Affinage

Showing SERPINF1 — PEDF is a alias.

SERPINF1

Pigment epithelium-derived factor · UniProt P36955

Length
418 aa
Mass
46.3 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SERPINF1 encodes PEDF, a secreted non-inhibitory serpin that acts as a multifunctional extracellular signaling factor coordinating angiogenesis, cell survival, lipid metabolism, and bone homeostasis through distinct cell-surface receptors and peptide domains (PMID:9433504, PMID:25535841). Its anti-angiogenic activity is mediated by direct binding to the extracellular domains of VEGFR-1 and VEGFR-2, blocking VEGF-A-induced receptor phosphorylation and downstream PI3K/AKT/FAK/Src/PLC-γ signaling (PMID:34742690), and by a γ-secretase-dependent pathway that preserves adherens and tight junction integrity to limit vascular permeability (PMID:21695048); this anti-angiogenic function is carried by the 34-mer peptide region, whereas the 44-mer is inactive in angiogenesis (PMID:19850839). PEDF promotes retinal and RPE cell survival by binding PEDF-R (PNPLA2) at ectodomain L4, stimulating its phospholipase A2 activity to drive PPARγ and STAT3 signaling and protect against oxidative stress, ferroptosis, and apoptosis (PMID:20237999, PMID:23818523, PMID:29186716, PMID:38153666), and signals additionally through the transmembrane receptors PLXDC1 and PLXDC2, which it activates by dissociating their basal homooligomers (PMID:25535841). PEDF controls lipid homeostasis by acting on adipose triglyceride lipase (ATGL): it stimulates ATGL-dependent triglyceride degradation in cardiomyocytes and promotes COP1-mediated nuclear proteasomal degradation of ATGL in hepatocytes (PMID:25890298, PMID:30926171). In bone, loss of PEDF activates TGF-β signaling in osteoblasts, delaying maturation and mineralization and elevating bone vascularization, while PEDF suppresses osteoclasts via osteoprotegerin upregulation (PMID:19945427, PMID:35258129). Truncating and in-frame loss-of-function mutations in SERPINF1 cause autosomal-recessive osteogenesis imperfecta type VI through a collagen-independent mechanism, with mutant PEDF retained in the ER or degraded intracellularly (PMID:21353196, PMID:21826736, PMID:25868797).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1997 Medium

    Establishing that PEDF is a non-inhibitory serpin reframed it as a signaling protein rather than a protease inhibitor and localized its neurotrophic activity to an N-terminal peptide region.

    Evidence serpin biochemical characterization and peptide dissection

    PMID:9433504

    Open questions at the time
    • No receptor identified for the neurotrophic activity in this study
    • Serpin loop role left undefined beyond being dispensable
  2. 2000 Medium

    Growth-arrest induction of EPC-1/PEDF was shown to be governed posttranscriptionally through mRNA stability rather than transcription, defining how its expression tracks cell-cycle state.

    Evidence transcriptional run-on, hnRNA RT-PCR and mRNA stability measurement in WI-38 fibroblasts (extends 1995 Northern-blot work)

    PMID:10972981 PMID:7814443

    Open questions at the time
    • The stability-determining RNA elements/factors were not identified
    • Link to a downstream growth-arrest effector not established
  3. 2003 Medium

    Reciprocal antibody-neutralization and recombinant-protein addition established that PEDF protein causally enforces G0 growth arrest and proliferation control, going beyond a correlation with expression.

    Evidence antibody neutralization and recombinant protein addition with DNA synthesis assays in fibroblasts and carcinoma cells

    PMID:10047456 PMID:12599204

    Open questions at the time
    • Receptor and signaling pathway for growth arrest not defined
    • Cell-type selectivity mechanism unexplained
  4. 2005 Medium

    Identification of a functional RARE in the PEDF promoter and reciprocal regulation of retinoic acid receptors connected PEDF expression to retinoid signaling in retinal and endothelial cells.

    Evidence luciferase reporter with PEDF promoter-RARE construct, qPCR and Western blot with ATRA treatment

    PMID:15051476

    Open questions at the time
    • Whether retinoid regulation operates in vivo not shown
    • Mechanism of PEDF feedback on RAR/RXR expression unresolved
  5. 2005 Medium

    In vivo and knockdown studies placed PEDF as a negative regulator of vascular permeability and inflammatory cytokine output in retinopathy models, anchoring its anti-angiogenic/anti-inflammatory role.

    Evidence intravitreal injection in rat retinopathy models, siRNA knockdown in Müller cells, cytokine ELISA

    PMID:16368716

    Open questions at the time
    • Receptor mediating the anti-permeability effect not identified here
    • Direct vs indirect VEGF suppression not separated
  6. 2009 Medium

    Identification of PEDF-R/PNPLA2 as a high-affinity cell-surface phospholipase A2 receptor for PEDF provided the first defined receptor-coupled biochemical activity, linking PEDF binding to fatty-acid release.

    Evidence binding assays, PLA2 enzymatic activity assays and topology analysis on retina/RPE cells

    PMID:20237999

    Open questions at the time
    • Downstream lipid mediators not yet mapped to a survival pathway
    • Binding interface on PEDF-R not localized in this study
  7. 2009 Medium

    Demonstrating that PEDF inhibits osteoclast differentiation and resorption while upregulating OPG defined an active role for PEDF in bone remodeling, distinct from its vascular activities.

    Evidence osteoclast differentiation and bone resorption assays with OPG expression analysis

    PMID:19945427

    Open questions at the time
    • Receptor mediating osteoblast OPG induction not identified
    • In vivo bone relevance addressed only later by genetics
  8. 2009 High

    Limited proteolysis and synthetic peptides localized the anti-angiogenic activity to the 34-mer (Asp44-Asn77) and showed the 44-mer is inactive in angiogenesis, separating PEDF's functional domains.

    Evidence chymotrypsin proteolysis, ex vivo aortic sprouting and rat laser-induced CNV models with synthetic peptides

    PMID:19850839

    Open questions at the time
    • Receptor engaged by the 34-mer in angiogenesis not defined here
    • Structural basis of peptide activity not resolved
  9. 2011 High

    Human genetics established SERPINF1 loss-of-function as the cause of osteogenesis imperfecta type VI through a collagen-independent mechanism, converting PEDF's bone activity from in vitro observation to causal disease biology.

    Evidence exome sequencing, homozygosity mapping and collagen biochemistry across multiple families with bone histomorphometry

    PMID:21353196 PMID:21826736

    Open questions at the time
    • The molecular pathway linking PEDF loss to defective mineralization was not yet defined
    • Whether secreted PEDF acts on osteoblasts or osteoclasts in vivo unresolved at this stage
  10. 2011 High

    Mechanistic dissection showed PEDF blocks VEGF-induced permeability via a γ-secretase-dependent pathway that stabilizes adherens and tight junctions, providing a junctional mechanism for its vascular barrier protection.

    Evidence transendothelial resistance, paracellular flux, in vivo leakage, reciprocal immunoprecipitation and γ-secretase inhibitor

    PMID:21695048

    Open questions at the time
    • The receptor coupling PEDF to γ-secretase not identified
    • γ-secretase substrate driving junction stabilization not named
  11. 2013 High

    Mapping the PEDF binding site to PEDF-R ectodomain L4 (His203-Leu232) and showing knockdown abolishes survival defined the receptor element required for PEDF's retinal pro-survival and STAT3-activating activity.

    Evidence truncation-mutant binding, peptide competition, siRNA knockdown and viability assays; conditioned-medium STAT3 activation

    PMID:23818523 PMID:29186716

    Open questions at the time
    • How PLA2 activation couples to STAT3 not fully traced
    • Contribution of PEDF-R vs other receptors to survival in vivo not separated
  12. 2014 High

    Identification of PLXDC1 and PLXDC2 as PEDF receptors that are activated by PEDF-induced dissociation of their basal homooligomers expanded the receptor repertoire and defined a distinct activation mechanism.

    Evidence gain/loss-of-function cellular assays, oligomerization studies and intracellular-domain mutagenesis

    PMID:25535841

    Open questions at the time
    • Cell-type-specific downstream signaling of PLXDC receptors not mapped
    • Relative use of PLXDC vs PEDF-R vs VEGFRs in a given tissue unresolved
  13. 2014 Medium

    PEDF was shown to protect RPE cells from oxidative stress by stabilizing mitochondria through PI3K/Akt signaling and controlling ROS via UCP2, connecting receptor engagement to mitochondrial protection.

    Evidence pharmacological pathway inhibitors, mitochondrial membrane potential/ATP/ROS assays and UCP2-deficient cell rescue

    PMID:25212780

    Open questions at the time
    • Receptor upstream of PI3K/Akt in this context not specified
    • Mechanism of UCP2 induction not defined
  14. 2015 Medium

    PEDF and its 44-mer were shown to drive cardiac triglyceride degradation through ATGL, establishing ATGL as a key effector of PEDF lipid metabolism and assigning the 44-mer a metabolic role distinct from the anti-angiogenic 34-mer.

    Evidence ATGL inhibitor (atglistatin), ATGL siRNA, lipid assays and PEDF manipulation in an AMI mouse model

    PMID:25890298

    Open questions at the time
    • Receptor coupling PEDF to ATGL activation in cardiomyocytes not pinned down
    • Directness of PEDF-ATGL link not established
  15. 2015 Medium

    Demonstrating that OI type VI in-frame mutants are retained in the ER or degraded intracellularly and impair mineralization showed the disease arises from loss of secreted PEDF function.

    Evidence immunofluorescence localization, ER stress assays and mineralization assays in transfected osteoblastic cells

    PMID:25868797

    Open questions at the time
    • Whether ER retention contributes additional toxicity beyond loss of secretion unresolved
    • Direct osteoblast signaling defect not yet linked to TGF-β
  16. 2018 Medium

    Identifying COP1-mediated nuclear proteasomal degradation of ATGL in hepatocytes, and an ATGL/lipid-MTOC axis in fibroblasts, broadened PEDF's lipid-metabolic role to nuclear regulation of lipase abundance.

    Evidence co-IP, subcellular fractionation, proteasome inhibition and COP1 knockdown in hepatocytes; lipid/MTOC quantification in prostate fibroblasts

    PMID:29792311 PMID:30926171

    Open questions at the time
    • How extracellular PEDF reaches the nuclear compartment unexplained
    • COP1 recruitment mechanism to nuclear ATGL not defined
  17. 2018 Medium

    Cardioprotective signaling was extended by showing PEDF engages PEDF-R/iPLA2 to limit NLRP3 inflammasome activation and drives mitophagy via a PKCα-ULK1 axis, linking PEDF to mitochondrial quality control.

    Evidence PEDF-R siRNA, iPLA2 inhibition, co-IP of PKCα-ULK1 with deletion mutant and phosphorylation-site mapping in OGD cardiomyocytes

    PMID:27973457 PMID:30230261

    Open questions at the time
    • How PEDF-R signaling connects to PKCα activation not traced
    • In vivo cardioprotection contribution of mitophagy not quantified
  18. 2019 Medium

    Pathway dissection showed PEDF triggers protective autophagy in endothelial cells via p53→sestrin2→mTOR inhibition and induces 34-mer-driven apoptosis in prostate cancer through the laminin receptor, FasL and PPARγ, defining receptor-specific survival/death outcomes.

    Evidence sequential siRNA knockdowns, autophagy markers, caspase-8 activation and laminin-receptor blockade with xenograft

    PMID:25261795 PMID:31173218

    Open questions at the time
    • Why PEDF promotes survival in some cells and apoptosis in others mechanistically unresolved
    • Direct PEDF-laminin receptor binding not structurally characterized
  19. 2021 Medium

    Direct binding of PEDF to VEGFR-1 and VEGFR-2 extracellular domains, blocking specific receptor phosphorylation sites and downstream signaling, provided a defined molecular mechanism for its anti-angiogenic activity validated across multiple tumor and ocular settings.

    Evidence direct binding assay and phosphorylation-site Western blots with endothelial functional assays; antibody-neutralization in iCCA and corneal models

    PMID:29075761 PMID:34329660 PMID:34742690

    Open questions at the time
    • Stoichiometry and structural basis of PEDF-VEGFR binding not resolved
    • Integration of VEGFR blockade with γ-secretase and receptor-dissociation mechanisms not reconciled
  20. 2022 High

    A Serpinf1-/- mouse model defined PEDF as a functional antagonist of TGF-β signaling in osteoblasts, explaining delayed maturation, defective mineralization and increased bone vascularization in PEDF loss and linking the OI type VI phenotype to a signaling pathway.

    Evidence Serpinf1-/- mice, primary osteoblast culture, RNA-Seq, vessel-density imaging and recombinant PEDF rescue of TGF-β effects

    PMID:35258129

    Open questions at the time
    • Receptor mediating PEDF-TGF-β antagonism in osteoblasts not identified
    • Relationship between osteoblast TGF-β antagonism and the earlier OPG/osteoclast mechanism not integrated
  21. 2023 Medium

    PEDF was shown to protect RPE cells from ferroptosis by upregulating GPX4 and FTH1, with PEDF-knockout mice developing dry AMD-like pathology, extending PEDF's cytoprotective repertoire to ferroptosis defense.

    Evidence PEDF knockout and overexpression, lipid peroxidation assays, GPX4/FTH1 Western blot and retinal imaging

    PMID:38153666

    Open questions at the time
    • Receptor and signaling cascade upstream of GPX4/FTH1 induction not defined
    • Whether ferroptosis protection is direct or secondary to broader survival signaling unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PEDF selects among its multiple receptors (PEDF-R, PLXDC1/2, VEGFR-1/2, laminin receptor) to produce opposing outcomes (survival vs apoptosis, autophagy vs proliferation arrest) in a given cell type remains the central unresolved question.
  • No unified model of receptor selection or competition
  • Structural basis distinguishing 34-mer vs 44-mer receptor engagement not established
  • How extracellular PEDF accesses nuclear ATGL/COP1 machinery unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 3 GO:0005634 nucleus 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1266738 Developmental Biology 2 R-HSA-9612973 Autophagy 2
Partners
ATGLCOP1FLT1KDRPLXDC1PLXDC2PNPLA2ULK1

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 PEDF is a non-inhibitory serpin: it has characteristics of a substrate rather than an inhibitor of serine proteases, and an N-terminal peptide region provides its neurotrophic function while the serpin exposed loop and oligosaccharides are dispensable for this activity. Structure-function analysis, peptide dissection, serpin biochemical characterization Advances in experimental medicine and biology Medium 9433504
1995 EPC-1/PEDF mRNA is induced under growth arrest (density-dependent contact inhibition and serum deprivation) in early-passage but not senescent WI-38 fibroblasts; the regulation is cell-cycle dependent and expression is limited to specific cell types with conserved genomic sequences across mammalian species. Northern blot, serum stimulation/starvation experiments, interspecies Southern blot Journal of cellular physiology Medium 7814443
2000 Regulation of EPC-1/PEDF expression in fibroblasts is posttranscriptional: transcription rates are unchanged between proliferating, quiescent and senescent cells; regulation occurs at the hnRNA level, and mRNA stability is reduced when cells exit G0. Transcriptional run-on assays, RT-PCR of hnRNA, mRNA stability measurements Journal of cellular biochemistry Medium 10972981
2003 EPC-1/PEDF protein plays a role in G0 growth arrest of human diploid fibroblasts: antibodies blocking EPC-1 increase DNA synthesis in near-plateau early-passage cultures, and addition of recombinant EPC-1 decreases DNA synthesis in logarithmically growing cells; EPC-1 expression is lost with senescence and SV40 transformation. Antibody neutralization, recombinant protein addition, DNA synthesis assay (BrdU/[3H]-thymidine incorporation), Western blot, mRNA analysis Journal of cellular physiology Medium 12599204
1999 PEDF/EPC-1 protein inhibits anchorage-dependent and anchorage-independent proliferation of endometrial carcinoma cells in a dose- and time-dependent manner, but has no effect on stromal fibroblast proliferation; secreted PEDF/EPC-1 levels decline as endometrial stromal fibroblasts age in vitro. Recombinant protein treatment, cell proliferation assays (anchorage-dependent and soft agar), ELISA, Western blot Experimental cell research Medium 10047456
2004 Retinoic acid (ATRA) upregulates PEDF protein and RNA in retinal and endothelial cells through a functional retinoic acid receptor element (RARE) in the PEDF promoter; dexamethasone also increases PEDF RNA levels; conversely, PEDF treatment alters expression of retinoic acid receptors RARα, RXRγ, RARβ and RXRβ in retinal cells. Luciferase reporter assay with PEDF promoter-RARE construct, quantitative PCR, Western blot, ATRA treatment Experimental eye research Medium 15051476
2005 PEDF is a negative acute-phase protein in endotoxin-induced uveitis; intravitreal PEDF injection reduces vascular hyper-permeability in diabetic and oxygen-induced retinopathy models, correlating with decreased retinal VEGF, VEGFR-2, MCP-1, TNF-α, and ICAM-1; siRNA knockdown of PEDF in Müller cells increases VEGF and TNF-α secretion. Western blot, ELISA, intravitreal injection in rat models, siRNA knockdown, cell culture under hypoxia FASEB journal Medium 16368716
2008 PEDF is the predominant fibroblast chemoattractant in mesenchymal stem cell secretome: immunodepletion of PEDF abolishes fibroblast chemotaxis, and reconstitution restores it; PEDF stimulates fibroblast migration (in contrast to its known inhibition of endothelial cell migration). Proteomic identification of secretome, immunodepletion and reconstitution, fibroblast chemotaxis assay, immunofluorescence Journal of cellular biochemistry Medium 18348263
2009 PEDF inhibits osteoclast differentiation, RANKL-mediated survival, and bone resorption activity in a dose-dependent manner; PEDF upregulates osteoprotegerin (OPG) in primary osteoblasts and osteoclast precursor cells, suggesting PEDF inhibits osteoclast function via OPG regulation. In vitro osteoclast differentiation assay, bone resorption assay, Western blot/ELISA for OPG expression Biochemical and biophysical research communications Medium 19945427
2009 PEDF-R, a member of the patatin-like phospholipase domain-containing 2 (PNPLA2) family, is a transmembrane phospholipase A2 on the surface of retina and RPE cells with high-affinity specific binding for PEDF; PEDF binding stimulates PEDF-R phospholipase A2 enzymatic activity, releasing fatty acids. Binding assays, phospholipase A2 enzymatic activity assay, cell surface localization, transmembrane topology analysis Advances in experimental medicine and biology Medium 20237999
2011 PEDF inhibits VEGF-induced vascular permeability via a γ-secretase-dependent pathway: PEDF prevents dissociation of adherens junction (VE-cadherin, β-catenin) and tight junction (claudin-5) proteins, regulates VEGF receptor association with adherens junction proteins, and inhibits phosphorylation of VE-cadherin and β-catenin; γ-secretase inhibitor blocks PEDF's anti-permeability effect. Transendothelial resistance assay, paracellular dextran flux, FITC-albumin leakage in vivo, immunoprecipitation, Western blot, immunohistochemistry with γ-secretase inhibitor PloS one High 21695048
2011 Truncating mutations in SERPINF1 cause autosomal-recessive osteogenesis imperfecta type VI; PEDF loss is associated with severe bone fragility without impairment of collagen folding, posttranslational modification, or secretion, establishing a collagen-independent role for PEDF in bone homeostasis. Exome sequencing, homozygosity mapping, Sanger sequencing, collagen biochemical analysis in dermal fibroblasts American journal of human genetics High 21353196
2011 Loss-of-function mutations in SERPINF1 cause OI type VI, characterized by increased unmineralized osteoid, establishing PEDF involvement in bone mineralization through a mechanism distinct from collagen processing. Homozygosity mapping, next-generation sequencing, clinical bone histomorphometry Journal of bone and mineral research High 21826736
2012 PEDF deficiency combined with oncogenic Kras mutation induces invasive pancreatic ductal adenocarcinoma and adipose-rich stroma in mice; loss of PEDF is associated with enhanced MMP-2 and MMP-9 expression, increased peripancreatic adipocyte hypertrophy, elevated lipid droplet proteins (TIP47, ADRP) and decreased adipose triglyceride lipase. Genetic mouse model (EL-Kras/PEDF-deficient), histology, immunohistochemistry, Western blot, ELISA Gut Medium 22234980
2013 PEDF-R (encoded by PNPLA2) is required for PEDF-mediated retinal cell survival and antiapoptotic activity: the PEDF binding site on PEDF-R is within ectodomain L4 (specifically residues His203-Leu232); siRNA knockdown of PEDF-R abolishes PEDF-mediated cell survival; peptides spanning the binding site block PEDF-PEDF-R interaction and survival activity. Recombinant protein binding assays with truncation mutants, synthetic peptide competition, siRNA knockdown, cell viability assay, cell surface labeling The Journal of biological chemistry High 23818523
2013 Müller cell-secreted PEDF promotes retinal ganglion cell survival through STAT3 activation via PEDF-R (encoded by PNPLA2): neutralization of PEDF in Müller cell conditioned medium attenuates STAT3 activation; ablation of PEDF-R attenuates conditioned medium-induced STAT3 activation and compromises PEDF-exposed cell viability. Conditioned medium transfer, PEDF neutralizing antibody, siRNA knockdown of PEDF-R, Western blot for STAT3 phosphorylation, cell viability assay Cellular physiology and biochemistry Medium 29186716
2014 PLXDC1 and PLXDC2 are identified as cell-surface transmembrane receptors for PEDF: loss-of-function and gain-of-function studies demonstrate cell type-specific receptor activities; PEDF receptors form homooligomers under basal conditions and PEDF dissociates the homooligomer to activate them; mutations in the intracellular domain profoundly affect receptor activity. Loss-of-function and gain-of-function cellular assays, receptor oligomerization studies, intracellular domain mutagenesis eLife High 25535841
2014 PEDF protects RPE cells against oxidative stress by stabilizing mitochondrial networks and function through PI3K/Akt signaling: PEDF unblocks PI3K/Akt and MAPK signaling inhibited by oxidative stress; PI3K/Akt pathway (not MAPK) is specifically required for mitochondrial stabilization; PEDF controls ROS via UCP2 regulation (PEDF-induced UCP2 expression decreases ROS in UCP2-deficient cells). Pharmacological inhibitors (LY294002, SH6, U0126), Western blot, mitochondrial membrane potential and ATP measurements, ROS assay, UCP2-deficient cell rescue Investigative ophthalmology & visual science Medium 25212780
2015 PEDF and its 44-mer peptide stimulate cardiac triglyceride degradation via adipose triglyceride lipase (ATGL): an ATGL-specific inhibitor (atglistatin) and ATGL siRNA knockdown abolish PEDF/44mer-induced triglyceride lipolysis in cardiomyocytes. ATGL pharmacological inhibition, ATGL siRNA knockdown, Oil Red O staining, triglyceride assay, PEDF lentiviral overexpression/knockdown in AMI mouse model Journal of translational medicine Medium 25890298
2015 In-frame SERPINF1 mutations causing OI type VI result in retention of PEDF in the endoplasmic reticulum (for deletion mutations p.F277del and exon 5 deletion) or intracellular degradation (for p.Ala91_Ser93dup) without ER retention; both mechanisms block PEDF secretion; stable expression of p.Ala91_Ser93dup PEDF in osteoblasts decreases collagen type I deposition and mineralization. Immunofluorescence localization in transfected osteoblastic cells, ER stress assay, RT-PCR, mineralization assay in stably transfected MC3T3-E1 cells Bone Medium 25868797
2016 PEDF inhibits NLRP3 inflammasome activation in hypoxic cardiomyocytes through PEDF-R/iPLA2: PEDF reduces Drp1-induced mitochondrial fission, limits cytosolic release of mitochondrial DNA and mitochondrial ROS (which activate NLRP3), acting via PEDF-R/iPLA2 signaling. PEDF-R siRNA knockdown, iPLA2 inhibition, mitochondrial fission assay, NLRP3 inflammasome activation assay, mtDNA and mtROS measurement International journal of molecular sciences Medium 27973457
2016 PEDF and 44-mer peptide reduce oxidative stress and apoptosis in OGD-treated cardiomyocytes via PEDF-R and subsequent PPARγ activation: PEDF-R siRNA or PPARγ antagonist abolishes PEDF/44mer-mediated ROS reduction and anti-apoptotic effects; PEDF/44mer increase LPA, PLA2 activity, and PPARγ expression downstream of PEDF-R. PEDF-R siRNA knockdown, PPARγ antagonist (GW9662), ROS assay, TUNEL/caspase-3 apoptosis assay, ELISA for LPA and PLA2, qPCR and Western blot Biochemical and biophysical research communications Medium 26966066
2017 PEDF is a direct antiangiogenic factor secreted by corneal mesenchymal stromal cells (Co-MSCs): immunoprecipitation removal of PEDF from Co-MSC secretome significantly diminishes antiangiogenic effects; SERPINF1-/- Co-MSCs have significantly reduced antiangiogenic activity compared to wild-type. Immunoprecipitation depletion from secretome, HUVEC tube formation assay, fibrin gel bead assay, SERPINF1-/- mouse-derived Co-MSC comparison, in vivo corneal neovascularization model Investigative ophthalmology & visual science High 29075761
2018 PEDF deficiency (PEDF-/-) in retinal endothelial cells alters proangiogenic properties through changes in cell adhesion mechanisms: PEDF-/- retinal EC are more proliferative, less apoptotic under H2O2 challenge, less migratory and less adherent; PEDF loss increases tenascin-C, fibronectin, thrombospondin-1 and collagen IV and alters integrin expression (α2, αv, β1, β8, αvβ3) and cell-cell adhesion molecules (CD31, ZO-1, occludin). PEDF-/- mouse-derived retinal EC, proliferation/migration/adhesion/apoptosis assays, Western blot for ECM and adhesion proteins, capillary morphogenesis assay American journal of physiology. Cell physiology Medium 28747334
2018 PEDF regulates MTOC number and lipid metabolism in prostate cancer-associated fibroblasts (CAFs) via an ATGL-dependent lipid-MTOC axis: PEDF and ATGL are co-expressed in normal prostate fibroblasts but nearly absent in CAFs; PEDF treatment suppresses lipid content and MTOC amplification in CAFs. Primary human NF and CAF isolation, neutral lipid staining, MTOC quantification by immunofluorescence, PEDF treatment, Western blot for ATGL and PEDF Journal of cell science Medium 29792311
2018 PEDF promotes nuclear degradation of ATGL through COP1-mediated proteasomal degradation in hepatocytes: PEDF (itself present in the nuclear compartment) enhances nuclear import of cytosolic ATGL leading to COP1-dependent polyubiquitylation and proteasomal degradation; this controls hepatocyte lipid accumulation and mobilization. Co-immunoprecipitation, subcellular fractionation, proteasome inhibitor experiments, COP1 knockdown, lipid accumulation assays Biochemical and biophysical research communications Medium 30926171
2018 PEDF promotes mitophagy in OGD-treated cardiomyocytes via a PKCα-ULK1 axis that replaces AMPK: PEDF increases PKCα/p-PKCα, which directly interacts with ULK1 at its serine/threonine-rich domain; phospho-PKCα phosphorylates ULK1 at Ser317/555/777 and Raptor; a ULK1 deletion mutant lacking the PKCα-binding domain is defective in PEDF-induced mitophagy. Co-immunoprecipitation of PKCα-ULK1, ULK1 deletion mutant assay, Western blot for phosphorylation sites, mitochondrial ROS and DNA release measurement, mitophagy assay Journal of cellular and molecular medicine Medium 30230261
2019 PEDF induces PEDF-mediated autophagy in endothelial cells via sequential induction of p53 and sestrin2 with downstream mTOR inhibition: p53 siRNA eliminates sestrin2 induction; p53 or sestrin2 siRNA attenuate PEDF-induced autophagy; PEDF-treated cells show reduced p70S6K and 4E-BP1 phosphorylation (mTOR suppression). p53 and sestrin2 siRNA knockdown, Western blot for LC3 I/II, p62, p70S6K and 4E-BP1 phosphorylation, fluorescence microscopy for autophagosome formation, RT-qPCR Molecular medicine reports Medium 31173218
2019 PEDF 34-mer peptide induces apoptosis in prostate cancer cells via the extrinsic death receptor pathway through the laminin receptor: PEDF34 upregulates FasL and activates caspase-8; FasL knockdown or JNK inhibition attenuates PEDF34-induced apoptosis; PPARγ (not NF-κB) is required for FasL upregulation; blocking the laminin receptor abolishes FasL and PPARγ upregulation by PEDF34. siRNA knockdown (FasL, PPARγ, NF-κB, laminin receptor), pharmacological inhibitors (GW9662, PDTC, JNK inhibitor), caspase-8 activation assay, Western blot, in vivo xenograft Biochemical pharmacology Medium 25261795
2021 PEDF is a direct antiangiogenic factor in intrahepatic cholangiocarcinoma: antibodies blocking PEDF (along with THBS1 and THBS2) restore endothelial tube formation and cell viability inhibited by iCCA extracellular fluid; in transplanted SCID mice, PEDF expression is required for inhibition of blood vessel formation and promotion of lymphangiogenesis. Quantitative proteomics of extracellular fluid, antibody-blocking of PEDF in 3D vascular assembly assay, endothelial migration/proliferation/viability assays, in vivo heterotopic transplantation in SCID mice Journal of hepatology Medium 34329660
2021 PEDF inhibits angiogenesis by binding directly to the extracellular domain of VEGFR-2 and VEGFR-1, blocking VEGF-A-induced phosphorylation of VEGFR-2 at Tyr951 and Tyr1175, and inhibiting downstream signaling through PI3K, AKT, FAK, Src (Y416), and PLC-γ. Direct binding assay (ELISA-type), phosphorylation analysis by Western blot, endothelial cell proliferation/migration/tube formation assays Experimental eye research Medium 34742690
2022 Loss of PEDF in Serpinf1-/- mice activates TGF-β signaling in osteoblasts, delays osteoblast maturation and ECM mineralization, and increases bone vascularization (elevated CD31+/Endomucin+ endothelial cells); PEDF functionally antagonizes TGF-β: TGF-β stimulation and PEDF deficiency have additive effects on suppression of osteogenic markers; exogenous PEDF attenuates TGF-β-induced pro-angiogenic factor expression. Serpinf1-/- mouse model, primary osteoblast culture, RNA-Seq transcriptome, barium sulfate perfusion for vessel density, immunofluorescence for CD31/Endomucin, TGF-β stimulation with recombinant PEDF rescue Journal of bone and mineral research High 35258129
2023 PEDF protects RPE cells from ferroptosis by upregulating GPX4 and ferritin heavy chain-1 (FTH1): overexpression of PEDF increases GPX4 and FTH1 expression, inhibiting lipid peroxidation and RPE ferroptosis in sodium iodate-treated mice; PEDF-knockout mice develop dry AMD-like retinal pathology. PEDF knockout mouse model, PEDF overexpression, lipid peroxidation assay, transmission electron microscopy, Western blot and immunofluorescence for GPX4 and FTH1, electroretinography, OCT GeroScience Medium 38153666
2009 PEDF 34-mer peptide (Asp44-Asn77) carries the anti-angiogenic activity of full-length PEDF: cleaved PEDF and 34-mer peptide inhibit ex vivo vessel sprouting and reduce CNV lesion volumes in rats; the 44-mer peptide (Val78-Thr121) has no antiangiogenic effect in these assays. Chymotrypsin limited proteolysis, ex vivo chick aortic vessel sprouting assay, rat laser-induced CNV model, subconjunctival injection, confocal immunofluorescence Investigative ophthalmology & visual science High 19850839

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Pigment epithelium-derived factor (PEDF) is an endogenous antiinflammatory factor. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 261 16368716
2011 Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. American journal of human genetics 246 21353196
2004 Neuroprotective and antiangiogenic actions of PEDF in the eye: molecular targets and therapeutic potential. Progress in retinal and eye research 198 15302351
2013 The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential. Nature reviews. Cancer 185 23486238
2009 Characterization of PEDF: a multi-functional serpin family protein. Journal of cellular biochemistry 176 19180572
2011 Mutations in SERPINF1 cause osteogenesis imperfecta type VI. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 136 21826736
2015 PEDF and its roles in physiological and pathological conditions: implication in diabetic and hypoxia-induced angiogenic diseases. Clinical science (London, England : 1979) 123 25881671
2006 PEDF: a potential molecular therapeutic target with multiple anti-cancer activities. Trends in molecular medicine 115 16962374
1997 Structure-function studies on PEDF. A noninhibitory serpin with neurotrophic activity. Advances in experimental medicine and biology 92 9433504
2006 Expression of VEGF and PEDF in choroidal neovascular membranes following verteporfin photodynamic therapy. American journal of ophthalmology 82 16815256
2005 The neuroprotective and angiogenesis inhibitory serpin, PEDF: new insights into phylogeny, function, and signaling. Frontiers in bioscience : a journal and virtual library 75 15970483
2021 Thrombospondin 1 and 2 along with PEDF inhibit angiogenesis and promote lymphangiogenesis in intrahepatic cholangiocarcinoma. Journal of hepatology 72 34329660
2014 Identification of PLXDC1 and PLXDC2 as the transmembrane receptors for the multifunctional factor PEDF. eLife 72 25535841
2013 Pigment epithelium-derived factor (PEDF) prevents retinal cell death via PEDF Receptor (PEDF-R): identification of a functional ligand binding site. The Journal of biological chemistry 70 23818523
2009 Pigment epithelium-derived factor (PEDF) as a therapeutic target in cardiovascular disease. Expert opinion on therapeutic targets 70 19694500
2006 Contribution of VEGF and PEDF to choroidal angiogenesis: a need for balanced expressions. Clinical biochemistry 70 16409998
2021 Pigment epithelium-derived factor (PEDF) plays anti-inflammatory roles in the pathogenesis of dry eye disease. The ocular surface 68 33412338
2009 Effects of human recombinant PEDF protein and PEDF-derived peptide 34-mer on choroidal neovascularization. Investigative ophthalmology & visual science 68 19850839
2014 PEDF and PEDF-derived peptide 44mer protect cardiomyocytes against hypoxia-induced apoptosis and necroptosis via anti-oxidative effect. Scientific reports 66 25012184
2012 Concurrent PEDF deficiency and Kras mutation induce invasive pancreatic cancer and adipose-rich stroma in mice. Gut 66 22234980
2011 PEDF regulates vascular permeability by a γ-secretase-mediated pathway. PloS one 65 21695048
2012 Lack of expression of SERPINF1, the gene coding for pigment epithelium-derived factor, causes progressively deforming osteogenesis imperfecta with normal type I collagen. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 64 22113968
2014 PEDF improves mitochondrial function in RPE cells during oxidative stress. Investigative ophthalmology & visual science 60 25212780
2013 PEDF promotes self-renewal of limbal stem cell and accelerates corneal epithelial wound healing. Stem cells (Dayton, Ohio) 60 23553951
2017 Corneal Mesenchymal Stromal Cells Are Directly Antiangiogenic via PEDF and sFLT-1. Investigative ophthalmology & visual science 59 29075761
2009 PEDF regulates osteoclasts via osteoprotegerin and RANKL. Biochemical and biophysical research communications 59 19945427
2012 PEDF inhibits AGE-induced podocyte apoptosis via PPAR-gamma activation. Microvascular research 50 23108227
2008 PEDF from mouse mesenchymal stem cell secretome attracts fibroblasts. Journal of cellular biochemistry 50 18348263
1999 Age-related expression of PEDF/EPC-1 in human endometrial stromal fibroblasts: implications for interactive senescence. Experimental cell research 50 10047456
2007 Adenovirus-mediated PEDF expression inhibits prostate cancer cell growth and results in augmented expression of PAI-2. Cancer biology & therapy 47 17471021
2010 Pigment epithelium-derived factor receptor (PEDF-R): a plasma membrane-linked phospholipase with PEDF binding affinity. Advances in experimental medicine and biology 46 20237999
2009 PEDF inhibits growth of retinoblastoma by anti-angiogenic activity. Cancer science 46 19832843
2016 Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression. Cancer biology & therapy 45 26987032
2010 Anti-chondrosarcoma effects of PEDF mediated via molecules important to apoptosis, cell cycling, adhesion and invasion. Biochemical and biophysical research communications 45 20501323
2013 The many facets of PEDF in drug discovery and disease: a diamond in the rough or split personality disorder? Expert opinion on drug discovery 44 23642051
2017 Ginsenoside-Rb1-Mediated Anti-angiogenesis via Regulating PEDF and miR-33a through the Activation of PPAR-γ Pathway. Frontiers in pharmacology 43 29180961
2014 Mechanisms of PEDF-mediated protection against reactive oxygen species damage in diabetic retinopathy and neuropathy. The Journal of endocrinology 43 24928938
2010 The neuroprotective role of PEDF: implication for the therapy of neurological disorders. Current molecular medicine 43 20236058
2003 Putative role for EPC-1/PEDF in the G0 growth arrest of human diploid fibroblasts. Journal of cellular physiology 43 12599204
2005 Expression of angiogenesis factors in human umbilical vein endothelial cells and their regulation by PEDF. Biochemical and biophysical research communications 42 15582590
2016 PEDF Inhibits the Activation of NLRP3 Inflammasome in Hypoxia Cardiomyocytes through PEDF Receptor/Phospholipase A2. International journal of molecular sciences 41 27973457
2004 Retinoic acid and dexamethasone regulate the expression of PEDF in retinal and endothelial cells. Experimental eye research 41 15051476
2018 Pigment Epithelium-Derived Factor (PEDF) as a Regulator of Wound Angiogenesis. Scientific reports 40 30042381
2017 PEDF improves atherosclerotic plaque stability by inhibiting macrophage inflammation response. International journal of cardiology 40 28262343
2016 Anti-tumor effects of pigment epithelium-derived factor (PEDF): implication for cancer therapy. A mini-review. Journal of experimental & clinical cancer research : CR 39 26746675
2019 PEDF peptides promote photoreceptor survival in rd10 retina models. Experimental eye research 38 30980815
2010 Anti-atherothrombogenic properties of PEDF. Current molecular medicine 38 20236055
2009 Cancer cell apoptotic pathways mediated by PEDF: prospects for therapy. Trends in molecular medicine 38 19783213
2010 The pathophysiological role of PEDF in bone diseases. Current molecular medicine 36 20236053
2010 CFH, VEGF, and PEDF genotypes and the response to intravitreous injection of bevacizumab for the treatment of age-related macular degeneration. Journal of ocular biology, diseases, and informatics 35 21811649
2005 Transscleral-RPE permeability of PEDF and ovalbumin proteins: implications for subconjunctival protein delivery. Investigative ophthalmology & visual science 35 16303924
2004 Loss of EPC-1/PEDF expression during skin aging in vivo. The Journal of investigative dermatology 34 15140209
2017 PEDF plus DHA modulate inflammation and stimulate nerve regeneration after HSV-1 infection. Experimental eye research 33 28642110
2015 PEDF and PEDF-derived peptide 44mer stimulate cardiac triglyceride degradation via ATGL. Journal of translational medicine 33 25890298
2014 PEDF-induced alteration of metabolism leading to insulin resistance. Molecular and cellular endocrinology 33 25462587
2017 TXNDC5 is a cervical tumor susceptibility gene that stimulates cell migration, vasculogenic mimicry and angiogenesis by down-regulating SERPINF1 and TRAF1 expression. Oncotarget 31 29207620
2002 Pigment epithelium-derived factor (PEDF), a serpin with potent anti-angiogenic and neurite outgrowth-promoting properties. Biological chemistry 31 12530532
2023 Enhanced therapeutic effect of PEDF-loaded mesenchymal stem cell-derived small extracellular vesicles against oxygen-induced retinopathy through increased stability and penetrability of PEDF. Journal of nanobiotechnology 30 37684667
2019 Cancer-targeted PEDF-DNA therapy for metastatic colorectal cancer. International journal of pharmaceutics 30 31893541
2016 Mutations and altered expression of SERPINF1 in patients with familial otosclerosis. Human molecular genetics 30 27056980
2019 Novel anti-angiogenic PEDF-derived small peptides mitigate choroidal neovascularization. Experimental eye research 29 31520600
2017 Müller Cell-Derived PEDF Mediates Neuroprotection via STAT3 Activation. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 29 29186716
2016 PEDF inhibits pancreatic tumorigenesis by attenuating the fibro-inflammatory reaction. Oncotarget 29 27058416
2023 Receptors that bind to PEDF and their therapeutic roles in retinal diseases. Frontiers in endocrinology 27 37139333
2023 PEDF protects retinal pigment epithelium from ferroptosis and ameliorates dry AMD-like pathology in a murine model. GeroScience 27 38153666
2021 PEDF is an endogenous inhibitor of VEGF-R2 angiogenesis signaling in endothelial cells. Experimental eye research 27 34742690
1995 Analysis of EPC-1 growth state-dependent expression, specificity, and conservation of related sequences. Journal of cellular physiology 27 7814443
2019 Autophagy: a new mechanism for regulating VEGF and PEDF expression in retinal pigment epithelium cells. International journal of ophthalmology 26 31024806
2018 PEDF expression affects the oxidative and inflammatory state of choroidal endothelial cells. American journal of physiology. Cell physiology 26 29351407
2016 C3a Increases VEGF and Decreases PEDF mRNA Levels in Human Retinal Pigment Epithelial Cells. BioMed research international 26 27747237
2016 Identification of novel targets of diabetic nephropathy and PEDF peptide treatment using RNA-seq. BMC genomics 26 27855634
2000 Regulation of EPC-1/PEDF in normal human fibroblasts is posttranscriptional. Journal of cellular biochemistry 26 10972981
2018 MicroRNA-93 promotes bladder cancer proliferation and invasion by targeting PEDF. Urologic oncology 25 30455080
2014 Proapoptotic PEDF functional peptides inhibit prostate tumor growth--a mechanistic study. Biochemical pharmacology 25 25261795
2008 PEDF as an emerging therapeutic candidate for osteosarcoma. Current cancer drug targets 25 19075591
2012 Cell and molecular biology underpinning the effects of PEDF on cancers in general and osteosarcoma in particular. Journal of biomedicine & biotechnology 24 22690122
2018 PEDF regulates plasticity of a novel lipid-MTOC axis in prostate cancer-associated fibroblasts. Journal of cell science 23 29792311
2018 Chemerin and PEDF Are Metaflammation-Related Biomarkers of Disease Activity and Obesity in Rheumatoid Arthritis. Frontiers in medicine 22 30123797
2017 PEDF expression affects retinal endothelial cell proangiogenic properties through alterations in cell adhesive mechanisms. American journal of physiology. Cell physiology 22 28747334
2016 Novel Mutations in SERPINF1 Result in Rare Osteogenesis Imperfecta Type VI. Calcified tissue international 22 27796462
2020 Pigment Epithelium-Derived Factor (PEDF) Receptors Are Involved in Survival of Retinal Neurons. International journal of molecular sciences 21 33396450
2016 pEPito-driven PEDF Expression Ameliorates Diabetic Retinopathy Hallmarks. Human gene therapy methods 21 26942449
2015 The effect of SERPINF1 in-frame mutations in osteogenesis imperfecta type VI. Bone 21 25868797
2014 Hormonal regulation of pigment epithelium-derived factor (PEDF) expression in the endometrium. Molecular and cellular endocrinology 21 24769282
1998 Structural and comparative analysis of the mouse gene for pigment epithelium-derived factor (PEDF). Molecular vision 21 9565647
2020 PEDF promotes the repair of bone marrow endothelial cell injury and accelerates hematopoietic reconstruction after bone marrow transplantation. Journal of biomedical science 20 32873283
2020 Epigallocatechin-3-Gallate and PEDF 335 Peptide, 67LR Activators, Attenuate Vasogenic Edema, and Astroglial Degeneration Following Status Epilepticus. Antioxidants (Basel, Switzerland) 20 32933011
2019 The contrary intracellular and extracellular functions of PEDF in HCC development. Cell death & disease 20 31582735
2019 Signaling Mechanisms Involved in PEDF-Mediated Retinoprotection. Advances in experimental medicine and biology 20 31884652
2015 Recombinant pigment epithelium-derived factor PEDF binds vascular endothelial growth factor receptors 1 and 2. In vitro cellular & developmental biology. Animal 20 25948043
2013 PEDF expression regulates the proangiogenic and proinflammatory phenotype of the lung endothelium. American journal of physiology. Lung cellular and molecular physiology 20 24318110
2020 PEDF deficiency increases the susceptibility of rd10 mice to retinal degeneration. Experimental eye research 19 32721425
2019 p53 mediates PEDF‑induced autophagy in human umbilical vein endothelial cells through sestrin2 signaling. Molecular medicine reports 19 31173218
2024 Tissue-targeted and localized AAV5-DCN and AAV5-PEDF combination gene therapy abrogates corneal fibrosis and concurrent neovascularization in rabbit eyes in vivo. The ocular surface 18 38191093
2021 MiR-186-5p Dysregulation Leads to Depression-like Behavior by De-repressing SERPINF1 in Hippocampus. Neuroscience 18 34648865
2019 PEDF promotes nuclear degradation of ATGL through COP1. Biochemical and biophysical research communications 18 30926171
2018 PKCα replaces AMPK to regulate mitophagy: Another PEDF role on ischaemic cardioprotection. Journal of cellular and molecular medicine 18 30230261
2016 PEDF and PEDF-derived peptide 44mer inhibit oxygen-glucose deprivation-induced oxidative stress through upregulating PPARγ via PEDF-R in H9c2 cells. Biochemical and biophysical research communications 18 26966066
2022 Antagonism Between PEDF and TGF-β Contributes to Type VI Osteogenesis Imperfecta Bone and Vascular Pathogenesis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 17 35258129
2018 PEDF Reduces the Severity of Herpetic Simplex Keratitis in Mice. Investigative ophthalmology & visual science 17 30025136

Missed literature

Know a paper Affinage missed for SERPINF1? Flag it for the maintainers and the community.

No submissions yet.