inducibility of the uPA gene. AP-1 factors (c-Jun, JunD, ATF-2, c-Fos) and Ets transcription factors bind these elements, with c-Fos specifically binding the −6.9 kb element only after induction. DNase I hypersensitivity mapping, deletion analysis/transient transfection, EMSA with specific antibodies, dominant-negative Ets-2 expression Gene High 9409785
1999 uPA-stimulated cell migration requires uPAR ligation and proceeds via a signaling cascade: Ras → MEK → ERK → myosin light chain kinase (MLCK). MLCK is phosphorylated by a MEK-dependent pathway and leads to serine-phosphorylation of myosin II regulatory light chain. Migration is integrin-selective, occurring on vitronectin via β1-integrin (αVβ1) and αVβ5 but blocked by αVβ3. Dominant-negative and constitutively active Ras/MEK mutants, MLCK inhibitors, αVβ3 neutralizing antibody, migration assays on differentially coated surfaces The Journal of cell biology High 10402467
2000 Matriptase, an epithelial membrane serine protease, activates pro-uPA (urokinase) to its active form. Matriptase converts pro-HGF and pro-uPA but has no effect on plasminogen, positioning matriptase as an upstream membrane activator of uPA. In vitro cleavage assays with active matriptase isolated from human milk, synthetic substrate kinetics, functional HGF scatter assay, c-Met phosphorylation The Journal of biological chemistry High 10962009
2000 MNNG-induced uPA gene transcription is mediated by the JNK signaling pathway via an AP-1 enhancer element at −2.4 kb. Dominant-negative MEKK1, MKK7, JNKK, and JIP-1 and curcumin (JNK inhibitor) all inhibited MNNG-induced uPA transcription, while dominant-negative MKK6 and SB203580 (p38 inhibitor) did not. Dominant-negative kinase constructs, pharmacological inhibitors, uPA promoter-reporter transfection assays Blood High 10942386
2003 Downregulation of uPA by antisense transfection in human glioblastoma cells disrupts actin cytoskeleton formation, decreases cell migration, and reduces PI3K and Akt phosphorylation, causing G2/M-phase arrest and decreased clonogenic survival, positioning uPA upstream of the PI3K/Akt signaling pathway. Stable antisense uPA transfection, Western blot for phospho-PI3K/Akt, cell migration assays, cell cycle analysis, clonogenic survival assay Oncogene Medium 12545160
2006 The uPA kringle domain binds directly to integrin αVβ3 (and also α4β1 and α9β1) independent of uPAR, enhancing plasminogen activation on CHO cells depleted of uPAR and inducing cell migration in an αVβ3-dependent manner. Plasminogen kringles 1-3/1-4 (angiostatin) blocked this interaction. Binding assays on uPAR-depleted CHO cells, purified soluble αVβ3 binding, cell migration assays with blocking antibodies, plasminogen activation assays Thrombosis and haemostasis High 16525582
2006 Crystal structure of uPA complexed with its receptor (uPAR) and an antibody was determined at 1.9 Å resolution. The three domains of uPAR form a concave shape with a central cone-shaped cavity where the uPA amino-terminal fragment inserts, explaining the molecular basis of uPA-uPAR interaction. X-ray crystallography at 1.9 Å Science High 16456079
2006 uPA activates SREBP-1 processing and increases nuclear mature SREBP-1 content (5.7-fold) in THP-1 macrophages via PI3K-dependent activation of MEK/ERK, upregulating HMGCoA reductase expression and increasing macrophage cholesterol biosynthesis by 172%. Western blot for HMGCR protein/mRNA, SREBP-1 nuclear fractionation, PI3K inhibitor (LY294002), MEK inhibitor, cholesterol biosynthesis assays with statins Atherosclerosis Medium 17681345
2007 uPA binding to uPAR increases uPAR association with lipid rafts (detergent-resistant membrane fractions) in a manner independent of uPA catalytic activity. Disruption of lipid rafts by methyl-β-cyclodextrin inhibits uPA-induced ERK phosphorylation, showing that lipid raft association is required for uPA/uPAR intracellular signaling. Sucrose gradient fractionation of detergent-resistant membranes, uPAR immunoprecipitation from DRM fractions, ERK phosphorylation assays, methyl-β-cyclodextrin treatment, glycosphingolipid analysis Biochimica et biophysica acta Medium 17963689
2009 Quebec platelet disorder (QPD), a dominant bleeding disorder, is caused by a direct tandem duplication of a 78-kb genomic segment containing PLAU. This duplication specifically increases uPA mRNA during megakaryocyte differentiation without altering expression of flanking genes. Genomic copy number variation analysis, array CGH, fluorescence in situ hybridization on 38 QPD subjects and 425 controls Blood High 20007542
2010 Prior to induction, the uPA (PLAU) gene is predominantly associated with 'poised transcription factories' containing RNA Pol II phosphorylated on Ser5 but not Ser2. After activation, the uPA locus associates with 'active factories' (Ser5+/Ser2+) and loops out from its chromosome territory. Gene positioning relative to the chromosome territory is independent of factory association levels. RNA FISH, immunofluorescence with phospho-specific Pol II antibodies, 3D nuclear localization analysis PLoS biology Medium 20052287
2011 uPA induces pulmonary microvascular endothelial permeability through LRP-dependent activation of endothelial NOS (eNOS) via PKA signaling. uPA induces eNOS phosphorylation at Ser1177, NO generation, and β-catenin nitrosylation/dissociation from VE-cadherin. This pathway is independent of PI3K-Akt. In vitro PMVEC monolayer permeability assay, eNOS phosphorylation Western blot, LRP antibody/RAP antagonist, PKA inhibitor (myristoylated PKI), in vivo lung permeability measurement The Journal of biological chemistry High 21540184
2014 TMPRSS4, a type II transmembrane serine protease, directly converts inactive pro-uPA to the active two-chain form through its proteolytic activity. Active TMPRSS4 protease domain is released from cells and is membrane-associated; TMPRSS4 increases pro-uPA-mediated invasion in a serine protease activity-dependent manner, positioning TMPRSS4 as an upstream activator of pro-uPA. Pro-uPA cleavage assay with conditioned medium from TMPRSS4-overexpressing cells, active site mutant controls, Transwell invasion assays, Western blot Biochemical and biophysical research communications Medium 24434139
2014 Fra-1/AP-1 drives uPA (PLAU) overexpression in aggressive breast cancer cells via two AP-1 enhancers at −1.9 kb (ABR-1.9) and −4.1 kb (ABR-4.1) from the Plau-001 TSS. RNA Pol II is also recruited to the ABR regions, producing short unstable RNAs that track toward the TSS and convert to productive mRNA. A minor mRNA, Plau-004, is transcribed from ABR-1.9 and is repressed by Fra-1. ChIP, RNAi knockdown of Fra-1, pharmacological inhibition, RNA Pol II occupancy mapping Nucleic acids research Medium 25200076
2015 Small-molecule pyrrolone inhibitors of the uPAR·uPA protein-protein interaction (Ki ~0.7 µM for labeled peptide displacement, IC50 ~18 µM for uPAR·uPA-ATF) allosterically inhibit the distal uPAR·vitronectin interaction, demonstrating cooperative binding between uPA and vitronectin on uPAR. These compounds reduce FAK phosphorylation, Rac1 activation, and MDA-MB-231 breast cancer cell invasion. Fluorescence polarization, surface plasmon resonance competition, ELISA, molecular dynamics simulations, free energy calculations, cellular FAK phosphorylation, Rac1 activation assay, Matrigel invasion assay ACS chemical biology High 25671694
2016 uPA binding to uPAR promotes axonal regeneration in the CNS by a plasminogen-independent mechanism: uPA/uPAR binding induces membrane recruitment and activation of β1-integrin via LRP1, leading to Rac1 GTPase activation and Rac1-induced axonal regeneration in injured axons. In vitro axonal injury models, in vivo CNS injury models, recombinant uPA treatment, LRP1 inhibition, β1-integrin blocking, Rac1 activity assay The Journal of biological chemistry High 27986809
2017 QPD PLAU duplication dysregulates PLAU expression in a megakaryocyte-specific manner: QPD megakaryocytes overexpress normal PLAU transcripts >100-fold (from the disease chromosome) while QPD granulocytes show only ~3.9-fold increase, suggesting an active regulatory mechanism controlling uPA levels in blood that is specifically disrupted in megakaryocytes by the duplication. RNA-seq, quantitative RT-PCR, allele-specific transcript analysis, protein expression analysis in primary cells and cultured megakaryocytes PloS one Medium 28301587
2018 uPA induces local synthesis of ezrin in astrocytes and triggers formation of peripheral astrocytic processes (PAPs) that contact the synapse, protecting the tripartite synapse from ischemic injury. Recombinant uPA treatment in vivo induces PAP formation in the ischemic brain. In vitro astrocyte cultures, in vivo ischemic stroke models, uPAR knockout mice, recombinant uPA treatment, immunofluorescence for ezrin and synaptic markers Journal of cerebral blood flow and metabolism Medium 29890880
2018 uPA-uPAR binding induces local synthesis of ezrin in cortical neurons at the synapse and recruits β3-integrin to the postsynaptic density (PSD) via ICAM-5, followed by phosphorylation of ezrin at Thr-567 and reorganization of the actin cytoskeleton in the postsynaptic terminal, leading to recovery of dendritic spines and synapses damaged by ischemic stroke. In vitro cortical neuron cultures, in vivo ischemic stroke models, β3-integrin knockdown/blocking, ICAM-5 studies, phospho-ezrin Western blot, dendritic spine imaging The Journal of biological chemistry Medium 29720403
2018 YAP/TEAD transcription factor activity directly regulates Plau (uPA) expression in epidermal keratinocytes, promoting their proliferation. RNA-seq of YAP2-5SA-ΔC transgenic mouse skin identified Plau as a dysregulated gene containing YAP/TEAD binding motifs in its 3' UTR, confirmed by functional characterization assays. RNA-seq of transgenic mouse skin, YAP/TEAD motif analysis, functional proliferation assays Cell death & disease Medium 30382077
2019 Protein O-fucosyltransferase 1 (poFUT1) increases O-fucosylation on uPA and activates the RhoA signaling pathway, facilitating uterine angiogenesis and vascular remodeling. Knockdown of poFUT1 reduces uPA O-fucosylation and impairs angiogenesis. Glycoprotein O-fucosylation analysis, RhoA activity assay, hESC and mouse model experiments, siRNA knockdown Cell death & disease Medium 31601791
2021 PLAU (uPA) promotes conversion of fibroblasts to inflammatory cancer-associated fibroblasts via the uPAR/Akt/NF-κB pathway, inducing IL-8 secretion. IL-8 from CAFs in turn promotes high PLAU expression in tumor cells (ESCC), creating a positive feedback loop. PLAU also promotes tumor cell proliferation via the MAPK pathway and migration by upregulating Slug and MMP9. Loss-of-function and gain-of-function experiments, RNA sequencing, cytokine array, RT-qPCR, MEK inhibitor U0126, Akt/NF-κB pathway inhibition Cell death discovery Medium 33574243
2021 uPA mediates endothelial tubular network (ETN) formation in HUVEC-MSC co-culture via cross-talk of uPAR, uPA's catalytic activity, uPA's binding to uPAR, and uPA nuclear translocation, coordinated with αV-integrins, VEGFR2, and Notch receptor/ligand pathways. HUVEC-MSC co-culture angiogenesis assay, siRNA knockdown of pathway components, pharmacological inhibitors at multiple steps, mRNA expression analysis Biochimica et biophysica acta. Molecular cell research Medium 34619163
2022 AQR promotes endothelial cell senescence via PLAU: AQR overexpression upregulates PLAU, and knockdown of PLAU rescues senescence-related phenotypes (SA-β-gal staining, P21 upregulation, G2/M arrest) induced by AQR overexpression or TNF-α treatment, establishing an AQR/PLAU signaling axis in endothelial cell senescence. Transcriptomic analysis of AQR overexpression/knockdown in HUVECs, SA-β-gal staining, CDKN1A Western blot, colony formation, cell cycle analysis, PLAU siRNA rescue International journal of molecular sciences Medium 35270021
2022 METTL3 stabilizes PLAU mRNA in an m6A-dependent manner, promoting colorectal cancer metastasis via the MAPK/ERK pathway and angiogenesis. m6A-seq, METTL3 overexpression/knockdown, RNA stability assays, MAPK/ERK pathway analysis, in vivo tumor models Biochemical and biophysical research communications Medium 35567945
2023 PLAU (uPA) knockout by CRISPR-Cas9 completely stops matrix remodeling (measured by AFM-based stiffness changes) and significantly reduces cancer cell invasion in a 3D tumouroid model, confirming uPA's enzymatic role in ECM degradation as a driver of invasion. Pharmacological uPA inhibition (UK-371,801) showed similarly reduced matrix degradation and invasion. CRISPR-Cas9 knockout of PLAU, 3D tumouroid culture, atomic force microscopy (AFM) stiffness measurement, invasion quantification, pharmacological inhibitor UK-371,801 Matrix biology plus High 38020586
2024 PLAU interacts with TM4SF1 to activate Akt signaling, promoting NSCLC cell growth, cisplatin resistance, and survival. TM4SF1 knockdown or anti-TM4SF1 neutralizing antibody phenocopies PLAU inhibition, and PLAU overexpression stabilizes TM4SF1 at the cell surface. Co-immunoprecipitation, overexpression/knockdown experiments, Akt phosphorylation Western blot, nude mouse xenograft, anti-TM4SF1 antibody treatment Biology direct Medium 38229120

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1990 Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface, plasmin dependent proteolysis. The EMBO journal 630 1689240
1996 The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature 589 8837777
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
1992 Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor. The EMBO journal 530 1334458
2011 Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation. Nature cell biology 490 21423176
1976 Isolation and characterization of alpha2-plasmin inhibitor from human plasma. A novel proteinase inhibitor which inhibits activator-induced clot lysis. The Journal of biological chemistry 465 134998
1987 The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. The Journal of biological chemistry 460 3031025
1991 Plasminogen activation by receptor-bound urokinase. A kinetic study with both cell-associated and isolated receptor. The Journal of biological chemistry 453 1829461
1990 The receptor for urokinase type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes. The Journal of cell biology 453 2166055
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
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2014 The DNA methylation-regulated miR-193a-3p dictates the multi-chemoresistance of bladder cancer via repression of SRSF2/PLAU/HIC2 expression. Cell death & disease 93 25188512
2012 VEGF-initiated angiogenesis and the uPA/uPAR system. Cell adhesion & migration 89 23076133
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2007 Targeting uPA/uPAR in prostate cancer. Cancer treatment reviews 82 17658220
2013 The apparent uPA/PAI-1 paradox in cancer: more than meets the eye. Seminars in thrombosis and hemostasis 68 23532574
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2021 PLAU directs conversion of fibroblasts to inflammatory cancer-associated fibroblasts, promoting esophageal squamous cell carcinoma progression via uPAR/Akt/NF-κB/IL8 pathway. Cell death discovery 61 33574243
2017 Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium. Human reproduction (Oxford, England) 59 28130434
2003 Association of late-onset Alzheimer disease with a genotype of PLAU, the gene encoding urokinase-type plasminogen activator on chromosome 10q22.2. Neurogenetics 59 12898287
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2013 Human hepatocytes and hematolymphoid dual reconstitution in treosulfan-conditioned uPA-NOG mice. The American journal of pathology 56 24200850
2006 Direct interaction of the kringle domain of urokinase-type plasminogen activator (uPA) and integrin alpha v beta 3 induces signal transduction and enhances plasminogen activation. Thrombosis and haemostasis 53 16525582
2019 Fluid shear stress stimulates breast cancer cells to display invasive and chemoresistant phenotypes while upregulating PLAU in a 3D bioreactor. Biotechnology and bioengineering 52 31317530
1999 Ets-1 positively regulates expression of urokinase-type plasminogen activator (uPA) and invasiveness of astrocytic tumors. Journal of neuropathology and experimental neurology 52 10218628
2016 Urokinase-type Plasminogen Activator (uPA) Binding to the uPA Receptor (uPAR) Promotes Axonal Regeneration in the Central Nervous System. The Journal of biological chemistry 51 27986809
2001 Polyphyenolics increase t-PA and u-PA gene transcription in cultured human endothelial cells. Alcoholism, clinical and experimental research 50 11236827
2021 Targeting uPA-uPAR interaction to improve intestinal epithelial barrier integrity in inflammatory bowel disease. EBioMedicine 49 34933179
2013 Role of uPA/uPAR in the modulation of angiogenesis. Chemical immunology and allergy 48 24217605
2023 The uPA/uPAR System Orchestrates the Inflammatory Response, Vascular Homeostasis, and Immune System in Fibrosis Progression. International journal of molecular sciences 46 36675310
2020 FOXM1 functions collaboratively with PLAU to promote gastric cancer progression. Journal of Cancer 46 31949481
2003 Mice without uPA, tPA, or plasminogen genes are resistant to experimental choroidal neovascularization. Investigative ophthalmology & visual science 44 12657615
2022 Hyperglycemia Promotes Endothelial Cell Senescence through AQR/PLAU Signaling Axis. International journal of molecular sciences 43 35270021
2019 Urokinase-type plasminogen activator (uPA) is not essential for epithelial sodium channel (ENaC)-mediated sodium retention in experimental nephrotic syndrome. Acta physiologica (Oxford, England) 43 31006168
2022 Metastatic phenotype and immunosuppressive tumour microenvironment in pancreatic ductal adenocarcinoma: Key role of the urokinase plasminogen activator (PLAU). Frontiers in immunology 42 36591282
2014 Transcriptional complexity and roles of Fra-1/AP-1 at the uPA/Plau locus in aggressive breast cancer. Nucleic acids research 41 25200076
2020 Triptolide inhibits pancreatic cancer cell proliferation and migration via down-regulating PLAU based on network pharmacology of Tripterygium wilfordii Hook F. European journal of pharmacology 37 32464191
2008 Endo180 expression with cofunctional partners MT1-MMP and uPAR-uPA is correlated with prostate cancer progression. European journal of cancer (Oxford, England : 1990) 35 19112015
2002 Dynamics of metalloproteinase-2 and -9, TGF-beta, and uPA activities during normoxic vs. hyperoxic alveolarization. American journal of physiology. Lung cellular and molecular physiology 35 12225951
2016 cRGD inhibits vasculogenic mimicry formation by down-regulating uPA expression and reducing EMT in ovarian cancer. Oncotarget 34 26992227
2007 Urokinase plasminogen activator (uPA) stimulates cholesterol biosynthesis in macrophages through activation of SREBP-1 in a PI3-kinase and MEK-dependent manner. Atherosclerosis 34 17681345
2011 Structural basis for therapeutic intervention of uPA/uPAR system. Current drug targets 33 21707478
2018 Naringenin Attenuated Prostate Cancer Invasion via Reversal of Epithelial-to-Mesenchymal Transition and Inhibited uPA Activity. Anticancer research 32 30504386
2013 TGF-β2 promotes RPE cell invasion into a collagen gel by mediating urokinase-type plasminogen activator (uPA) expression. Experimental eye research 29 23810810
2007 ECRG2 inhibits cancer cell migration, invasion and metastasis through the down-regulation of uPA/plasmin activity. Carcinogenesis 29 17602171
2006 Pitavastatin attenuates the PDGF-induced LR11/uPA receptor-mediated migration of smooth muscle cells. Biochemical and biophysical research communications 29 16919601
2002 Expression of UPA and UPAR is associated with the clinical course of urinary bladder neoplasms. International journal of cancer 28 12115506
2021 Overexpression of PSMC2 promotes the tumorigenesis and development of human breast cancer via regulating plasminogen activator urokinase (PLAU). Cell death & disease 27 34244472
2018 Urokinase-type plasminogen activator (uPA) protects the tripartite synapse in the ischemic brain via ezrin-mediated formation of peripheral astrocytic processes. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 27 29890880
2018 Plau and Tgfbr3 are YAP-regulated genes that promote keratinocyte proliferation. Cell death & disease 27 30382077
2015 A new class of orthosteric uPAR·uPA small-molecule antagonists are allosteric inhibitors of the uPAR·vitronectin interaction. ACS chemical biology 27 25671694
2010 Osteopontin promotes hepatocellular carcinoma invasion by up-regulating MMP-2 and uPA expression. Molecular biology reports 27 21104439
2014 TMPRSS4 induces cancer cell invasion through pro-uPA processing. Biochemical and biophysical research communications 26 24434139
2011 Suppression of uPA and uPAR blocks radiation-induced MCP-1 mediated recruitment of endothelial cells in meningioma. Cellular signalling 26 21426933
2008 uPA and PAI-1 in rectal cancer--relationship to radiotherapy and clinical outcome. The Journal of surgical research 26 18533186
2006 Differential uPA expression by TGF-beta1 in gingival fibroblasts. Journal of dental research 26 16434733
2022 METTL3 promotes colorectal cancer metastasis by stabilizing PLAU mRNA in an m6A-dependent manner. Biochemical and biophysical research communications 25 35567945
2000 The cJun N-terminal kinase (JNK) signaling pathway mediates induction of urokinase-type plasminogen activator (uPA) by the alkylating agent MNNG. Blood 25 10942386
2015 Non-viral transfer of BDNF and uPA stimulates peripheral nerve regeneration. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 24 26349964
2014 uPA-uPAR molecular complex is involved in cell signaling during neuronal migration and neuritogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 24 24481918
2020 Curcumol may reverse early and advanced liver fibrogenesis through downregulating the uPA/uPAR pathway. Phytotherapy research : PTR 22 31989700
2017 Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models. Journal of immunology (Baltimore, Md. : 1950) 22 29282305
2011 Urokinase-type plasminogen activator (uPA) induces pulmonary microvascular endothelial permeability through low density lipoprotein receptor-related protein (LRP)-dependent activation of endothelial nitric-oxide synthase. The Journal of biological chemistry 22 21540184
2016 Matrine Suppresses Proliferation and Invasion of SGC7901 Cells through Inactivation of PI3K/Akt/uPA Pathway. Annals of clinical and laboratory science 21 27650610
2007 uPA binding increases UPAR localization to lipid rafts and modifies the receptor microdomain composition. Biochimica et biophysica acta 21 17963689
2001 The uPA/uPA receptor system as a target for tumor therapy. Drug news & perspectives 21 12813583
2021 Mesenchymal stromal cells enhance self-assembly of a HUVEC tubular network through uPA-uPAR/VEGFR2/integrin/NOTCH crosstalk. Biochimica et biophysica acta. Molecular cell research 20 34619163
2013 Clinical significance of the uPA system in gastric cancer with peritoneal metastasis. European journal of medical research 20 23985164
2008 Thrombospondin-2 inhibits tumor cell invasion through the modulation of MMP-9 and uPA in pancreatic cancer cells. Molecular medicine reports 20 21479427
2018 Urokinase-type plasminogen activator (uPA) promotes ezrin-mediated reorganization of the synaptic cytoskeleton in the ischemic brain. The Journal of biological chemistry 19 29720403
2019 poFUT1 promotes uterine angiogenesis and vascular remodeling via enhancing the O-fucosylation on uPA. Cell death & disease 18 31601791
2019 A functional investigation of the suppression of CpG and UpA dinucleotide frequencies in plant RNA virus genomes. Scientific reports 18 31797900
2013 Urokinase-type plasminogen activator (uPA) modulates monocyte-to-macrophage differentiation and prevents Ox-LDL-induced macrophage apoptosis. Atherosclerosis 18 24125407
2011 Concomitant lack of MMP9 and uPA disturbs physiological tissue remodeling. Developmental biology 18 21802414
2005 Urokinase plasminogen activator, uPa receptor, and its inhibitor in vernal keratoconjunctivitis. Investigative ophthalmology & visual science 18 15790903
2023 circPSD3 is a promising inhibitor of uPA system to inhibit vascular invasion and metastasis in hepatocellular carcinoma. Molecular cancer 17 37884951
2017 The duplication mutation of Quebec platelet disorder dysregulates PLAU, but not C10orf55, selectively increasing production of normal PLAU transcripts by megakaryocytes but not granulocytes. PloS one 17 28301587
2007 Immunohistochemical detection of uPA, uPAR, PAI-1, and maspin in ameloblastic tumors. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 17 17686008
2003 The role of urokinase-type plasminogen activator (uPA)/uPA receptor in HIV-1 infection. Journal of leukocyte biology 17 12960238
2001 Regulation of the uPA gene in various grades of human glioma cells. International journal of oncology 17 11115541
2017 Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) promote neurorepair in the ischemic brain. Receptors & clinical investigation 16 28804736
2002 IL-2-mediated upregulation of uPA and uPAR in natural killer cells. Biochemical and biophysical research communications 16 11890690
2023 Extracellular vesicles from human urine-derived stem cells delay aging through the transfer of PLAU and TIMP1. Acta pharmaceutica Sinica. B 15 38487008
2021 Salivary KLK5 and uPA are potential biomarkers for malignant transformation of OLK and OLP. Cancer biomarkers : section A of Disease markers 15 33896830
2018 AP1 mediates uPA/uPAR induced FUT4 expression and trophoblast invasion. Journal of cellular biochemistry 15 29278651
2005 Deflazacort modulates the fibrinolytic pattern and reduces uPA-dependent chemioinvasion and proliferation in rheumatoid arthritis synoviocytes. Rheumatology (Oxford, England) 15 15998634
2018 Lysophosphatidic acid increases in vitro maturation efficiency via uPA-uPAR signaling pathway in cumulus cells. Theriogenology 14 29554602
2013 Snail mediates invasion through uPA/uPAR and the MAPK signaling pathway in prostate cancer cells. Oncology letters 14 26889270
2004 Overexpression of urinary plasminogen activator (uPA) protein and mRNA in thyroid carcinogenesis. Diagnostic molecular pathology : the American journal of surgical pathology, part B 14 15538115
2024 PLAU promotes growth and attenuates cisplatin chemosensitivity in ARID1A-depleted non-small cell lung cancer through interaction with TM4SF1. Biology direct 13 38229120
2023 Urokinase-type plasminogen activator (uPA) regulates invasion and matrix remodelling in colorectal cancer. Matrix biology plus 13 38020586
2022 The uPA System Differentially Alters Fibroblast Fate and Profibrotic Ability in Skin Fibrosis. Frontiers in immunology 13 35371006
2022 Cinnamaldehyde decreases the invasion and u-PA expression of osteosarcoma by down-regulating the FAK signalling pathway. Food & function 13 35678522
2014 BRMS1 inhibits expression of NF-kappaB subunit p65, uPA and OPN in ovarian cancer cells. European journal of gynaecological oncology 13 24984534
2010 Radiation-inducible silencing of uPA and uPAR in vitro and in vivo in meningioma. International journal of oncology 13 20198323
2005 No association of a non-synonymous PLAU polymorphism with Alzheimer's disease and disease-related traits. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 13 15558716
2002 Effects of hormones on uPA, PAI-1 and suPAR from cultured endometrial and ovarian endometriotic stromal cells. Acta obstetricia et gynecologica Scandinavica 13 12027810
2001 uPA and uPAR contribute to NK cell invasion through the extracellular matrix. Anticancer research 13 11497249