Affinage

SERPINE1

Plasminogen activator inhibitor 1 · UniProt P05121

Round 2 corrected
Length
402 aa
Mass
45.1 kDa
Annotated
2026-04-28
130 papers in source corpus 36 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SERPINE1 encodes plasminogen activator inhibitor 1 (PAI-1), a secreted serpin that functions as the principal physiological inhibitor of tissue-type (tPA) and urokinase-type (uPA) plasminogen activators through covalent acyl-enzyme complex formation, thereby governing fibrinolysis, extracellular matrix remodeling, and cell migration (PMID:3090045, PMID:1435917). A unique structural feature—spontaneous insertion of its reactive-center loop into β-sheet A without proteolytic cleavage—converts PAI-1 to a stable latent conformation, while vitronectin binding to the somatomedin B domain stabilizes the active state and simultaneously occludes integrin αVβ3 and uPAR binding sites, enabling PAI-1 to regulate cell adhesion and motility independently of its antiprotease activity (PMID:1731226, PMID:12808446, PMID:8837777). PAI-1 drives LRP1-dependent endocytic clearance and recycling of uPA–uPAR complexes, controls macrophage and smooth muscle cell migration through integrin-to-LRP switching, and regulates vascular smooth muscle stiffness via AMPK–cofilin-mediated F-actin remodeling (PMID:9184208, PMID:16601674, PMID:38868940). Beyond its extracellular roles, PAI-1 is a critical p53/TGF-β–Smad target gene that enforces replicative senescence by suppressing PI3K–PKB–GSK3β–cyclin D1 signaling, can translocate to the nucleus to act as a transcriptional co-repressor, and stabilizes p53 by binding and inhibiting proteasome subunits (PMID:16862142, PMID:27759037, PMID:35842542, PMID:37566086).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1986 High

    Molecular cloning and biochemical characterization established PAI-1 as a serpin-family serine protease inhibitor that forms covalent complexes with uPA and tPA via an acyl-enzyme mechanism, defining its primary molecular activity.

    Evidence cDNA cloning from endothelial cells by three independent groups; purification and kinetic analysis of covalent complex formation with uPA/tPA

    PMID:2430793 PMID:3090045 PMID:3092219 PMID:3097076

    Open questions at the time
    • No structural basis for PAI-1's unusual spontaneous loss of activity
    • No in vivo validation of physiological necessity
  2. 1990 High

    Demonstration that PAI-1 inhibits receptor-bound uPA and triggers internalization and lysosomal degradation of the uPA–PAI-1 complex via uPAR established the first cellular clearance mechanism for plasminogen activators.

    Evidence Radiolabeled ligand internalization assays on U937 cells with chloroquine inhibition and kinetic measurements

    PMID:2157592 PMID:2161846

    Open questions at the time
    • Endocytic receptor mediating internalization not yet identified
    • Fate of uPAR after internalization unknown
  3. 1992 High

    The crystal structure of latent PAI-1 revealed that full reactive-loop insertion into β-sheet A without cleavage explains the serpin's unique spontaneous conversion to a stable inactive form, resolving a long-standing structural puzzle.

    Evidence X-ray crystallography at 2.6 Å resolution

    PMID:1731226

    Open questions at the time
    • Structure of the active conformation and mechanism of latency transition not resolved
    • Vitronectin-mediated stabilization not structurally explained
  4. 1992 High

    Identification of a human frameshift mutation causing complete PAI-1 deficiency with severe bleeding confirmed PAI-1 as the essential in vivo inhibitor of plasminogen activators.

    Evidence Genetic analysis of a PAI-1-deficient patient with hyperfibrinolytic bleeding diathesis

    PMID:1435917

    Open questions at the time
    • No systematic characterization of heterozygous carriers
    • Tissue-specific consequences of PAI-1 loss not defined
  5. 1995 High

    Characterization of the 4G/5G promoter polymorphism revealed that differential transcription factor binding (activator on both alleles, repressor only on 5G) explains allele-specific PAI-1 expression levels and associated cardiovascular risk.

    Evidence EMSA with allele-specific probes, transcription reporter assays, population study of myocardial infarction

    PMID:7892190

    Open questions at the time
    • Identity of the repressor protein binding the 5G allele not determined
    • Causality between polymorphism and MI not established by the association study alone
  6. 1996 High

    Discovery that PAI-1 competes with uPAR and αVβ3 integrin for vitronectin binding—and that this is independent of protease inhibition—established a second major function: regulation of cell adhesion and migration through extracellular matrix interactions.

    Evidence Domain-swap mutagenesis of vitronectin, cell detachment assays, smooth muscle cell migration with PAI-1 mutants deficient in protease inhibition

    PMID:8830783 PMID:8837777

    Open questions at the time
    • Atomic details of PAI-1–vitronectin interface not yet resolved
    • Relative contribution of anti-adhesive versus antiproteolytic function in vivo not quantified
  7. 1997 High

    Identification of LRP as the endocytic receptor for uPA–PAI-1 complexes and demonstration of uPAR recycling after internalization completed the cellular clearance cycle model and explained how cells regenerate uPA-binding capacity.

    Evidence Surface biotinylation pulse-chase, PI-PLC treatment, immunoelectron microscopy on U937 and HT1080 cells; PAI-1 knockout mice with arterial injury showing enhanced SMC migration rescued by adenoviral PAI-1

    PMID:9184208 PMID:9386191

    Open questions at the time
    • Sorting signals directing uPAR recycling versus LRP/ligand degradation not defined
    • Whether other endocytic receptors contribute in specific tissues not tested
  8. 2003 High

    The crystal structure of PAI-1 bound to the vitronectin SMB domain provided the atomic basis for vitronectin stabilization of active PAI-1 and confirmed steric occlusion of integrin and uPAR binding sites, unifying the structural and cell-biological observations.

    Evidence X-ray crystallography at 2.3 Å resolution of the PAI-1–SMB domain complex

    PMID:12808446

    Open questions at the time
    • Structure of the full-length vitronectin–PAI-1 complex not available
    • Dynamics of the active-to-latent transition in the presence of vitronectin not captured
  9. 2006 High

    Three studies collectively expanded PAI-1's role beyond fibrinolysis: PAI-1 was shown to be an essential p53 target enforcing replicative senescence via PI3K–PKB–GSK3β–cyclin D1 suppression, to orchestrate macrophage migration through a sequential Mac-1/tPA/PAI-1/LRP adhesion-to-detachment switch, and to be transcriptionally co-regulated by HIF-1α, Egr-1, and C/EBPα under hypoxia.

    Evidence RNAi knockdown and ectopic expression in fibroblasts with pathway analysis (senescence); multiple genetic knockouts with PAI-1 LRP-binding mutant rescue in vivo (macrophage migration); PAI-1 promoter mutagenesis, EMSA, and ChIP under hypoxia (transcription)

    PMID:16601674 PMID:16862142 PMID:17197388

    Open questions at the time
    • Whether PAI-1's senescence function requires a specific receptor or is intracellular not resolved
    • Relative importance of each hypoxia-responsive element in different tissues not established
    • Mac-1/tPA/PAI-1/LRP pathway not tested in human macrophages
  10. 2014 Medium

    Multiple studies dissected PAI-1's dual functional domains in disease contexts: vitronectin-binding (not antiprotease) activity protects against cardiac fibrosis; PAI-1 supports HIF-2α-driven angiogenesis by maintaining low plasmin; and the prolactin fragment 16K PRL directly binds PAI-1 to modulate fibrinolysis and angiogenesis.

    Evidence PAI-1 domain-specific variants in mouse cardiac fibrosis model; epistatic shRNA knockdown with aprotinin rescue in HepG2 spheroids; direct 16K PRL–PAI-1 binding assay with PAI-1 KO mice

    PMID:24687120 PMID:24929950 PMID:25489981

    Open questions at the time
    • Whether vitronectin-binding function is protective in non-cardiac fibrosis settings not tested
    • HIF-2α–PAI-1 axis validated only in hepatocellular carcinoma model
    • 16K PRL–PAI-1 binding site not mapped
  11. 2016 High

    Elucidation of TGF-β-induced PAI-1 transcription through a p53–Smad2/3–CBP complex on the PAI-1 promoter mechanistically linked p53 and TGF-β cytostatic signaling, with PAI-1 as an effector mediating growth arrest.

    Evidence Co-immunoprecipitation of p53–Smad complex, ChIP for promoter occupancy, histone acetylation analysis, p53 siRNA epistasis

    PMID:27759037

    Open questions at the time
    • Whether this complex operates in non-epithelial cell types not tested
    • Genome-wide p53–Smad co-regulation beyond PAI-1 not explored
  12. 2021 High

    Cell-autonomous and paracrine senescence functions of PAI-1 were defined: PAI-1 overexpression in tubular epithelial cells drives dedifferentiation and fibrosis through klotho loss, p53, and ligand-independent TGF-βRI/SMAD3 activation; meanwhile, senescent endothelial cell-secreted PAI-1 induces podocyte apoptosis in a paracrine manner, with endothelial-specific PAI-1 deletion protecting against age-related glomerular injury.

    Evidence Stable PAI-1 overexpression with epistasis (klotho rescue, p53 siRNA, TGF-βRI inhibitor) in HK-2 cells; endothelial cell-specific PAI-1 conditional KO mice with conditioned medium transfer

    PMID:34110636 PMID:34725920

    Open questions at the time
    • Whether intracellular PAI-1 drives these effects through proteasome inhibition or another mechanism not fully resolved
    • Identity of the podocyte receptor for secreted PAI-1 unknown
  13. 2023 Medium

    Two novel intracellular functions were described: nuclear PAI-1 occupies distal intergenic chromatin regions and acts as a transcriptional co-repressor, and pre-secretory PAI-1 binds proteasome subunits to stabilize p53 and promote senescence in epithelial cells.

    Evidence ChIP-seq and RNA-seq integration with RIME in bladder cancer cells (nuclear function); co-immunoprecipitation with proteasome subunits and proteasome activity assay with wild-type versus secretion-deficient PAI-1 in ATII cells

    PMID:35842542 PMID:37566086

    Open questions at the time
    • Nuclear PAI-1 chromatin-binding partners and co-repressor complex composition not fully defined
    • Proteasome interaction surfaces on PAI-1 not mapped
    • Both findings from single laboratories; independent replication pending
  14. 2024 Medium

    PAI-1 was shown to regulate vascular smooth muscle cell intrinsic stiffness by controlling F-actin content through AMPK-dependent cofilin activation, independent of uPAR/LRP, identifying a mechanotransduction function relevant to arterial stiffness.

    Evidence Atomic force microscopy, AMPK signaling analysis, PAI-1 siRNA and PAI-1−/− SMCs, in vivo aortic pulse wave velocity measurement

    PMID:38868940

    Open questions at the time
    • Direct PAI-1 target upstream of AMPK not identified
    • Whether this mechanism operates in non-vascular cell types unknown
    • Single-lab finding awaiting independent validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the identity of the receptor(s) mediating PAI-1's intracellular senescence and anti-apoptotic functions (independent of uPAR/LRP/vitronectin), the structural basis for PAI-1's nuclear translocation and chromatin binding, and whether proteasome inhibition and transcriptional co-repression represent a unified intracellular mechanism or distinct activities.
  • No receptor identified for PAI-1's GPCR/PI3K-dependent anti-apoptotic signaling in neutrophils
  • Nuclear localization signal or import mechanism not characterized
  • Relationship between pre-secretory proteasome binding and nuclear chromatin occupancy not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 4 GO:0098772 molecular function regulator activity 4 GO:0098631 cell adhesion mediator activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005576 extracellular region 6 GO:0031012 extracellular matrix 5 GO:0005634 nucleus 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1474244 Extracellular matrix organization 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-109582 Hemostasis 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
LRP1PLATPLAUPLAURSMAD3TP53VTN
Complex memberships
p53–Smad2/3–CBP transcriptional complex on PAI-1 promoteruPA–PAI-1–uPAR–LRP1 endocytic complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 PAI-1 (SERPINE1) was cloned from human endothelial cell cDNA libraries; the mature protein is 379–402 amino acids, belongs to the serpin superfamily (homology with α1-antitrypsin and antithrombin III), lacks cysteine residues, has three N-linked glycosylation sites, and is encoded by a gene on chromosome 7. Two mRNA species (~2.2 and ~3.0 kb) arise from a single gene. cDNA cloning, nucleotide sequencing, Northern blot, immunological screening of expression libraries Proceedings of the National Academy of Sciences / Journal of Clinical Investigation / EMBO Journal High 2430793 3092219 3097076
1992 Crystal structure of intact latent PAI-1 at 2.6 Å resolution revealed that the reactive-site loop (residues N-terminal to the scissile bond) is inserted as a central β-strand into the major β-sheet (analogous to cleaved serpins), while C-terminal residues occupy a distinct surface position. This structural rearrangement explains PAI-1's unique ability to spontaneously convert to a stable latent (inactive) form without cleavage, and why inhibitory activity can be restored by denaturation/renaturation. Single-crystal X-ray diffraction (2.6 Å resolution) Nature High 1731226
1986 PAI-1 purified from U-937 cells forms covalent complexes with urokinase (uPA) and two-chain tPA with second-order rate constants of ~0.9×10⁶ M⁻¹s⁻¹ and ~0.2×10⁶ M⁻¹s⁻¹ respectively; the 47-kDa inhibitor is a member of the antithrombin III (serpin) family and the covalent complex can be hydrolyzed by NH₄OH to yield a 35-kDa inhibitor fragment, consistent with acyl-enzyme (serpin) mechanism. Protein purification, SDS-PAGE, covalent complex formation assay, kinetic analysis, partial amino acid sequencing The Journal of biological chemistry High 3090045
1990 Receptor-bound uPA on U937 cell surfaces is efficiently inhibited by PAI-1 (rate constant ~4.5×10⁶ M⁻¹s⁻¹, ~40% lower than for free uPA); PAI-1 also inhibits receptor-bound uPA. The resulting uPA–PAI-1 complex on the uPA receptor (uPAR) is then internalized and degraded via lysosomes (inhibitable by chloroquine), while free uPA, ATF, or DFP-uPA are not internalized, establishing a cellular clearance cycle for uPA. Radiolabeled ligand internalization assay, acid dissociation, TCA precipitation, chloroquine inhibition, kinetic rate constant measurements The EMBO journal / The Journal of biological chemistry High 2157592 2161846
1992 Complete PAI-1 deficiency in humans, caused by a frameshift mutation, results in a severe bleeding disorder (hyperfibrinolysis), establishing PAI-1 as the essential physiological inhibitor of plasminogen activators in vivo. Genetic analysis (frameshift mutation identification) in a PAI-1-deficient patient with bleeding diathesis The New England journal of medicine High 1435917
1995 The 4G allele of the PAI-1 promoter 4G/5G polymorphism confers higher basal PAI-1 transcription than the 5G allele because both alleles bind a transcriptional activator, but only the 5G allele additionally binds a repressor protein at an overlapping site; this mechanism was associated with higher plasma PAI-1 activity and higher prevalence of myocardial infarction before age 45. Allele-specific transcription analysis, electrophoretic mobility shift assay (EMSA), population genetics Proceedings of the National Academy of Sciences of the United States of America High 7892190
1996 PAI-1 and the urokinase receptor (uPAR) bind to the same somatomedin B (SMB) domain of vitronectin (VN) competitively; PAI-1 displaces VN from uPAR and detaches U937 cells from VN substrate independently of its protease inhibitory activity. uPA rapidly reverses this detachment. This established PAI-1 as a molecular switch governing uPAR-mediated cell adhesion and release from the extracellular matrix. Domain-swapping and site-directed mutagenesis of VN, competitive binding assays, cell detachment assays The Journal of cell biology High 8830783
1996 Active PAI-1 inhibits smooth muscle cell (SMC) migration on vitronectin by blocking αVβ3 integrin binding to vitronectin—an effect requiring high-affinity PAI-1 binding to vitronectin but independent of PAI-1's protease inhibitory function. Formation of a PAI-1–plasminogen activator complex abolishes PAI-1's affinity for vitronectin and restores cell migration, directly linking plasminogen activator activity to integrin-mediated migration control. SMC migration assay, function-blocking antibodies, PAI-1 mutants deficient in protease inhibition, integrin-blocking experiments Nature High 8837777
1997 After uPA–PAI-1 complex internalization via uPAR and LRP (α2MR-LRP), uPAR is recycled back to the cell surface in a PI-PLC-sensitive (GPI-anchored) form, as demonstrated by surface biotinylation pulse-chase. The receptor recycles through an intracellular compartment that temporarily renders it PI-PLC resistant, while LRP is required for internalization but not recycling. Cell surface biotinylation, FACScan, immunofluorescence, immunoelectron microscopy, PI-PLC treatment, pulse-chase recycling assay The EMBO journal High 9184208
1997 PAI-1 gene-deficient (PAI-1⁻/⁻) mice show enhanced and accelerated smooth muscle cell migration into vascular wounds and increased neointima formation after arterial injury compared to wild-type, while adenoviral PAI-1 gene transfer suppresses neointima formation. Smooth muscle cell proliferation was unaffected, establishing that PAI-1 inhibits vascular remodeling specifically by restraining cell migration. PAI-1 knockout mice, perivascular electric and transluminal mechanical arterial injury, morphometric analysis, immunostaining, adenoviral gene transfer Circulation High 9386191
2003 Crystal structure (2.3 Å) of the somatomedin B (SMB) domain of vitronectin in complex with PAI-1 revealed the molecular basis for vitronectin stabilization of active PAI-1 conformation and showed that PAI-1 sterically occludes the binding sites for both uPAR and integrins on vitronectin, explaining how PAI-1 controls cell adhesion and motility through competition for vitronectin. X-ray crystallography (2.3 Å resolution) of PAI-1–vitronectin SMB domain complex Nature structural biology High 12808446
2001 PAI-1 inhibits uPA-induced cell chemotaxis by triggering uPAR internalization via LRP; the uPA–PAI-1 complex has no intrinsic chemotactic activity, but blocking LRP-mediated internalization (with RAP or anti-LRP antibodies) converts the complex into a chemoattractant that induces cytoskeleton reorganization and ERK/MAPK activation. Chemotaxis assay, receptor internalization assay with RAP and anti-LRP antibodies, cytoskeleton staining, ERK phosphorylation Western blot FEBS letters High 11566185
2006 PAI-1 is an essential downstream target of p53 required for replicative senescence: RNAi knockdown of PAI-1 allows escape from senescence in primary mouse and human fibroblasts, associated with sustained PI3K–PKB–GSK3β pathway activation and nuclear retention of cyclin D1. Conversely, ectopic PAI-1 expression in p53-deficient proliferating fibroblasts induces all hallmarks of replicative senescence. PAI-1 knockdown results are independent of its antiproteolytic serpin activity. RNAi knockdown, ectopic overexpression, senescence assays (SA-β-gal, BrdU incorporation), Western blot for PI3K–PKB–GSK3β–cyclin D1 pathway, primary mouse and human fibroblasts Nature cell biology High 16862142
2006 Efficient macrophage migration in an inflammatory environment requires a sequential molecular cycle: Mac-1 integrin binds a fibrin–tPA binary complex; PAI-1 then neutralizes tPA, and the resulting integrin–tPA–PAI-1 ternary complex binds the endocytic receptor LRP, triggering a switch from cell adhesion to detachment. Genetic inactivation of Mac-1, tPA, PAI-1 or LRP (but not uPA) abolishes macrophage migration. A PAI-1 mutant unable to interact with LRP fails to rescue migration in PAI-1⁻/⁻ mice. Genetic knockout mice (Mac-1, tPA, PAI-1, LRP, uPA), PAI-1 LRP-binding mutant rescue, in vitro adhesion/retraction assays, intravital microscopy The EMBO journal High 16601674
2006 Hypoxia induces PAI-1 transcription in macrophages through three transcription factors—Egr-1, HIF-1α, and C/EBPα—each binding distinct sites in the PAI-1 promoter. Mutation of individual or combined sites reduces hypoxia-driven transcription. ChIP analysis confirmed chromatin binding of all three factors under hypoxic conditions; HIF-1α dominates but Egr-1 and C/EBPα augment the response independently of each other. PAI-1 promoter deletion/mutation reporter assays, EMSA with supershift, ChIP analysis, primary peritoneal macrophages and RAW264.7 cells FASEB journal High 17197388
2008 PAI-1 is deposited along keratinocyte migration trails during wound repair and is required for optimal wound closure: recombinant active PAI-1 stimulates directional motility and cell spreading, while antisense-mediated knockdown or neutralizing antibodies impair wound repair and induce plasminogen-dependent anoikis. PAI-1 thus acts as a survival factor and migration regulator during epidermal injury response. PAI-1-GFP live imaging, recombinant PAI-1 addition, antisense knockdown, neutralizing antibodies, wound closure assays in wild-type and PAI-1⁻/⁻ cells, apoptosis assays Archives of dermatological research High 18386027
2012 Matrix-bound PAI-1 maintains cell blebbing (amoeboid migration mode) in colorectal cancer cells by localizing PDK1 and ROCK1 at the cell membrane and sustaining RhoA/ROCK1/MLC phosphorylation; tumor periphery modeling predicts heterogeneous PAI-1 concentrations sufficient to drive mesenchymal-to-amoeboid transition. Immunoblotting, activity assay, immunofluorescence, RhoA/ROCK1/MLC pathway analysis, mathematical modeling of PAI-1 distribution PloS one Medium 22363817
2014 The N-terminal fragment of prolactin (16K PRL) binds PAI-1 and inhibits its antifibrinolytic activity, thereby promoting thrombolysis; simultaneously, 16K PRL acts through the PAI-1–uPA–uPAR ternary complex to exert antiangiogenic and antitumoral effects. Loss of PAI-1 abolishes both antitumoral and antiangiogenic effects of 16K PRL. Direct binding assay (16K PRL–PAI-1 interaction), PAI-1 knockout mice, fibrinolysis assay, tumor angiogenesis models Nature medicine High 24929950
2015 PAI-1 modulates cell migration in a LRP1-dependent manner: PAI-1 induces β-catenin expression and transcriptional activity in LRP1-competent MEFs but not in LRP1-deficient cells; PAI-1-induced ERK1/2 activation is more prominent in LRP1-deficient cells and is abolished by β-catenin knockdown, placing PAI-1 upstream of both the β-catenin and ERK1/2 MAPK pathways through LRP1. LRP1 knockout MEFs, siRNA knockdown of β-catenin, Western blot, luciferase reporter for β-catenin transcriptional activity, migration assays Thrombosis and haemostasis Medium 25694133
2016 TGF-β induces PAI-1 transcription through a p53–Smad2/3 complex formed on the PAI-1 promoter: p53 recruits the histone acetyltransferase CBP to this complex, enhancing H3 acetylation and transcriptional activation. p53 is required for TGF-β-induced cytostasis, and PAI-1 mediates part of this cytostatic activity, identifying PAI-1 as a mechanistic link between p53 and TGF-β cytostasis. Co-immunoprecipitation (p53–Smad complex), ChIP (promoter occupancy), histone acetylation assay, p53 siRNA, PAI-1 reporter assays, cell growth assays Scientific reports High 27759037
2018 Stress granules (SGs) sequester PAI-1 in proliferating and presenescent cells; SG assembly alone is sufficient to decrease the number of senescent cells. SG-localized PAI-1 promotes nuclear translocation of cyclin D1, RB phosphorylation, and maintenance of a proliferative state, establishing a non-cell-autonomous mechanism by which SG-mediated PAI-1 sequestration counteracts senescence. Stress granule induction, PAI-1 localization by immunofluorescence, SA-β-gal senescence assay, cyclin D1 nuclear fractionation, pRB Western blot EMBO reports Medium 29592859
2011 PAI-1 inhibits neutrophil apoptosis (spontaneous and TRAIL-induced) through activation of PKB/Akt, Mcl-1, and Bcl-xL antiapoptotic pathways, mediated by pertussis toxin-sensitive G protein-coupled receptors and PI3K—not through uPAR, LRP, or vitronectin. In PAI-1⁻/⁻ mice, neutrophils accumulating in LPS-injured lungs show enhanced apoptosis compared to wild-type. Neutrophil apoptosis assay, pathway inhibitors (pertussis toxin, PI3K inhibitor), receptor-blocking antibodies, PAI-1⁻/⁻ mice, Western blot for Akt/Mcl-1/Bcl-xL American journal of physiology. Lung cellular and molecular physiology Medium 21622848
2018 Thrombin promotes PAI-1 mRNA expression and keratinocyte migration via PAR-1 transactivation of EGFR, downstream ERK1/2 phosphorylation, and specific phosphorylation of Smad2 linker region at Ser250 (but not Ser245 or Ser255); ERK1/2 inhibition but not p38 or JNK inhibition blocks Smad2L phosphorylation and PAI-1 induction. Selective kinase inhibitors, Western blot for Smad2 linker phosphorylation, qRT-PCR for PAI-1, scratch wound migration assay Cellular signalling Medium 29577978
2021 Tubular epithelial cell-autonomous PAI-1 overexpression causes dedifferentiation (E-cadherin loss, vimentin gain), G2/M arrest, fibrosis (fibronectin, collagen-1, CCN2 induction), and apoptosis in HK-2 cells via three interconnected pathways: (1) loss of klotho, (2) p53 upregulation, and (3) TGF-βRI/SMAD3 activation independent of TGF-β1 ligand. Ectopic klotho restoration reversed fibrogenesis and proliferative defects; p53 suppression blocked maladaptive repair; TGF-βRI inhibition attenuated epithelial dysfunction. Stable PAI-1 overexpression in HK-2 cells, ectopic klotho restoration, p53 siRNA, TGF-βRI inhibitor, Western blot (pSMAD3, cleaved caspase-3, pHistone3), flow cytometry (annexin-V) FASEB journal Medium 34110636
2021 Senescent glomerular endothelial cells secrete PAI-1 that drives podocyte apoptosis; selective genetic inactivation of PAI-1 in endothelial cells protects glomeruli from age-related lesion development and podocyte loss in mice. Blocking PAI-1 in conditioned medium from senescent endothelial cells prevented podocyte apoptosis in vitro. Endothelial cell-specific PAI-1 conditional knockout mice, aged p16INK-ATTAC transgenic mice (senescent cell depletion), conditioned medium transfer with PAI-1 neutralization, podocyte apoptosis assay EMBO molecular medicine High 34725920
2023 PAI-1 binds LRP1 on lymphatic endothelial cells (LECs) and activates AKT/ERK1/2 signaling to promote endothelial-mesenchymal transition (EndoMT), leading to aberrant lymphangiogenesis and lymphatic metastasis; blockade of PAI-1 or LRP1/AKT/ERK1/2 abrogates EndoMT and tumor neolymphangiogenesis. CAF-conditioned medium, LRP1 interaction assay, Western blot (AKT/ERK phosphorylation), transwell/tube formation/transendothelial migration assays, popliteal LN metastasis mouse model, PAI-1 knockdown/inhibitor Journal of experimental & clinical cancer research Medium 37415190
2023 Nuclear PAI-1 can bind chromatin at distal intergenic regions and function as a transcriptional co-repressor: ChIP-seq in bladder cancer cells showed PAI-1 chromatin occupancy, PAI-1 knockdown upregulated 57 candidate target genes (integration of ChIP-seq and RNA-seq), and rapid immunoprecipitation mass spectrometry identified nuclear PAI-1 interaction partners consistent with transcriptional regulatory complexes. ChIP-sequencing, RNA-sequencing, RIME (rapid immunoprecipitation mass spectrometry), immunohistochemistry of 939 tumor specimens Scientific reports Medium 35842542
2023 PAI-1 binds proteasome components and inhibits proteasomal activity, thereby reducing p53 degradation and promoting senescence in alveolar epithelial type II (ATII) cells; only the wild-type (secretion-competent) form of PAI-1 induces p53 accumulation and SA-β-gal activity, whereas a secretion-deficient mature form induces senescence markers without p53 induction, indicating the premature (pre-secretory) form interacts with the proteasome. Co-immunoprecipitation of PAI-1 with proteasome subunits, proteasome activity assay, stable overexpression of wtPAI-1 vs. secretion-deficient PAI-1, SA-β-gal, p53/p21/pRb Western blot Cells Medium 37566086
2024 PAI-1 regulates vascular smooth muscle cell (SMC) intrinsic stiffness by controlling cytoplasmic F-actin content: PAI-1 inhibition (PAI-039) or siRNA knockdown decreases SMC stiffness and F-actin, activates the F-actin depolymerase cofilin via AMPK signaling (not through uPAR/LRP), and reduces aortic pulse wave velocity in vivo; these effects are absent in PAI-1-deficient SMCs. Atomic force microscopy (SMC stiffness), F-actin staining, cofilin activity assay, AMPK inhibition, RNA-sequencing, PAI-1 siRNA, PAI-1⁻/⁻ murine SMCs, in vivo aortic pulse wave velocity Arteriosclerosis, thrombosis, and vascular biology Medium 38868940
2014 PAI-1 (via inhibition of uPA/tPA and consequent maintenance of low plasmin levels) supports angiogenesis in hepatocellular carcinoma downstream of HIF-2α: HIF-2α knockdown reduces PAI-1 expression and angiogenesis; PAI-1 knockdown similarly reduces angiogenesis; restoring low plasmin activity with aprotinin in HIF-2α KD cells rescues angiogenesis, confirming a HIF-2α→PAI-1→plasmin inhibition→angiogenesis axis. Stable shRNA knockdown of HIF-1α/HIF-2α/PAI-1, HepG2 spheroid–embryoid body co-culture angiogenesis model, aprotinin (plasmin inhibitor) rescue, microarray gene expression Experimental cell research Medium 25489981
2019 Tumor-secreted PAI-1 activates PI3K/AKT signaling in adjacent adipocytes, promoting nuclear translocation of FOXP1 which enhances PLOD2 promoter activity, leading to collagen crosslinking/remodeling by cancer-associated adipocytes (CAAs) that facilitates breast cancer invasion and metastasis. Co-culture proteomics, ELISA, ChIP assay (FOXP1 on PLOD2 promoter), Western blot (AKT/FOXP1), siRNA knockdown, 3D collagen invasion assay, in vivo co-implantation mouse model Cell communication and signaling Medium 31170987
2014 RNA aptamers (R10-4 and R10-2) that bind PAI-1 with nanomolar affinity inhibit PAI-1's antiproteolytic activity against tPA, prevent stable covalent complex formation between PAI-1 and tPA, and increase the amount of cleaved (substrate) PAI-1 in a concentration-dependent manner, demonstrating direct targeting of the tPA-docking site of PAI-1. SELEX aptamer selection, in vitro PAI-1 inhibition assay, covalent complex formation assay, dose-response analysis Nucleic acid therapeutics Medium 24922319
2014 Vitronectin-binding (but not protease-inhibitory) activity of PAI-1 protects against cardiac fibrosis: in angiotensin II–infused mice, the non-vitronectin-binding PAI-1 variant (AK) increased cardiac fibrosis, fibroblast marker (periostin), and Col1 mRNA, while the vitronectin-binding but non-protease-inhibitory variant (RR) and control PAI-1 (CPAI) were protective. In cardiac fibroblasts, RR and CPAI reduced integrin β3 expression, vitronectin supernatant levels, and fibroblast adhesion to vitronectin, and preserved apoptotic over antiapoptotic/proliferative signaling. In vivo mouse cardiac fibrosis model with PAI-1 variant infusion, cardiac fibroblast culture with variant PAI-1 treatments, morphometry, qPCR, integrin/vitronectin assays Laboratory investigation Medium 24687120

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
1999 Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature genetics 1381 10391209
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
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
1995 Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proceedings of the National Academy of Sciences of the United States of America 665 7892190
2004 The human plasma proteome: a nonredundant list developed by combination of four separate sources. Molecular & cellular proteomics : MCP 658 14718574
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 610 16713569
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
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