Affinage

IGFBP3

Insulin-like growth factor-binding protein 3 · UniProt P17936

Length
291 aa
Mass
31.7 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IGFBP-3 is a multifunctional secreted glycoprotein that serves as the principal circulating carrier for IGF-I and IGF-II, sequestering IGFs with ~50 pM affinity to regulate their bioavailability and half-life, while also exerting extensive IGF-independent signaling through nuclear translocation, receptor engagement, and intracellular protein interactions (PMID:7683528, PMID:28330997). Its transcription is induced by p53, HIF-1α, TGF-β, BMP2, and METTL3-mediated m6A modification, and its proteolytic degradation by proteases such as ADAM28 releases free IGF-I to drive proliferation (PMID:22415309, PMID:10873390, PMID:32975335, PMID:30429106). In the nucleus, IGFBP-3 forms complexes with EGFR, DNA-PKcs, NONO, and SFPQ to promote NHEJ-dependent DNA double-strand break repair, facilitates nuclear export of the pro-apoptotic Nur77/RXRα complex, mediates SUMOylation-dependent nuclear translocation of IGF-1R, and regulates mitochondrial homeostasis through the BNIP3L/NIX mitophagy receptor (PMID:30725116, PMID:26340041, PMID:30078228, PMID:34918377). IGFBP-3 signals through the death receptor TMEM219 to induce pancreatic beta cell apoptosis, and TMEM219 ablation or IGFBP-3 blockade preserves beta cell mass and delays diabetes onset in preclinical models (PMID:35115561).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 High

    Establishing IGFBP-3 as a high-affinity IGF-I carrier that extends IGF half-life in vivo resolved how circulating IGFs are stabilized and buffered from rapid clearance.

    Evidence Recombinant glycosylated and non-glycosylated IGFBP-3 binding assays (BIA, competition binding) plus rat in vivo pharmacokinetics with gel filtration

    PMID:7683528

    Open questions at the time
    • Ternary complex formation with ALS not directly characterized in this study
    • Tissue-specific release kinetics not addressed
  2. 1996 High

    Mapping protease-generated IGFBP-3 fragments with distinct IGF- versus heparin-binding capacities revealed that proteolysis is not merely degradation but a mechanism to generate functionally distinct modules.

    Evidence Plasmin/thrombin digestion with N-terminal sequencing and ligand blotting for IGF and heparin binding

    PMID:8843739

    Open questions at the time
    • Physiological protease(s) responsible in vivo not identified
    • Fragment stability and clearance in circulation not measured
  3. 2000 High

    Demonstrating that p53 and TGF-β1 transcriptionally induce IGFBP-3 placed it at the intersection of tumor suppression and growth factor signaling, revealing context-dependent growth-inhibitory and growth-stimulatory roles.

    Evidence Antisense oligonucleotide and neutralizing antibody blockade of IGFBP-3 abolished TGF-β1-induced proliferation in airway smooth muscle cells; p53-IGFBP3 transcriptional activation established by promoter studies

    PMID:10710527 PMID:10873390

    Open questions at the time
    • Direct p53 binding site on IGFBP3 promoter not mapped in these studies
    • Mechanism by which IGFBP-3 switches between growth promotion and inhibition unresolved
  4. 2007 High

    Using IGF-binding-deficient IGFBP-3 mutants in xenografts dissected the IGF-dependent tumor suppressor activity from an IGF-independent growth-stimulatory activity, establishing that IGFBP-3 is bifunctional in cancer.

    Evidence Wild-type vs. Ile56Gly/Leu80Gly/Leu81Gly mutant IGFBP-3 in Ras-transformed esophageal cell xenografts with AKT/IGF-1R signaling readouts

    PMID:17457048

    Open questions at the time
    • Receptor or target mediating the IGF-independent growth-stimulatory effect not identified
    • Relevance beyond esophageal cancer not tested
  5. 2012 High

    Identifying a distal HIF-1α-bound HRE 57 kb upstream of IGFBP3 and showing cap-independent polysomal loading of IGFBP3 mRNA under hypoxia explained how IGFBP-3 protein levels are maintained when global translation is suppressed.

    Evidence ChIP for HIF-1α, HIF-1α/HIF-2α RNAi, reporter assays, polysome fractionation, and metabolic labeling in esophageal cancer cells

    PMID:22415309

    Open questions at the time
    • IRES or other cap-independent translation element in IGFBP3 mRNA not mapped
    • Whether this mechanism operates in non-cancer hypoxic tissues unknown
  6. 2013 High

    Discovering that IGFBP-3 physically interacts with RXRα and facilitates Nur77 nuclear export to the cytoplasm for pro-apoptotic action revealed a direct intracellular apoptosis-promoting mechanism independent of IGF sequestration.

    Evidence Reciprocal Co-IP, siRNA knockdown, nuclear fractionation, immunofluorescence, and caspase-3/7 activity assays

    PMID:26340041

    Open questions at the time
    • Structural basis of IGFBP-3/RXRα/Nur77 ternary complex unknown
    • Whether Nur77 export depends on IGFBP-3 nuclear import via importin-β1 not tested
  7. 2013 High

    Demonstrating that IGFBP-3 feeds back on TGF-β1 signaling by attenuating ERK/Akt activation and enhancing non-canonical Smad2 linker phosphorylation established IGFBP-3 as a context-dependent modulator of Smad versus non-Smad TGF-β outputs.

    Evidence IGFBP-3 siRNA with western blot for phospho-ERK, phospho-Akt, and phospho-Smad2 (Ser245/250/255) in osteosarcoma cells

    PMID:23831640

    Open questions at the time
    • Direct physical interaction between IGFBP-3 and TGF-β signaling components not shown
    • Generalizability beyond osteosarcoma untested
  8. 2015 Medium

    Showing that humanin competes with importin-β1 for IGFBP-3 binding and blocks nuclear translocation identified the nuclear import pathway and a mechanism of IGFBP-3 functional regulation.

    Evidence Competitive binding assays (dot blot, Co-IP, ELISA) plus apoptosis rescue in lung adenocarcinoma cells

    PMID:26216267

    Open questions at the time
    • IGFBP-3 NLS mapping not performed
    • Whether humanin regulation operates physiologically at endogenous concentrations unclear
  9. 2018 Medium

    Identifying ADAM28 as a protease that degrades IGFBP-3 to release free IGF-I in AML provided a disease-relevant proteolytic activation mechanism by which tumors co-opt the IGF axis.

    Evidence ADAM28 knockout xenotransplantation model, IGFBP-3 degradation assay, IGF-I signaling measurement

    PMID:30429106

    Open questions at the time
    • Cleavage site(s) on IGFBP-3 not mapped
    • Contribution relative to other IGFBP-3 proteases in AML not assessed
  10. 2018 Medium

    Demonstrating that IGFBP-3 mediates IGF-1R nuclear translocation via SUMO2/3-dependent SUMOylation under stress revealed a non-canonical mechanism coupling the IGF axis to nuclear signaling independent of PI3K/Akt.

    Evidence Immunofluorescence, nuclear fractionation, SUMOylation assay, siRNA knockdown, and cell cycle analysis in corneal epithelial cells

    PMID:30078228

    Open questions at the time
    • SUMOylation site on IGF-1R not identified
    • Functional consequence of nuclear IGF-1R downstream of IGFBP-3 not characterized
  11. 2019 High

    Identifying a nuclear IGFBP-3/NONO/SFPQ/EGFR/DNA-PKcs complex required for NHEJ-mediated DSB repair — and showing PARP inhibitor sensitivity — established IGFBP-3 as a scaffold in the DNA damage response with therapeutic implications.

    Evidence LC-MS/MS interactome, Co-IP, proximity ligation assay, cell-free end-joining assay, γH2AX foci measurement, pharmacological and siRNA perturbation in TNBC cells

    PMID:30725116

    Open questions at the time
    • Structural basis of scaffold assembly unknown
    • Whether IGFBP-3 DNA repair function operates in non-cancer contexts not tested
    • Relative contribution of intracellular versus secreted IGFBP-3 pools to repair unclear
  12. 2020 High

    Demonstrating that IGFBP-3 signals through the death receptor TMEM219 to cause beta cell apoptosis, and that genetic or pharmacological blockade prevents diabetes, defined a receptor-mediated pro-death pathway with direct disease relevance.

    Evidence TMEM219 genetic ablation and pharmacological IGFBP3/TMEM219 inhibition in T1D/T2D preclinical models with diabetes onset monitoring

    PMID:35115561

    Open questions at the time
    • Downstream signaling cascade from TMEM219 not fully delineated
    • Human clinical validation of TMEM219 blockade pending
  13. 2020 High

    Elucidating the TGF-β/GIPC → epigenetic (H3K27ac/me3) → IGFBP-3 → integrin/Akt cascade in hepatic stellate cells, validated by Igfbp3 knockout reducing portal pressure, linked IGFBP-3 to liver fibrosis pathogenesis.

    Evidence RNA-seq, ChIP for H3K27ac/me3, Igfbp3 global knockout mouse with portal pressure measurement and HSC migration assays

    PMID:32447051

    Open questions at the time
    • Which integrin(s) transduce IGFBP-3's migration signal not identified
    • Cell-autonomous versus paracrine contribution in vivo not separated
  14. 2020 Medium

    Showing that intracellular IGFBP-3 activates THBS1 transcription to inhibit angiogenesis, with THBS1 knockdown reversing the effect, identified THBS1 as a key effector of IGFBP-3's anti-angiogenic function.

    Evidence Inducible IGFBP3 overexpression, THBS1 promoter luciferase assay, THBS1 siRNA rescue, HUVEC tube formation, CAM assay, xenograft vascular assessment

    PMID:32642286

    Open questions at the time
    • Transcription factor mediating IGFBP-3's activation of THBS1 promoter not identified
    • Whether IGFBP-3 binds THBS1 promoter directly not tested
  15. 2022 Medium

    Identifying IGFBP-3 as a regulator of the BNIP3L/NIX short isoform and mitochondrial cristae morphology established it as a modulator of mitophagy and mitochondrial quality control.

    Evidence IGFBP-3 siRNA and overexpression with sBNIP3L/NIX western blot, mitochondrial respiration measurement, nuclear fractionation, and electron microscopy in corneal epithelial cells

    PMID:34918377

    Open questions at the time
    • Mechanism by which IGFBP-3 controls sBNIP3L/NIX isoform expression unknown
    • Whether this mitophagy function is tissue-specific not explored
  16. 2023 Medium

    Demonstrating that METTL3-mediated m6A modification of IGFBP3 mRNA drives cardiac fibroblast activation added an epitranscriptomic regulatory layer to IGFBP-3 biology in cardiac fibrosis.

    Evidence METTL3 shRNA knockdown, m6A methylation analysis, TGF-β1 stimulation, fibroblast assays, and TAC/isoproterenol mouse models

    PMID:36657656

    Open questions at the time
    • Specific m6A site(s) on IGFBP3 mRNA not mapped
    • m6A reader protein mediating IGFBP3 mRNA stabilization not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for IGFBP-3's nuclear scaffolding functions, the signaling cascade downstream of TMEM219, the mechanism governing the switch between IGF-dependent and IGF-independent activities, and the relative contributions of intracellular versus extracellular IGFBP-3 pools to its diverse biological functions.
  • No atomic-resolution structure of IGFBP-3 in complex with nuclear partners
  • TMEM219 downstream signaling intermediates remain uncharacterized
  • Context determinants of pro-growth versus pro-apoptotic switching undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 5 GO:0005576 extracellular region 4 GO:0005739 mitochondrion 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-5357801 Programmed Cell Death 5 R-HSA-1643685 Disease 4 R-HSA-73894 DNA Repair 1
Partners
EGFRIGF1NONONR4A1PRKDCRXRASFPQTMEM219
Complex memberships
IGFBP-3/IGF/ALS ternary circulating complexIGFBP-3/NONO/SFPQ/EGFR/DNA-PKcs NHEJ repair complexIGFBP-3/Nur77/RXRα nuclear export complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Glycosylated and non-glycosylated forms of recombinant IGFBP-3 bind IGF-I with equal affinity (Kd ~50 pM), and both forms extend IGF-I half-life in vivo by forming a 40–140 kDa circulating complex; glycosylation delays peak IGF-I levels post-injection but does not alter overall bioavailability. Competition binding assay, real-time biospecific interaction analysis (BIA), in vivo subcutaneous injection in rats with gel filtration of serum Growth regulation High 7683528
1996 Proteolysis of IGFBP-3 by plasmin, thrombin, and pregnancy serum generates multiple fragments with differential IGF-binding and heparin-binding capacities; the dominant mid-fragment retains both IGF and heparin affinity, while NH2-terminal fragments retain only IGF affinity, demonstrating structural separation of binding domains. Protease digestion, N-terminal sequencing of fragments, ligand blotting for IGF and heparin binding The American journal of physiology High 8843739
1998 Hepatic IGFBP-3 gene transcription is regulated by insulin through an insulin-responsive element that recruits insulin-responsive nuclear factors (demonstrated by gel mobility shift and southwestern blot), while IGF-I increases IGFBP-3 mRNA stability in hepatic non-parenchymal cells. In vitro transcription, gel mobility shift assay, southwestern blot, mRNA stability assay Progress in nucleic acid research and molecular biology Medium 9594576
2000 IGFBP-3 mediates TGF-β1-induced cell growth (not only inhibition) in human airway smooth muscle cells; TGF-β1 induces a 10–20-fold increase in IGFBP-3 expression, and blocking IGFBP-3 with antisense oligomers or neutralizing antibody abolishes TGF-β1-induced proliferation. Antisense oligonucleotide knockdown, neutralizing antibody, cell proliferation assay, mRNA/protein expression analysis American journal of physiology. Lung cellular and molecular physiology High 10710527
2000 IGFBP-3 is a transcriptional target of p53; genotoxic stress activates p53, which induces IGFBP-3 expression, linking p53-mediated apoptosis to the IGF axis through IGFBP-3 induction. Transcriptional regulation analysis, p53 pathway studies (reviewed with cited experimental evidence) Molecular genetics and metabolism Medium 10873390
2007 IGFBP-3 suppresses esophageal tumor formation via IGF-dependent mechanisms (blocking IGF-1R and AKT activation) as shown by IGF-binding mutant IGFBP-3 (Ile56Gly/Leu80Gly/Leu81Gly) losing tumor suppressor activity in vivo, while the mutant also reveals an IGF-independent growth-stimulatory activity. Stable transduction of wild-type vs. IGF-binding mutant IGFBP-3 in Ras-transformed human esophageal cells, xenograft tumor formation, in vivo bioluminescence imaging, AKT/IGF-1R signaling assays Cancer biology & therapy High 17457048
2008 IGFBP-3 regulates the appearance of senescence biomarkers in human diploid fibroblasts; siRNA knockdown of IGFBP-3 attenuates stress-induced premature senescence following repeated oxidative insults. siRNA knockdown, DNA array screening, senescence biomarker assays Free radical biology & medicine Medium 18329388
2009 IGFBP3 co-localizes with hypocretin/orexin in hypothalamic neurons and overexpression of IGFBP3 in transgenic mice decreases hypocretin mRNA and peptide levels and increases sleep, likely through decreased hypocretin promoter activity. Transgenic mouse overexpression, mRNA expression analysis, hypocretin peptide measurement, sleep phenotyping, promoter activity assay PloS one Medium 19158946
2012 Hypoxia induces IGFBP3 in esophageal squamous cancer cells through HIF-1α (but not HIF-2α) binding to a novel hypoxia-responsive element (HRE) 57 kb upstream of the transcription start site; under hypoxia, global cap-dependent translation is suppressed but IGFBP3 mRNA remains enriched in polysomes allowing continued synthesis. RNAi (HIF-1α vs HIF-2α), chromatin immunoprecipitation, transfection reporter assays, metabolic labeling, 7-methyl GTP-cap binding assay, mTOR pharmacological inhibition, polysome fractionation FASEB journal High 22415309
2013 IGFBP-3 interacts with the retinoid X receptor-α (RXRα) and facilitates phosphorylation and nuclear export of the orphan nuclear receptor Nur77 to the cytoplasm in response to apoptotic stimuli, where Nur77 exerts its pro-apoptotic effect; IGFBP-3 knockdown attenuates caspase-3/7 activation and Nur77 nuclear export. Co-immunoprecipitation, siRNA knockdown, indirect immunofluorescence, cell fractionation, caspase activity assay Endocrinology (2015 paper) High 26340041
2013 TGF-β1 induces IGFBP-3 expression in osteosarcoma cells, and IGFBP-3 then attenuates TGF-β1 activation of ERK1/2 and Akt, inhibits TGF-β1-induced cell cycle progression, and enhances non-canonical Smad2 phosphorylation at Ser245/250/255; blocking IGFBP-3 induction enhances pSmad2 nuclear accumulation, revealing a negative-feedback loop. IGFBP-3 siRNA, IGF1R inhibition, western blotting for ERK, Akt, Smad2 phosphorylation, cell cycle analysis, proliferation assay Molecular and cellular endocrinology High 23831640
2013 IGFBP-3 signals through a specific IGFBP-3 receptor on retinal endothelial cells; overexpression of IGFBP-3 upregulates its receptor, and siRNA knockdown of the receptor abolishes IGFBP-3's anti-apoptotic effect, demonstrating receptor-dependent signaling to regulate Bcl-xL, Bax, cytochrome C, and Akt. Co-immunoprecipitation, co-localization, siRNA knockdown of IGFBP-3 receptor, western blotting, cell death ELISA, caspase-3 ELISA Apoptosis Medium 23291901
2013 Novel ligands of IGFBP-3 include the retinoid X receptor, retinoic acid receptor-α, Nur77, vitamin D receptor, PPARγ, TGFβ/Smad signaling components, LRP1, TMEM219, EGFR, DNA-PK, and GRP78; these interactions mediate IGF-independent functions including apoptosis (via caspase-8 and -9), DNA DSB repair, and autophagy. Multiple binding and functional studies cited in review including Co-IP, cell-free binding assays, and loss-of-function experiments Journal of cell communication and signaling Medium 23700234
2015 Humanin peptide directly binds IGFBP-3 (Kd ~5.05 µM) and competitively inhibits IGFBP-3 binding to importin-β1 (IC50 ~18.1 µM), thereby blocking nuclear translocation of IGFBP-3 and attenuating IGFBP-3-induced apoptosis in lung adenocarcinoma cells. Competitive ligand dot blotting, co-immunoprecipitation, ELISA-based binding assay, apoptosis assay Protein and peptide letters Medium 26216267
2016 Pancreatic cancer cell-derived IGFBP-3 causes muscle wasting by inhibiting IGF signaling, impairing myogenesis, and enhancing protein degradation in muscle cells; conditioned medium from IGFBP3-knockdown pancreatic cancer cells or IGFBP-3 antibody neutralization reverses these effects. siRNA knockdown, conditioned medium transfer, IGFBP-3 neutralizing antibody, myogenesis assays, protein degradation assays, C2C12 muscle cell biochemical assays Journal of experimental & clinical cancer research High 26975989
2017 IGFBP3 modulates lung tumor growth through IGF1 signaling; Igfbp3-null mice show >2-fold increased lung tumor burden in a Kras model, and overexpression of wild-type IGFBP3 (but not an IGF-binding mutant) in NSCLC cells induces apoptosis (10-fold increase in cleaved caspase-3) and inactivates IGF1 and MAPK signaling. Igfbp3 knockout mouse crossed with Kras lung tumor model, wild-type vs. IGF-binding mutant IGFBP3 overexpression, caspase-3 cleavage assay, IGF1/MAPK signaling analysis Molecular cancer research High 28330997
2018 IGFBP-3 mediates nuclear translocation of IGF-1R in corneal epithelial cells under serum-free/stress conditions via SUMO 2/3-mediated SUMOylation; IGFBP-3 and IGF-1R undergo reciprocal regulation independent of PI3K/Akt, with IGFBP-3 arresting the cell cycle in G0/G1 and maintaining nuclear IGF-1R levels under stress. Immunofluorescence, nuclear fractionation, SUMOylation assay, siRNA knockdown, cell cycle analysis Journal of cellular physiology Medium 30078228
2019 IGFBP-3 forms nuclear complexes with NONO and SFPQ (non-POU domain-containing octamer-binding protein and splicing factor, proline/glutamine-rich) in a PARP-dependent and EGFR/DNA-PKcs-dependent manner in triple-negative breast cancer cells in response to DNA damage; these complexes promote DSB repair by NHEJ and are blocked by PARP inhibitors; LINP1 lncRNA is required for complex formation. LC-MS/MS interactome, co-immunoprecipitation, proximity ligation assay, cell-free biochemical binding assay, DNA end-joining in vitro assay, γH2AX foci measurement, pharmacological inhibitors, siRNA knockdown Cellular and molecular life sciences High 30725116
2019 ROS- and HIF-1α-dependent upregulation of IGFBP3 under high-glucose/hyperglycemic conditions sequesters extracellular IGF1 from the IGF1 survival pathway, blocking IGF1R signaling and leading to cardiomyocyte apoptosis; PHD inhibition stabilizes HIF1α to drive this cascade. Co-IP assay, western blotting, siRNA knockdown, gain/loss-of-function, pharmacological inhibitors, hyperglycemic cell models and diabetic rat in vivo Journal of cellular physiology Medium 30659610
2020 TGF-β increases IGFBP-3 expression in hepatic stellate cells (HSCs) through GIPC/synectin via epigenetic changes (increased H3K27 acetylation, decreased H3K27me3); IGFBP-3 in turn promotes HSC migration through integrin-dependent phosphorylation of Akt; global Igfbp3 knockout mice show attenuated HSC activation and reduced portal pressure. mRNA sequencing, ELISA, qPCR, targeted chromatin immunoprecipitation (H3K27ac/me3), western blot, Igfbp3 global knockout mouse, portal pressure measurement, in vitro migration assay Cellular and molecular gastroenterology and hepatology High 32447051
2020 IGFBP3 signaling through the death receptor TMEM219 on pancreatic beta cells causes beta cell loss and dysfunction; TMEM219 genetic ablation or short-term IGFBP3/TMEM219 inhibition preserves beta cells and prevents/delays diabetes onset, while long-term blockade allows beta cell expansion. TMEM219 genetic ablation, pharmacological IGFBP3/TMEM219 inhibition in vitro and in vivo, diabetes onset monitoring in T1D/T2D preclinical models, human patient cohort correlation Nature communications High 35115561
2020 BMP2 upregulates IGFBP3 in human endometrial stromal cells through ALK3 receptor and ID1 as an intermediary; IGFBP3 in turn promotes MMP2 expression and cell migration; knockdown of either IGFBP3 or ID1 abolishes BMP2-induced MMP2 upregulation and migration. siRNA knockdown of ALK3, ID1, and IGFBP3, dose-response and time-course expression studies, cell migration assay in human endometrial stromal cells FASEB journal High 32975335
2020 Hepatic stellate cell-derived IGFBP3 directly induces lipid droplet formation, triglyceride accumulation, and lipogenic gene expression in hepatocytes in vitro; recombinant IGFBP3 treatment phenocopies and IGFBP3 serum levels are elevated in alcoholic hepatitis patients. HSC supernatant transfer, adipokine antibody array, recombinant IGFBP3 treatment of hepatocytes, triglyceride assay, lipid droplet staining, lipogenic gene expression, NRP-1 HSC-selective knockout mouse model Journal of hepatology Medium 32087348
2022 IGFBP-3 acts as a molecular switch regulating mitochondrial homeostasis in corneal epithelial cells by controlling the short isoform of the BNIP3L/NIX mitophagy receptor; both loss and gain of IGFBP-3 function increase mitochondrial respiration associated with nuclear accumulation of IGFBP-3, and IGFBP-3 regulates lamellar cristae morphology and mitochondrial dynamics. IGFBP-3 siRNA knockdown and overexpression, mitophagy receptor (sBNIP3L/NIX) western blotting, mitochondrial respiration measurement, nuclear fractionation, electron microscopy of cristae morphology FASEB journal Medium 34918377
2023 METTL3-mediated m6A RNA modification upregulates IGFBP3 expression in cardiac fibroblasts; METTL3 silencing downregulates IGFBP3 and inhibits cardiac fibroblast activation, migration and proliferation both in vitro and in vivo in TAC and isoproterenol cardiac fibrosis models. RNA-seq, shRNA knockdown of METTL3, m6A methylation analysis, TGF-β1 stimulation, fibroblast migration and proliferation assays, in vivo mouse cardiac fibrosis models European journal of pharmacology Medium 36657656
2018 ADAM28 metalloprotease degrades IGFBP-3, thereby increasing free IGF-I availability and promoting IGF-I-induced proliferation and migration of acute myeloid leukemia cells; ADAM28 knockout in a xenotransplantation mouse model reduces leukemic cell growth and dissemination. ADAM28 knockout, IGFBP-3 degradation assay, IGF-I signaling measurement, xenotransplantation mouse model, proliferation and migration assays Cancer letters Medium 30429106
2020 IGFBP-3 induces apoptosis in chondrocytes through nucleus-to-mitochondria translocation of the nuclear receptor Nur77, mechanistically linking IGFBP-3 to osteoarthritis pathogenesis. Exogenous recombinant IGFBP-3 treatment of cultured chondrocytes, CCK-8 assay, flow cytometry, laser confocal microscopy for Nur77 localization International journal of clinical and experimental pathology Low 26884829
2020 IGFBP-3 inhibits angiogenesis through intracellular regulation of THBS1 (thrombospondin-1) expression via THBS1 promoter activation; intracellular IGFBP-3 shows stronger THBS1 promoter activation than extracellular IGFBP-3, and THBS1 silencing reverses IGFBP3-mediated inhibition of tube formation and blood vessel development. Inducible IGFBP3 overexpression in ovarian cancer cells, HUVEC capillary tube formation assay, CAM assay, luciferase promoter assay, THBS1 siRNA rescue, in vivo xenograft with vascular assessment American journal of cancer research Medium 32642286
2018 Epac1 activates IGFBP-3, which increases SIRT1 levels, leading to deacetylation of HMGB1 in retinal endothelial cells; IGFBP-3 siRNA abolishes the ability of an Epac1 agonist to reduce HMGB1 acetylation and SIRT1 levels, placing IGFBP-3 as a required intermediary in this signaling pathway. Epac1 conditional knockout mice, siRNA knockdown of IGFBP-3 and SIRT1, immunoprecipitation for acetylated HMGB1, western blot, ELISA Molecular vision Medium 30581279

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. The Lancet. Oncology 518 20472501
2014 MicroRNA-21 promotes glioblastoma tumorigenesis by down-regulating insulin-like growth factor-binding protein-3 (IGFBP3). The Journal of biological chemistry 136 25059666
2015 Insulin-like growth factor binding-protein-3 (IGFBP-3). Best practice & research. Clinical endocrinology & metabolism 128 26522455
2005 Essential roles of IGFBP-3 and IGFBP-rP1 in breast cancer. European journal of cancer (Oxford, England : 1990) 120 15979304
2004 Associations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 93 15247132
2000 P53 and IGFBP-3: apoptosis and cancer protection. Molecular genetics and metabolism 84 10873390
1998 Molecular regulation of insulin-like growth factor-I and its principal binding protein, IGFBP-3. Progress in nucleic acid research and molecular biology 82 9594576
2006 Characterization of the expression of the hypoxia-induced genes neuritin, TXNIP and IGFBP3 in cancer. FEBS letters 80 16723126
2008 Progesterone regulates FGF10, MET, IGFBP1, and IGFBP3 in the endometrium of the ovine uterus. Biology of reproduction 78 18753603
2013 Insulin-like growth factor binding protein-3 (IGFBP-3): Novel ligands mediate unexpected functions. Journal of cell communication and signaling 77 23700234
2020 Salvianolic acid B improves myocardial function in diabetic cardiomyopathy by suppressing IGFBP3. Journal of molecular and cellular cardiology 74 31982427
2016 Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits. Aging cell 70 27329260
2019 IGFBP-3 interacts with NONO and SFPQ in PARP-dependent DNA damage repair in triple-negative breast cancer. Cellular and molecular life sciences : CMLS 69 30725116
2000 IGFBP-3 mediates TGF-beta1-induced cell growth in human airway smooth muscle cells. American journal of physiology. Lung cellular and molecular physiology 67 10710527
2017 MicroRNA-34/449 targets IGFBP-3 and attenuates airway remodeling by suppressing Nur77-mediated autophagy. Cell death & disease 63 28796252
2001 IGFBP-3 and apoptosis--a license to kill? Apoptosis : an international journal on programmed cell death 61 11388669
2009 IGFBP3 colocalizes with and regulates hypocretin (orexin). PloS one 60 19158946
2014 IGFBP-3: a cell fate pivot in cancer and disease. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 59 24953254
2012 Low-level laser irradiation affects the release of basic fibroblast growth factor (bFGF), insulin-like growth factor-I (IGF-I), and receptor of IGF-I (IGFBP3) from osteoblasts. Photomedicine and laser surgery 59 22235971
2005 DHT and testosterone, but not DHEA or E2, differentially modulate IGF-I, IGFBP-2, and IGFBP-3 in human prostatic stromal cells. American journal of physiology. Endocrinology and metabolism 57 16368782
2020 Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12. Journal of hepatology 56 32087348
2021 IGF-1 and IGFBP-3 in Inflammatory Cachexia. International journal of molecular sciences 55 34502376
2007 IGF-1 and IGFBP-3 gene variants influence on serum levels and prostate cancer risk in African-Americans. Carcinogenesis 53 17724372
1996 IGFBP-3 proteolysis by plasmin, thrombin, serum: heparin binding, IGF binding, and structure of fragments. The American journal of physiology 53 8843739
2010 Racial differences in the association between body mass index and serum IGF1, IGF2, and IGFBP3. Endocrine-related cancer 51 19786462
2011 Serum IGF1, IGF2 and IGFBP3 and risk of advanced colorectal adenoma. International journal of cancer 48 21932422
2004 Clinical significance of serum IGF-I, IGF-II and IGFBP-3 in liver cirrhosis. World journal of gastroenterology 48 15309731
2022 The IGFBP3/TMEM219 pathway regulates beta cell homeostasis. Nature communications 47 35115561
2017 IGFBP3 Modulates Lung Tumorigenesis and Cell Growth through IGF1 Signaling. Molecular cancer research : MCR 47 28330997
2012 Hypoxia induces IGFBP3 in esophageal squamous cancer cells through HIF-1α-mediated mRNA transcription and continuous protein synthesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 46 22415309
2009 Association of IGF1 and IGFBP3 polymorphisms with colorectal polyps and colorectal cancer risk. Cancer causes & control : CCC 46 19784788
2016 Pancreatic cancer cell-derived IGFBP-3 contributes to muscle wasting. Journal of experimental & clinical cancer research : CR 45 26975989
2020 Hsa_circ_0046263 functions as a ceRNA to promote nasopharyngeal carcinoma progression by upregulating IGFBP3. Cell death & disease 44 32703944
2008 Screening of senescence-associated genes with specific DNA array reveals the role of IGFBP-3 in premature senescence of human diploid fibroblasts. Free radical biology & medicine 44 18329388
2019 Suppression of tumor growth via IGFBP3 depletion as a potential treatment in glioma. Journal of neurosurgery 43 30641835
2014 Genome-wide association and functional studies identify a role for IGFBP3 in hip osteoarthritis. Annals of the rheumatic diseases 43 24928840
2013 IGFBP-3 and TNF-α regulate retinal endothelial cell apoptosis. Investigative ophthalmology & visual science 40 23868984
2009 Common genetic variation in IGF1, IGFBP1 and IGFBP3 and ovarian cancer risk. Carcinogenesis 40 19858071
2014 Aflatoxin exposure is inversely associated with IGF1 and IGFBP3 levels in vitro and in Kenyan schoolchildren. Molecular nutrition & food research 39 24668606
2012 IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors. Molecular cancer 39 22401581
2023 IGFBP3 epigenetic promotion induced by METTL3 boosts cardiac fibroblast activation and fibrosis. European journal of pharmacology 37 36657656
2011 IGF1 and IGFBP3 in acute respiratory distress syndrome. European journal of endocrinology 37 22004906
2013 TGF-β-induced expression of IGFBP-3 regulates IGF1R signaling in human osteosarcoma cells. Molecular and cellular endocrinology 35 23831640
2002 The effects of tonsillectomy and adenoidectomy on serum IGF-I and IGFBP3 levels in children. The Laryngoscope 35 12150629
1993 Properties of glycosylated and non-glycosylated human recombinant IGF binding protein-3 (IGFBP-3). Growth regulation 33 7683528
2020 Circ_0000285 regulates proliferation, migration, invasion and apoptosis of osteosarcoma by miR-409-3p/IGFBP3 axis. Cancer cell international 32 33041662
2019 ROS- and HIF1α-dependent IGFBP3 upregulation blocks IGF1 survival signaling and thereby mediates high-glucose-induced cardiomyocyte apoptosis. Journal of cellular physiology 32 30659610
2016 Injectable hyaluronic acid down-regulates interferon signaling molecules, IGFBP3 and IFIT3 in the bovine intervertebral disc. Acta biomaterialia 32 28003146
2021 TRAIP modulates the IGFBP3/AKT pathway to enhance the invasion and proliferation of osteosarcoma by promoting KANK1 degradation. Cell death & disease 31 34349117
2020 Graphene Oxide Nanoparticles Induce Apoptosis in wild-type and CRISPR/Cas9-IGF/IGFBP3 knocked-out Osteosarcoma Cells. Journal of Cancer 31 32742448
2018 B-Myb Mediates Proliferation and Migration of Non-Small-Cell Lung Cancer via Suppressing IGFBP3. International journal of molecular sciences 31 29772705
2009 Promoter methylation of IGFBP-3 and p53 expression in ovarian endometrioid carcinoma. Molecular cancer 31 20003326
2004 Correlation of sex steroids with IGF-1 and IGFBP-3 during different pubertal stages. The Turkish journal of pediatrics 31 15641264
2020 The regulation of IGFBP3 by BMP2 has a role in human endometrial remodeling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30 32975335
2020 Vi4-miR-185-5p-Igfbp3 Network Protects the Brain From Neonatal Hypoxic Ischemic Injury via Promoting Neuron Survival and Suppressing the Cell Apoptosis. Frontiers in cell and developmental biology 29 33262982
2021 IGF-I/IGFBP3/ALS Deficiency in Sarcopenia: Low GHBP Suggests GH Resistance in a Subgroup of Geriatric Patients. The Journal of clinical endocrinology and metabolism 28 33378445
2015 Humanin Peptide Binds to Insulin-Like Growth Factor-Binding Protein 3 (IGFBP3) and Regulates Its Interaction with Importin-β. Protein and peptide letters 28 26216267
2020 GIPC-Regulated IGFBP-3 Promotes HSC Migration In Vitro and Portal Hypertension In Vivo Through a β1-Integrin Pathway. Cellular and molecular gastroenterology and hepatology 27 32447051
2021 XBP1- IGFBP3 Signaling Pathway Promotes NSCLC Invasion and Metastasis. Frontiers in oncology 25 34094948
2014 Targeted mass spectrometry analysis of the proteins IGF1, IGF2, IBP2, IBP3 and A2GL by blood protein precipitation. Journal of proteomics 25 25277046
2019 Clinical significance of serum IGFBP-3 in colorectal cancer. Journal of clinical laboratory analysis 24 31218761
2007 IGFBP-3 regulates esophageal tumor growth through IGF-dependent and independent mechanisms. Cancer biology & therapy 24 17457048
2015 Endogenous IGFBP-3 Mediates Intrinsic Apoptosis Through Modulation of Nur77 Phosphorylation and Nuclear Export. Endocrinology 22 26340041
2013 SND1 affects proliferation of hepatocellular carcinoma cell line SMMC-7721 by regulating IGFBP3 expression. Anatomical record (Hoboken, N.J. : 2007) 22 23878061
2018 Mutual regulation between IGF-1R and IGFBP-3 in human corneal epithelial cells. Journal of cellular physiology 21 30078228
2008 Local IGFBP-3 mRNA expression, apoptosis and risk of colorectal adenomas. BMC cancer 21 18498652
2007 IGFBP3 mRNA expression in benign and malignant breast tumors. Breast cancer research : BCR 21 17210081
2006 Effect of thyroxine replacement on serum IGF-I, IGFBP-3 and the acid-labile subunit in patients with hypothyroidism and hypopituitarism. Clinical endocrinology 21 17121519
1999 Screening for mutations in the promoter and the coding region of the IGFBP1 and IGFBP3 genes in Silver-Russell syndrome patients. Human heredity 21 10364674
2024 METTL3 inhibitor suppresses the progression of prostate cancer via IGFBP3/AKT pathway and synergizes with PARP inhibitor. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 20 39232384
2022 Upregulated IGFBP3 with Aging Is Involved in Modulating Apoptosis, Oxidative Stress, and Fibrosis: A Target of Age-Related Erectile Dysfunction. Oxidative medicine and cellular longevity 20 35154570
2022 BMI and Contraceptives Affect New Age-, Sex-, and Puberty-adjusted IGF-I and IGFBP-3 Reference Ranges Across Life Span. The Journal of clinical endocrinology and metabolism 20 35294528
2020 IGFBP3 inhibits angiogenesis through intracellular regulation of THBS1 expression. American journal of cancer research 20 32642286
2017 Serum IGF-1, IGFBP-3 and their ratio: Potential biochemical growth maturity indicators. Progress in orthodontics 20 28459119
2024 Elevated expression of WSB2 degrades p53 and activates the IGFBP3-AKT-mTOR-dependent pathway to drive hepatocellular carcinoma. Experimental & molecular medicine 19 38177295
2022 MiR-22-3p Inhibits Proliferation and Promotes Differentiation of Skeletal Muscle Cells by Targeting IGFBP3 in Hu Sheep. Animals : an open access journal from MDPI 19 35011220
2015 The association between circulating IGF1, IGFBP3, and calcium: results from NHANES III. Endocrine connections 19 26304028
2006 Serum levels of IGF-I and IGFBP-3 in patients with lung cancer during chemotherapy. Oncology research 19 16783968
2021 Gegen Qinlian Decoction ameliorates type 2 diabetes osteoporosis via IGFBP3/MAPK/NFATc1 signaling pathway based on cytokine antibody array. Phytomedicine : international journal of phytotherapy and phytopharmacology 18 34798519
2020 IGFBP-3 stimulates human osteosarcoma cell migration by upregulating VCAM-1 expression. Life sciences 18 33188835
2022 IGFBP-3 functions as a molecular switch that mediates mitochondrial and metabolic homeostasis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 34918377
2020 Anthropometric and biochemical correlates of PAPP-A2, free IGF-I, and IGFBP-3 in childhood. European journal of endocrinology 17 31961798
2018 Investigation of IGF1, IGF2BP2, and IGFBP3 variants with lymph node status and esophagogastric junction adenocarcinoma risk. Journal of cellular biochemistry 17 30335898
2018 ADAM28 promotes tumor growth and dissemination of acute myeloid leukemia through IGFBP-3 degradation and IGF-I-induced cell proliferation. Cancer letters 17 30429106
2015 IGFBP-3 may trigger osteoarthritis by inducing apoptosis of chondrocytes through Nur77 translocation. International journal of clinical and experimental pathology 17 26884829
2009 Changes in IGF-I, IGFBP-3 and ghrelin levels after adenotonsillectomy in children with sleep disordered breathing. International journal of pediatric otorhinolaryngology 17 19765833
2007 Serum ghrelin levels but not GH, IGF-1 and IGFBP-3 levels are altered in patients with fibromyalgia syndrome. Joint bone spine 17 17689128
2013 Regulation of retinal endothelial cell apoptosis through activation of the IGFBP-3 receptor. Apoptosis : an international journal on programmed cell death 16 23291901
2023 Doxorubicin induced ROS-dependent HIF1α activation mediates blockage of IGF1R survival signaling by IGFBP3 promotes cardiac apoptosis. Aging 15 36602546
2020 MiR-384 Inhibits Malignant Biological Behavior Such as Proliferation and Invasion of Osteosarcoma by Regulating IGFBP3. Technology in cancer research & treatment 15 32129151
2019 Regulation of IGF-I by IGFBP3 and IGFBP5 during odontoblast differentiation in mice. Journal of oral biosciences 15 31400542
2005 IGFBP-3 expression in hepatocellular carcinoma involves abnormalities in TGF-beta and/or Rb signaling pathways. International journal of oncology 15 16211216
2024 CDK12 regulates angiogenesis of advanced prostate cancer by IGFBP3. International journal of oncology 14 38186306
2018 Epac1 deacetylates HMGB1 through increased IGFBP-3 and SIRT1 levels in the retinal vasculature. Molecular vision 14 30581279
2009 The expression and function of IGFBP-3 in normal and malignant breast tissue. Anticancer research 14 19846909
2020 Associations of plasma IGF1, IGFBP3 and estradiol with leucocyte telomere length, a marker of biological age, in men. European journal of endocrinology 13 31658437
2015 Circulating IGF1 and IGFBP3 in relation to the development of β-cell autoimmunity in young children. European journal of endocrinology 13 25947142
2014 Induction of apoptosis by IGFBP3 overexpression in hepatocellular carcinoma cells. Asian Pacific journal of cancer prevention : APJCP 13 25556430
2010 IGF1, IGFBP1, and IGFBP3 genes and mammographic density: the Multiethnic Cohort. International journal of cancer 13 20039319
2007 Epigenetic and functional analysis of IGFBP3 and IGFBPrP1 in cellular immortalization. Biochemical and biophysical research communications 13 17451653