Affinage

SERPINE1

Plasminogen activator inhibitor 1 · UniProt P05121

Length
402 aa
Mass
45.1 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SERPINE1 (PAI-1) is the principal physiological inhibitor of the plasminogen activators tPA and uPA, forming stable covalent complexes that terminate cell-surface plasminogen activation, and it serves as a multifunctional regulator of cell adhesion, migration, survival, senescence, and tissue fibrosis (PMID:2157592, PMID:12808446). As an inhibitor it engages uPA bound to uPAR, and the resulting complex is internalized through an LRP-dependent endocytic cycle that recycles the receptor and switches cells from adhesion to migration; the LRP-binding capacity of PAI-1 is mechanistically essential, since an LRP-binding mutant fails to rescue macrophage migration (PMID:2157592, PMID:11566185, PMID:16601674). PAI-1 is conformationally stabilized in its active state by binding the somatomedin B domain of vitronectin, a structurally defined interaction that lets PAI-1 sterically compete with uPAR and integrins for vitronectin and thereby modulate adhesion (PMID:10190280, PMID:12437099, PMID:12808446). Beyond proteolysis control, PAI-1 signals through LRP1/VLDLr to activate β-catenin and ERK1/2 and drives cell motility, survival, and proliferation (PMID:17696882, PMID:25694133, PMID:37415190); it functions as a calreticulin-associated "don't eat me" signal that limits efferocytosis and inhibits neutrophil apoptosis via a Gi/PI3K/Akt axis independent of uPAR, LRP, or vitronectin (PMID:18689689, PMID:21622848). PAI-1 promotes cellular senescence by binding proteasome components to inhibit proteasome activity and stabilize p53, and its sequestration into stress granules suppresses senescence (PMID:29592859, PMID:37566086). In tissue injury PAI-1 drives fibrosis by recruiting macrophages and myofibroblasts and by activating klotho-loss/p53/TGF-βRI-SMAD3 tubular dysfunction, and it exacerbates inflammation by blocking tPA-mediated activation of TGF-β (PMID:11473641, PMID:30842312, PMID:34110636). Its transcription is induced under hypoxia by HIF-1α, HIF-2α, Egr-1, and C/EBP α (PMID:17197388, PMID:25489981).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1990 High

    Established that PAI-1 binding does more than block protease activity — it triggers receptor-mediated clearance, defining the endocytic cycle that terminates surface plasminogen activation.

    Evidence Radiolabeled ligand internalization with chloroquine block and acid-wash fractionation in U937 cells

    PMID:2157592

    Open questions at the time
    • The internalization receptor (later LRP) was not yet identified
    • Did not address downstream signaling consequences of internalization
  2. 1990 Medium

    Linked PAI-1 induction to TGF-β signaling, showing PAI-1 is a transcriptionally inducible node coupling growth-factor cues to net plasminogen activator activity.

    Evidence Northern blot, ELISA, and caseinolytic activity assay in TGF-β1-treated primary bronchial epithelial cells

    PMID:2221087

    Open questions at the time
    • Promoter elements mediating induction not mapped here
    • Restricted to one cell type and differentiation context
  3. 1991 Medium

    Mapped PAI-1 distribution to hemostatic and inflammatory tissues/cells, framing where its functions are physiologically deployed.

    Evidence Tissue activity assay and immunohistochemistry across human tissue panels

    PMID:1864986

    Open questions at the time
    • No functional consequence tied to localization
    • Descriptive survey only
  4. 2003 High

    Resolved the structural basis for PAI-1 stabilization and adhesion control by capturing the PAI-1–somatomedin B complex, explaining steric competition with uPAR and integrins.

    Evidence X-ray crystallography of the PAI-1–SMB complex at 2.3 Å, with binding-interface analysis; corroborated by earlier domain-mapping and competition assays

    PMID:10190280 PMID:12437099 PMID:12808446

    Open questions at the time
    • Structure does not capture the protease-inhibitor (tPA/uPA) covalent complex conformation
    • Secondary low-affinity vitronectin site not fully resolved
  5. 2006 High

    Placed PAI-1 precisely in a fibrin–tPA–PAI-1–LRP cascade governing the adhesion-to-detachment switch in migrating macrophages, demonstrating that the LRP-binding function is mechanistically required.

    Evidence Genetic KO of Mac-1, tPA, PAI-1, and LRP with rescue by wild-type vs. LRP-binding-deficient PAI-1 mutant in migration assays

    PMID:11566185 PMID:16601674

    Open questions at the time
    • Generalizability of the ternary complex to non-macrophage cells not established here
    • Did not define the cytoskeletal effectors downstream of LRP endocytosis
  6. 2006 High

    Defined the transcriptional logic of hypoxic PAI-1 induction, identifying three promoter-binding factors that cooperatively confer oxygen sensitivity.

    Evidence Promoter mutagenesis, EMSA supershift, and ChIP for Egr-1, HIF-1α, and C/EBPα in primary macrophages

    PMID:17197388

    Open questions at the time
    • Relative weighting of factors may be cell-type dependent
    • Did not address HIF-2α contribution (later shown in HCC)
  7. 2008 High

    Revealed a non-proteolytic immune role: surface PAI-1 acting with calreticulin as a 'don't eat me' signal that gates LRP-dependent efferocytosis.

    Evidence PAI-1(-/-) mice, antibody blockade, recombinant add-back, and colocalization microscopy on neutrophils

    PMID:18689689

    Open questions at the time
    • Molecular nature of the PAI-1/calreticulin association not structurally defined
    • Whether this operates in tissues beyond neutrophils unclear
  8. 2011 High

    Distinguished a receptor-independent anti-apoptotic pathway, showing PAI-1 prolongs neutrophil survival via Gi-coupled receptor/PI3K/Akt signaling separate from its uPAR/LRP/vitronectin functions.

    Evidence PAI-1(-/-) mice, pertussis toxin, PI3K inhibitors, receptor blockade, and in vivo LPS lung injury

    PMID:21622848

    Open questions at the time
    • The specific GPCR mediating the effect not identified
    • How the inhibitory and signaling activities of PAI-1 are partitioned in vivo unresolved
  9. 2014 Medium

    Provided a structural rationale for PAI-1's pro-survival/pro-proliferative signaling by mapping a cryptic VLDLr-binding site exposed upon uPA inhibition, absent in PAI-2.

    Evidence Biochemical/structural comparison of PAI-1 vs. PAI-2 binding to VLDLr with tyrosine phosphorylation and proliferation assays

    PMID:17696882

    Open questions at the time
    • Single-lab structural inference
    • In vivo relevance of VLDLr signaling not tested
  10. 2015 Medium

    Dissected the LRP1 signaling output of PAI-1, separating β-catenin transcriptional activation from ERK1/2 modulation in migration control.

    Evidence Isogenic LRP1-KO MEFs, β-catenin reporter, siRNA epistasis, and motility assays

    PMID:25694133

    Open questions at the time
    • LRP1-independent ERK1/2 receptor not identified
    • Single cell-system epistasis
  11. 2018 Medium

    Connected PAI-1 subcellular sequestration to cell-cycle control, showing stress-granule recruitment of PAI-1 sustains a proliferative, non-senescent state.

    Evidence Stress granule induction, PAI-1 colocalization, cyclin D1 fractionation and Rb phosphorylation in pre-senescent cells

    PMID:29592859

    Open questions at the time
    • Direct demonstration that PAI-1 within SGs is functionally inert is incomplete
    • Mechanism of PAI-1 recruitment to SGs unknown
  12. 2021 High

    Defined converging intracellular pathways by which PAI-1 drives renal tubular dysfunction, linking it to klotho loss, p53 stabilization, and TGF-βRI-SMAD3 signaling independent of TGF-β1 ligand synthesis.

    Evidence Stable PAI-1 overexpression in HK-2 cells with klotho rescue, p53 siRNA, and TGF-βRI inhibition plus differentiation/apoptosis readouts

    PMID:11473641 PMID:34110636 PMID:34725920

    Open questions at the time
    • How extracellular/cell-surface PAI-1 engages these intracellular pathways mechanistically not bridged
    • Receptor mediating TGF-βRI activation not identified
  13. 2023 Medium

    Identified a direct intracellular mechanism for PAI-1-driven senescence: binding proteasome components to inhibit proteasome activity and stabilize p53, requiring the premature secretion-competent form.

    Evidence Co-IP with proteasome components, proteasome activity assay, and wild-type vs. secretion-deficient PAI-1 comparison in lung epithelial cells

    PMID:37566086

    Open questions at the time
    • Single-lab Co-IP without reciprocal/structural validation of the proteasome interface
    • Reconciliation with the stress-granule senescence-suppressing role not addressed
  14. 2024 High

    Established a cytoskeletal/mechanical function, showing PAI-1 maintains vascular smooth muscle stiffness by restraining AMPK-dependent cofilin activation and F-actin turnover.

    Evidence PAI-039 inhibition, siRNA knockdown, atomic force microscopy, cofilin/AMPK assays and in vivo aortic pulse wave velocity, with PAI-1-deficient SMCs as control

    PMID:38868940

    Open questions at the time
    • The receptor/sensor coupling extracellular PAI-1 to intracellular AMPK not identified
    • Relationship to the RhoA/ROCK1 amoeboid program in cancer cells unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PAI-1's distinct molecular activities — protease inhibition, vitronectin-stabilized adhesion control, LRP/VLDLr signaling, intracellular proteasome and cytoskeletal regulation — are coordinated and partitioned within a single cell remains unresolved.
  • No unifying model linking secreted vs. intracellular PAI-1 pools
  • Receptors for several signaling and senescence functions remain unidentified
  • Conflicting senescence roles (proteasome inhibition vs. stress-granule sequestration) not reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 5 GO:0140096 catalytic activity, acting on a protein 3 GO:0140313 molecular sequestering activity 2
Localization
GO:0005576 extracellular region 4 GO:0005886 plasma membrane 4 GO:0031012 extracellular matrix 4 GO:0005829 cytosol 2
Pathway
R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-109582 Hemostasis 2 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
CALRLRP1PLATPLAUSERPINE1VLDLRVTN

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 The uPA-PAI-1 complex bound to the uPA receptor (uPAR) on cell surfaces is internalized and subsequently degraded in lysosomes; free uPA, ATF, or DFP-uPA are not internalized, demonstrating that PAI-1 binding to uPA triggers a specific receptor-mediated endocytic cycle. Radiolabeled ligand internalization assay with chloroquine inhibition and acid-wash fractionation in U937 cells The EMBO journal High 2157592
1990 TGF-β1 increases PAI-1 mRNA (~50-fold) and protein in human bronchial epithelial cells, resulting in a net ~50% reduction in plasminogen activator activity in conditioned medium; the effect requires a TGF-β-responsive differentiation pathway and is absent in cells that do not undergo squamous differentiation. Northern blot, ELISA, caseinolytic plasminogen activator activity assay in NHBE cells treated with TGF-β1 The American journal of physiology Medium 2221087
1991 PAI-1 protein and activity are distributed throughout the body, with highest abundance in liver and spleen; immunochemical staining localizes PAI-1 to endothelium, platelets, megakaryocytes, neutrophils, macrophages, vascular smooth muscle cells, and mesangial cells, placing it at sites of hemostasis and inflammation. Tissue extraction with functional PAI-1 activity assay and immunohistochemistry with monoclonal antibodies on human tissue panels Journal of clinical pathology Medium 1864986
1999 PAI-1 regulates uPAR-mediated cell adhesion to vitronectin by competing with uPAR for binding to the somatomedin B (SMB) domain of vitronectin; PAI-1 binding to the SMB domain also sterically hinders integrin binding to the adjacent RGD sequence, thereby modulating both uPAR- and integrin-mediated cell adhesion. Competitive binding assays and cell adhesion assays with defined recombinant proteins and domain-specific inhibitors APMIS Medium 10190280
2000 PAI-1 expression in wounded keratinocyte monolayers is required for normal wound repair: PAI-1 knockdown via antisense markedly impairs wound closure, while addition of recombinant PAI-1 rescues the defect; PAI-1 also rescues keratinocytes from plasminogen-induced substrate detachment/anoikis and enhances cell spread area. Antisense-mediated knockdown, recombinant PAI-1 rescue, PAI-1-neutralizing antibodies, wound-scratch assay, and cell spreading/anoikis assays in HaCaT keratinocytes Experimental cell research Medium 10896775
2001 PAI-1 deficiency attenuates renal fibrosis after ureteral obstruction; one key mechanism is that PAI-1 promotes the recruitment of fibrosis-inducing cells (macrophages and myofibroblasts), independently of changes in net renal plasminogen activator or plasmin activity. PAI-1 knockout vs. wild-type mouse comparison after UUO; interstitial fibrosis quantified by picrosirius red and collagen assay; cellular infiltrate by immunostaining; TGF-β and procollagen mRNAs by RT-PCR Kidney international High 11473641
2001 PAI-1 inhibits uPA-induced chemotaxis by triggering internalization of the uPAR via LRP; blocking LRP with the 39 kDa RAP or anti-LRP antibodies prevents uPAR internalization and converts the uPA-PAI-1 complex from a migration inhibitor into a chemoattractant that activates cytoskeletal reorganization and ERK/MAPK. Chemotaxis assays, anti-LRP antibody/RAP inhibition, cytoskeletal staining, ERK phosphorylation blotting FEBS letters Medium 11566185
2002 Mapping studies define the PAI-1 binding region on vitronectin to the N-terminal somatomedin B (SMB) domain, and the vitronectin-binding region on PAI-1 to the area around α-helices E and F; a secondary low-affinity PAI-1 binding site in the C-terminal region of vitronectin may support larger PAI-1/VN complexes. Peptide/domain competition binding assays, mutagenesis-based mapping, biochemical interaction studies reviewed from multiple labs Biological chemistry Medium 12437099
2003 Crystal structure (2.3 Å) of the PAI-1–somatomedin B (SMB) domain complex shows that vitronectin binding stabilizes the active conformation of PAI-1; structural analysis further reveals that PAI-1 sterically competes with uPAR and integrins for binding to vitronectin, explaining PAI-1's regulation of cell adhesion and tissue effects. X-ray crystallography of PAI-1–SMB complex at 2.3 Å resolution with structural interpretation of binding interfaces Nature structural biology High 12808446
2003 tPA contains two independent vasoactive epitopes with opposite effects on vascular tone; PAI-1 and a PAI-1-derived hexapeptide regulate these effects by binding tPA, and the stimulatory (vasoconstrictive) effect of tPA is mediated through LRP, as demonstrated by anti-LRP antibody blockade in isolated aorta rings and in vivo. Isolated aorta ring contraction assay, anti-LRP antibodies, tPA knockout mice, in vivo blood pressure and cerebrovascular resistance measurements in rats Blood Medium 14512309
2006 Efficient macrophage migration in an inflammatory environment requires the ordered formation of a fibrin–tPA–PAI-1 ternary complex at the cell surface: tPA promotes Mac-1-mediated adhesion to fibrin, PAI-1 inhibition of tPA exposes a site for LRP binding, and LRP-mediated endocytosis triggers the switch from adhesion to detachment. Genetic inactivation of PAI-1 abrogates macrophage migration, and this defect is rescued by wild-type PAI-1 but not by an LRP-binding mutant of PAI-1. Genetic KO of Mac-1, tPA, PAI-1, LRP in mice; in vitro migration assays; rescue with wild-type vs. LRP-binding-deficient PAI-1 mutant The EMBO journal High 16601674
2006 Hypoxia-induced PAI-1 transcription in macrophages is driven by three transcription factors—Egr-1, HIF-1α, and C/EBPα—all of which bind the PAI-1 promoter under hypoxia; mutation of each binding site reduces hypoxia-sensitivity, and ChIP confirms all three factors bind chromatin under hypoxic conditions. HIF-1α dominates but Egr-1 and C/EBPα greatly augment and can act independently. PAI-1 promoter deletion/mutation constructs, transfection, ChIP, gel-shift (EMSA) with supershift analysis, primary macrophage validation FASEB journal High 17197388
2007 PAI-1 inhibition of uPA by PAI-1 exposes a cryptic high-affinity binding site on the PAI-1 moiety for the VLDLr (very-low-density-lipoprotein receptor), sustaining cell signaling and promoting proliferation of breast cancer cells; PAI-2, despite also inhibiting uPA, does not contain this VLDLr binding site and does not sustain global tyrosine phosphorylation or cell proliferation, providing a structural basis for the divergent outcomes of PAI-1 vs. PAI-2 in cancer. Biochemical and structural analyses of PAI-1 vs. PAI-2 binding to VLDLr; global protein tyrosine phosphorylation assays; cell proliferation assays with uPA-PAI-1 vs. uPA-PAI-2 complexes The Biochemical journal Medium 17696882
2008 PAI-1 acts as a 'don't eat me' signal on viable neutrophils: surface PAI-1 colocalizes with calreticulin (CRT) on viable neutrophils and limits LRP-dependent phagocytosis; during apoptosis PAI-1 levels decrease on the cell surface, CRT colocalization is lost, and the increase in available CRT drives enhanced efferocytosis via LRP. PAI-1(-/-) mice, anti-PAI-1 antibody blockade, recombinant PAI-1 add-back, LRP/calreticulin functional studies, colocalization by fluorescence microscopy PNAS High 18689689
2008 SERPINE1 (PAI-1) protein is deposited into keratinocyte migration trails during wound repair; addition of recombinant PAI-1 stimulates directional motility in PAI-1(-/-) cells, and antibody-mediated PAI-1 blockade attenuates migration and causes apoptosis; the rescue from plasminogen-induced anoikis by PAI-1 identifies it as a keratinocyte survival factor. PAI-1-GFP live imaging, recombinant PAI-1 addition to PAI-1(-/-) cells, antisense knockdown, neutralizing antibodies, anoikis assay Archives of dermatological research High 18386027
2010 PAI-1 mediates the TGF-β1+EGF-induced 'scatter' (EMT) response in transformed keratinocytes: PAI-1 is the most highly induced transcript; MEK/ERK and p38 inhibition abolishes both maximal PAI-1 upregulation and cell locomotion; PAI-1 knockdown alone blocks TGF-β1+EGF-dependent scattering; and EGFR knockdown attenuates TGF-β1-induced PAI-1 expression, placing EGFR transactivation upstream of PAI-1 induction. mRNA profiling, MEK/p38 pharmacologic inhibition, PAI-1 siRNA knockdown, EGFR knockdown, wound scatter assay The Journal of investigative dermatology Medium 20428185
2011 PAI-1 inhibits neutrophil apoptosis through pertussis-toxin-sensitive G-protein-coupled receptors and PI3K, activating PKB/Akt, Mcl-1, and Bcl-xL; uPAR, LRP, and vitronectin are not required for this antiapoptotic function; in vivo, PAI-1(-/-) mice show enhanced neutrophil apoptosis in LPS-induced lung injury. PAI-1(-/-) mice, pertussis toxin, selective PI3K inhibitors, uPAR/LRP/vitronectin blockade, apoptosis assays, in vivo LPS-lung injury model American journal of physiology. Lung cellular and molecular physiology High 21622848
2012 Matrix-bound PAI-1 maintains cell blebbing (amoeboid migration) in colorectal cancer cells via the RhoA/ROCK1/MLC-P pathway; PAI-1 localizes PDK1 and ROCK1 to the cell membrane and sustains RhoA/ROCK1 activation, as determined by immunoblotting, activity assay, and immunofluorescence. Immunoblotting, ROCK1 activity assay, immunofluorescence, PAI-1 depletion in SW620 cells, RhoA pathway inhibition PloS one Medium 22363817
2014 16K prolactin (16K PRL) binds PAI-1 directly; loss of PAI-1 abrogates the antitumoral and antiangiogenic effects of 16K PRL; mechanistically, PAI-1 bound to the PAI-1–uPA–uPAR ternary complex exerts antiangiogenic effects, while 16K PRL inhibition of PAI-1's antifibrinolytic activity promotes arterial thrombolysis. Direct binding assay of 16K PRL and PAI-1, PAI-1 KO mouse models, in vivo tumor and angiogenesis assays, fibrin clot lysis assay Nature medicine High 24929950
2014 RNA aptamers that bind PAI-1 with nanomolar affinity inhibit its antiproteolytic activity against tPA, disrupt formation of the stable covalent PAI-1-tPA complex, and increase levels of cleaved (inactive) PAI-1; this identifies the tPA-docking region of PAI-1 as functionally targetable. SELEX aptamer generation, in vitro PAI-1 inhibition assay, complex formation assay, cleaved PAI-1 quantification Nucleic acid therapeutics Medium 24922319
2014 HIF-2α (not HIF-1α) drives PAI-1 expression in hepatocellular carcinoma cells; PAI-1 knockdown attenuates angiogenesis in coculture models; rescuing the HIF-2α knockdown by blocking plasmin (with aprotinin) restores angiogenesis, establishing the HIF-2α→PAI-1→reduced-plasmin→pro-angiogenic axis. Stable shRNA knockdown of HIF-1α/HIF-2α in HepG2, microarray identification of PAI-1 as target, PAI-1 knockdown, plasmin inhibition rescue, HepG2 spheroid-embryoid body coculture angiogenesis model Experimental cell research Medium 25489981
2015 PAI-1 promotes cell migration in an LRP1-dependent manner by activating β-catenin transcriptional activity and modulating ERK1/2; in LRP1-deficient MEFs, PAI-1-induced β-catenin responses are absent while ERK1/2 activation is enhanced, and knockdown of β-catenin abolishes the LRP1-independent ERK1/2 response. Wild-type vs. LRP1-KO MEFs, PAI-1 treatment, β-catenin reporter assay, ERK1/2 and β-catenin Western blotting, siRNA knockdown, proliferation and motility assays Thrombosis and haemostasis Medium 25694133
2018 Thrombin mediates PAI-1 mRNA expression and keratinocyte migration via PAR-1 transactivation of EGFR, downstream ERK1/2 activation, and phosphorylation of Smad2 linker region at Ser250 specifically; ERK1/2 inhibition (not p38 or JNK) blocks Smad2 linker phosphorylation, PAI-1 induction, and migration. Pharmacologic inhibitors (UO126, SB202190, SP600125), Western blot for Smad2 phospho-sites, qRT-PCR for PAI-1 mRNA, scratch wound migration assay in HaCaT cells Cellular signalling Medium 29577978
2018 PAI-1 is recruited to stress granules (SGs) in pre-senescent cells; SG assembly increases nuclear cyclin D1 translocation and Rb phosphorylation, maintaining a proliferative non-senescent state; PAI-1 sequestration in SGs is the mechanism linking SG formation to inhibition of senescence. Stress granule induction, PAI-1 colocalization with SG markers, cyclin D1 nuclear fractionation, Rb phosphorylation Western blot, senescence markers (SA-β-Gal) in proliferative and presenescent cells EMBO reports Medium 29592859
2019 In colitis, PAI-1 exacerbates mucosal damage by blocking tPA-mediated cleavage and activation of anti-inflammatory TGF-β; inhibition of PAI-1 reduces both mucosal damage and inflammation in mouse models, placing PAI-1 upstream of tPA-dependent TGF-β activation in intestinal inflammation. Mouse colitis models, PAI-1 inhibitor treatment, tPA measurement, TGF-β activation assay, intestinal injury quantification Science translational medicine High 30842312
2019 Tumor-secreted PAI-1 activates adipocytes via PI3K/AKT signaling, promoting nuclear translocation of FOXP1 which enhances PLOD2 promoter activity in cancer-associated adipocytes, driving collagen reorganization and breast cancer metastasis; pharmacologic blockade of PAI-1 or PLOD2 disrupts this collagen reorganization. 3D collagen invasion assay, co-culture, proteomics, ELISA, qPCR, Western blot, ChIP, loss-of-function assays, in vivo mouse co-implantation model Cell communication and signaling Medium 31170987
2021 Glomerular endothelial cell-derived PAI-1 drives podocyte apoptosis and age-related glomerular lesions; selective endothelial inactivation of PAI-1 protects glomeruli from lesion development and podocyte loss in aged mice; blocking PAI-1 in supernatants from senescent endothelial cells in vitro prevents podocyte apoptosis. Endothelial-specific PAI-1 conditional KO mice, aged mouse glomerular phenotype, conditioned medium from senescent endothelial cells + PAI-1 blockade, podocyte apoptosis assay EMBO molecular medicine High 34725920
2021 PAI-1 promotes renal tubular dysfunction via three converging pathways: (1) PAI-1 overexpression reduces klotho expression, (2) elevates p53, and (3) activates TGF-βRI/II-SMAD3 signaling, leading to dedifferentiation, G2/M arrest, fibrogenesis, and apoptosis; ectopic klotho restoration attenuates fibrogenesis and proliferative defects; genetic p53 suppression reverses PAI-1-driven maladaptive repair; TGF-βRI inhibition attenuates PAI-1-initiated epithelial dysfunction independently of TGF-β1 ligand synthesis. Stable PAI-1 overexpression in HK-2 cells, klotho rescue, p53 siRNA knockdown, TGF-βRI inhibitor, Western blot for E-cadherin/vimentin/fibronectin/collagen/CCN2/p-Histone3/p21/cleaved caspase-3, annexin-V flow cytometry FASEB journal High 34110636
2021 PAI-1 directly regulates transcription of genes involved in lipid homeostasis including PCSK9 and FGF21; pharmacologic or genetic reduction in PAI-1 activity ameliorates hyperlipidemia in vivo; genetic PAI-1 deficiency in humans is associated with reduced plasma PCSK9 levels. RNA sequencing in PAI-1-deficient vs. wild-type mice, pharmacologic PAI-1 inhibition in vivo, human genetic cohort PCSK9 measurement Scientific reports Medium 33432099
2021 SARS-CoV-2 spike protein (S1) stimulates PAI-1 production in human pulmonary microvascular endothelial cells; proteasomal degradation inhibition by bortezomib also induces PAI-1 but upregulates the repressor KLF2; ZMPSTE24 overexpression blunts spike-induced PAI-1 production, identifying ZMPSTE24-dependent proteasomal regulation as a control mechanism for endothelial PAI-1. Recombinant SARS-CoV-2-S1 treatment of HPMECs, bortezomib treatment, ZMPSTE24 overexpression, Western blot for PAI-1 and KLF2 American journal of respiratory cell and molecular biology Medium 34003736
2023 PAI-1 can bind to proteasome components and inhibit proteasome activity and p53 degradation in lung epithelial cells, promoting cellular senescence; this requires the premature (secretion-competent) form of PAI-1, as a secretion-deficient PAI-1 variant induces senescence markers without inducing p53, showing the premature form mediates proteasome interaction. Co-immunoprecipitation of PAI-1 with proteasome components, proteasome activity assay, overexpression of wild-type vs. secretion-deficient PAI-1, p53 and p21 Western blot, SA-β-Gal assay in A549 and primary mouse ATII cells Cells Medium 37566086
2023 CAF-derived PAI-1 promotes EndoMT in lymphatic endothelial cells by directly interacting with LRP1, activating AKT/ERK1/2 signaling; blockade of PAI-1 or LRP1/AKT/ERK1/2 inhibition abrogates EndoMT and reduces CAF-induced lymphangiogenesis and metastasis in cervical cancer models. Cytokine antibody arrays, recombinant PAI-1 treatment of LECs, LRP1 inhibition, AKT/ERK1/2 Western blotting, EndoMT marker profiling, transwell/tube formation/transendothelial migration assays, popliteal lymph node metastasis model in vivo Journal of experimental & clinical cancer research Medium 37415190
2024 PAI-1 regulates the cytoskeleton and intrinsic stiffness of vascular smooth muscle cells (SMCs): PAI-1 inhibition (PAI-039) or siRNA knockdown reduces cytoplasmic F-actin content and cell stiffness; PAI-1 inhibition activates cofilin (an F-actin depolymerase) via AMPK; AMPK inhibition prevents cofilin activation by PAI-039; PAI-039 reduces aortic stiffness in vivo without altering elastin or collagen. PAI-039 pharmacologic inhibition, siRNA knockdown, atomic force microscopy for cell stiffness, F-actin content assay, cofilin activity assay, AMPK Western blot, RNA sequencing, aortic pulse wave velocity in vivo, PAI-1-deficient murine SMCs as specificity control Arteriosclerosis, thrombosis, and vascular biology High 38868940

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 PAI-1 in tissue fibrosis. Journal of cellular physiology 573 21465481
1990 Receptor-mediated internalization and degradation of urokinase is caused by its specific inhibitor PAI-1. The EMBO journal 388 2157592
1997 PAI-1, obesity, insulin resistance and risk of cardiovascular events. Thrombosis and haemostasis 310 9198234
2001 PAI-1 deficiency attenuates the fibrogenic response to ureteral obstruction. Kidney international 242 11473641
2005 Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease. Thrombosis and haemostasis 227 15841306
2003 How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration. Nature structural biology 214 12808446
1992 The status of PAI-1 as a risk factor for arterial and thrombotic disease: a review. Atherosclerosis 169 1418086
2006 Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration. The EMBO journal 155 16601674
2011 PAI-1: An Integrator of Cell Signaling and Migration. International journal of cell biology 153 21837240
1995 Co-expression of urokinase, urokinase receptor and PAI-1 is necessary for optimum invasiveness of cultured lung cancer cells. International journal of cancer 141 7829264
1991 Distribution of plasminogen activator inhibitor (PAI-1) in tissues. Journal of clinical pathology 141 1864986
1999 Regulation of cell adhesion by PAI-1. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 138 10190280
2011 MicroRNA-30c promotes human adipocyte differentiation and co-represses PAI-1 and ALK2. RNA biology 119 21878751
2000 Hypofibrinolysis and increased PAI-1 are linked to atherothrombosis via insulin resistance and obesity. Annals of medicine 115 11209987
2007 Plasminogen activator inhibitor (PAI)-1 in vascular inflammation and thrombosis. Frontiers in bioscience : a journal and virtual library 114 17485272
2001 Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture. Hypertension (Dallas, Tex. : 1979) 114 11358950
2006 Molecular regulation of the PAI-1 gene by hypoxia: contributions of Egr-1, HIF-1alpha, and C/EBPalpha. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 108 17197388
2008 PAI-1 inhibits neutrophil efferocytosis. Proceedings of the National Academy of Sciences of the United States of America 102 18689689
2003 In vitro and in vivo effects of tPA and PAI-1 on blood vessel tone. Blood 94 14512309
2021 PAI-1 in Diabetes: Pathophysiology and Role as a Therapeutic Target. International journal of molecular sciences 89 33804680
2010 Endothelial regulation of eNOS, PAI-1 and t-PA by testosterone and dihydrotestosterone in vitro and in vivo. Molecular human reproduction 86 20547636
2002 Microangiopathic injury and augmented PAI-1 in human diabetic nephropathy. Kidney international 82 12028454
2014 PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin. Nature medicine 81 24929950
2000 Immunohistochemical expression of uPA, uPAR, and PAI-1 in breast carcinoma. Fibroblastic expression has strong associations with tumor pathology. The American journal of pathology 79 11021826
2009 PAI-1 and kidney fibrosis. Frontiers in bioscience (Landmark edition) 78 19273183
2020 PAI-1, the Plasminogen System, and Skeletal Muscle. International journal of molecular sciences 72 32993026
2021 Role of PAI-1 in hepatic steatosis and dyslipidemia. Scientific reports 70 33432099
2006 Senescence, wound healing and cancer: the PAI-1 connection. Cell cycle (Georgetown, Tex.) 68 17172853
2008 SERPINE1 (PAI-1) is deposited into keratinocyte migration "trails" and required for optimal monolayer wound repair. Archives of dermatological research 65 18386027
2006 TNFalpha-mediated induction of PAI-1 restricts invasion of HTR-8/SVneo trophoblast cells. Placenta 65 16338458
2019 PAI-1 augments mucosal damage in colitis. Science translational medicine 64 30842312
2007 PAI-1 - a potential therapeutic target in cancer. Current drug targets 64 17896954
2021 Glomerular endothelial cell senescence drives age-related kidney disease through PAI-1. EMBO molecular medicine 61 34725920
2019 Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling. Cell communication and signaling : CCS 61 31170987
2001 PAI-1 inhibits urokinase-induced chemotaxis by internalizing the urokinase receptor. FEBS letters 61 11566185
1990 TGF-beta 1 modulation of urokinase and PAI-1 expression in human bronchial epithelial cells. The American journal of physiology 61 2221087
2018 Stress granules counteract senescence by sequestration of PAI-1. EMBO reports 58 29592859
2008 Rapamycin inhibits PAI-1 expression and reduces interstitial fibrosis and glomerulosclerosis in chronic allograft nephropathy. Transplantation 50 18192922
2023 Cancer-associated fibroblast-derived PAI-1 promotes lymphatic metastasis via the induction of EndoMT in lymphatic endothelial cells. Journal of experimental & clinical cancer research : CR 49 37415190
2008 Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells. American journal of physiology. Endocrinology and metabolism 46 18664599
2010 Linking cell structure to gene regulation: signaling events and expression controls on the model genes PAI-1 and CTGF. Cellular signalling 45 20363319
2002 The 4G5G polymorphism in the gene for PAI-1 and the circadian oscillation of plasma PAI-1. Blood 44 12406875
2010 PAI-1 mediates the TGF-beta1+EGF-induced "scatter" response in transformed human keratinocytes. The Journal of investigative dermatology 43 20428185
2001 Regulation of PAI-1 expression by genetic polymorphisms. Impact on atherogenesis. Thrombosis research 43 11567663
2000 Protein kinase C-beta mediates lipoprotein-induced generation of PAI-1 from vascular endothelial cells. American journal of physiology. Endocrinology and metabolism 43 10751199
2000 Overexpression of GFAT activates PAI-1 promoter in mesangial cells. American journal of physiology. Renal physiology 41 10997922
2019 PAI-1 contributes to homocysteine-induced cellular senescence. Cellular signalling 40 31472244
2012 SuPAR and PAI-1 in critically ill, mechanically ventilated patients. Intensive care medicine 39 23100007
2014 HIF-2alpha-dependent PAI-1 induction contributes to angiogenesis in hepatocellular carcinoma. Experimental cell research 37 25489981
2011 Aldosterone perturbs adiponectin and PAI-1 expression and secretion in 3T3-L1 adipocytes. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 37 21667402
2021 PAI-1 induction during kidney injury promotes fibrotic epithelial dysfunction via deregulation of klotho, p53, and TGF-β1-receptor signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36 34110636
2007 PAI-1 as a target in kidney disease. Current drug targets 36 17896952
1999 Expression of the proteolytic factors, tPA and uPA, PAI-1 and VEGF during malignant glioma progression. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 36 10571409
2006 Genetic polymorphisms at FCER1B and PAI-1 and asthma susceptibility. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 35 16839401
2018 PAI-1 but Not PAI-2 Gene Deficiency Attenuates Ischemic Brain Injury After Experimental Stroke. Translational stroke research 34 29978354
2017 Increased expression of uPA, uPAR, and PAI-1 in psoriatic skin and in basal cell carcinomas. Archives of dermatological research 33 28429105
2011 Inhibition of neutrophil apoptosis by PAI-1. American journal of physiology. Lung cellular and molecular physiology 33 21622848
2007 A structural basis for differential cell signalling by PAI-1 and PAI-2 in breast cancer cells. The Biochemical journal 33 17696882
2005 Chronic allograft nephropathy: expression and localization of PAI-1 and PPAR-gamma. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 33 16221712
2004 Rho kinase and PAI-1 in Bartter's/Gitelman's syndromes: relationship to angiotensin II signaling. Journal of hypertension 32 15361768
2002 Interaction of plasminogen activator inhibitor type-1 (PAI-1) with vitronectin (Vn): mapping the binding sites on PAI-1 and Vn. Biological chemistry 31 12437099
2001 Interactive effect of PAI-1 4G/5G genotype and salt intake on PAI-1 antigen. Arteriosclerosis, thrombosis, and vascular biology 31 11397722
2000 Targeted inhibition of wound-induced PAI-1 expression alters migration and differentiation in human epidermal keratinocytes. Experimental cell research 31 10896775
2013 Polymorphisms in MTHFR, MTHFD, and PAI-1 and recurrent miscarriage among North Indian women. Archives of gynecology and obstetrics 30 23685927
2002 Aldosterone and PAI-1: implications for renal injury. Journal of nephrology 30 12113592
1996 Characterization of IGFBP-3, PAI-1 and SPARC mRNA expression in senescent fibroblasts. Mechanisms of ageing and development 30 9080393
2018 LDR-Induced miR-30a and miR-30b Target the PAI-1 Pathway to Control Adverse Effects of NSCLC Radiotherapy. Molecular therapy : the journal of the American Society of Gene Therapy 29 30424954
2012 Matrix-bound PAI-1 supports cell blebbing via RhoA/ROCK1 signaling. PloS one 29 22363817
2010 "Hypoxia-induced down-regulation of microRNA-449a/b impairs control over targeted SERPINE1 (PAI-1) mRNA - a mechanism involved in SERPINE1 (PAI-1) overexpression". Journal of translational medicine 28 20356416
2021 ZMPSTE24 Regulates SARS-CoV-2 Spike Protein-enhanced Expression of Endothelial PAI-1. American journal of respiratory cell and molecular biology 27 34003736
2018 Thrombin promotes PAI-1 expression and migration in keratinocytes via ERK dependent Smad linker region phosphorylation. Cellular signalling 27 29577978
2015 PAI-1 modulates cell migration in a LRP1-dependent manner via β-catenin and ERK1/2. Thrombosis and haemostasis 27 25694133
1999 Natriuretic peptides regulate the expression of tissue factor and PAI-1 in endothelial cells. Thrombosis and haemostasis 27 10595644
2013 PAI-1 4G/5G polymorphism contributes to cancer susceptibility: evidence from meta-analysis. PloS one 26 23437240
2022 PAI-1: A Major Player in the Vascular Dysfunction in Obstructive Sleep Apnea? International journal of molecular sciences 25 35628326
2024 Endothelial H2S-AMPK dysfunction upregulates the angiocrine factor PAI-1 and contributes to lung fibrosis. Redox biology 23 38266576
2023 FGFR2 upregulates PAI-1 via JAK2/STAT3 signaling to induce M2 polarization of macrophages in colorectal cancer. Biochimica et biophysica acta. Molecular basis of disease 23 36781088
2022 SIX5-activated LINC01468 promotes lung adenocarcinoma progression by recruiting SERBP1 to regulate SERPINE1 mRNA stability and recruiting USP5 to facilitate PAI1 protein deubiquitylation. Cell death & disease 23 35387981
2016 Hyperglycaemia-induced reciprocal changes in miR-30c and PAI-1 expression in platelets. Scientific reports 23 27819307
2014 Inhibition of PAI-1 antiproteolytic activity against tPA by RNA aptamers. Nucleic acid therapeutics 23 24922319
2014 The Role of TLR4 and Fyn Interaction on Lipopolysaccharide-Stimulated PAI-1 Expression in Astrocytes. Molecular neurobiology 23 25106729
2016 Intracellular Expression of PAI-1 Specific Aptamers Alters Breast Cancer Cell Migration, Invasion and Angiogenesis. PloS one 22 27755560
2015 Compression-induced HIF-1 enhances thrombosis and PAI-1 expression in mouse skin. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society 22 25939592
2017 A long-acting PAI-1 inhibitor reduces thrombus formation. Thrombosis and haemostasis 21 28405670
2011 Silencing of DLC1 upregulates PAI-1 expression and reduces migration in normal prostate cells. Molecular cancer research : MCR 21 22064653
2010 UPA and PAI-1 analysis from fixed tissues - new perspectives for a known set of predictive markers. Current medicinal chemistry 21 20939809
2008 PAI-1 and functional blockade of SNAI1 in breast cancer cell migration. Breast cancer research : BCR 21 19055748
2023 PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells. Cells 20 37566086
2022 Transgenic Anopheles mosquitoes expressing human PAI-1 impair malaria transmission. Nature communications 20 35618711
2020 PAI-1 is involved in delayed bone repair induced by glucocorticoids in mice. Bone 20 32142912
2019 Plasminogen activator inhibitor-1 (PAI-1) expression in endometriosis. PloS one 20 31315131
2015 Role of ACE and PAI-1 Polymorphisms in the Development and Progression of Diabetic Retinopathy. PloS one 20 26658948
2014 Expression of Bmi-1 and PAI-1 in esophageal squamous cell carcinoma. World journal of gastroenterology 18 24833884
2013 Relationship between post-SARS osteonecrosis and PAI-1 4G/5G gene polymorphisms. European journal of orthopaedic surgery & traumatology : orthopedie traumatologie 18 23589033
2010 Association of PAI-1 gene polymorphism with survival and chemotherapy-related vascular toxicity in testicular cancer. Cancer 18 20737565
2016 Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-β in orbital fibroblasts. The Journal of endocrinology 17 26979769
2022 Ligand-mediated PAI-1 inhibition in a mouse model of peritoneal carcinomatosis. Cell reports. Medicine 15 35243423
2022 PAI-1 is a potential transcriptional silencer that supports bladder cancer cell activity. Scientific reports 15 35842542
2012 Gastric expression of plasminogen activator inhibitor (PAI)-1 is associated with hyperphagia and obesity in mice. Endocrinology 15 23254194
2024 PAI-1 Regulates the Cytoskeleton and Intrinsic Stiffness of Vascular Smooth Muscle Cells. Arteriosclerosis, thrombosis, and vascular biology 14 38868940

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