{"gene":"IGFBP3","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2015,"finding":"IGFBP3 binds its receptor TMEM219 on colonic stem cells (CoSCs) in an IGF-I-independent manner, leading to disruption of CoSC function and prevention of organoid growth in vitro; restoration of normal IGFBP3/IGF-I levels rescued CoSC homeostasis.","method":"In vitro organoid growth assay, recombinant ecto-TMEM219 protein treatment, preclinical diabetic enteropathy model, proteomic profiling of patient serum","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal in vitro and in vivo experiments with receptor identification, multiple orthogonal methods (organoids, recombinant protein rescue, preclinical model), replicated in patient cohorts","pmids":["26431183"],"is_preprint":false},{"year":2022,"finding":"IGFBP3 signals through the death receptor TMEM219 on pancreatic beta cells, causing beta cell loss and dysfunction; genetic ablation of TMEM219 or pharmacological blockade of IGFBP3/TMEM219 preserved beta cell mass and prevented/delayed diabetes onset in preclinical models.","method":"TMEM219 knockout mice, in vitro beta cell treatment, in vivo IGFBP3/TMEM219 inhibition, patient cohort validation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with pharmacological inhibition and patient data, multiple orthogonal methods in one study","pmids":["35115561"],"is_preprint":false},{"year":2002,"finding":"IGFBP3 (using an IGF-binding-deficient mutant) upregulates STAT-1 mRNA and protein expression, induces STAT-1 phosphorylation and nuclear localization, and this IGF-independent STAT-1 induction mediates IGFBP3-induced apoptosis in chondrogenic cells; antisense STAT-1 oligonucleotides abolished IGFBP3-induced apoptosis.","method":"cDNA microarray, Northern blot, transfection with IGFBP3 mutant unable to bind IGFs, antisense oligonucleotide knockdown, immunolocalization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis (IGF-binding deficient mutant) plus functional rescue (antisense abolishes apoptosis), single lab but multiple orthogonal methods","pmids":["11886859"],"is_preprint":false},{"year":2002,"finding":"IGFBP-3 mediates p53-induced apoptosis during serum starvation; inhibition of IGFBP-3 with antibody or antisense oligomers reduced apoptosis to levels comparable to p53 degradation, and IGF-I co-treatment blocked IGFBP-3-dependent apoptosis.","method":"Doxycycline-inducible p53 model (p53-negative PC-3 cells), stable E6-transfected H460 cells to degrade p53, anti-IGFBP-3 antibody neutralization, IGFBP-3 antisense oligomers","journal":"International journal of oncology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two complementary cell models (gain and loss of p53), multiple inhibitory tools (antibody + antisense), single lab","pmids":["12118329"],"is_preprint":false},{"year":2019,"finding":"IGFBP-3 forms nuclear complexes with NONO and SFPQ (DNA/RNA-binding proteins) in a PARP-dependent and EGFR/DNA-PKcs-dependent manner in triple-negative breast cancer cells, promoting DNA double-strand break repair by non-homologous end-joining; PARP inhibitors and LINP1 siRNA blocked these interactions.","method":"LC-MS/MS interactome analysis, co-immunoprecipitation, proximity ligation assay, cell-free biochemical binding assay, DNA end-joining in vitro assay, γH2AX foci measurement, EGFR/DNA-PKcs inhibitors, PARP inhibitors, siRNA","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal Co-IP confirmed by cell-free assay and proximity ligation, functional end-joining assay, multiple inhibitor controls, single lab","pmids":["30725116"],"is_preprint":false},{"year":2012,"finding":"Hypoxia induces IGFBP3 mRNA transcription in esophageal squamous cancer cells via HIF-1α binding to a novel hypoxia-responsive element (HRE) at -57 kb upstream of the transcription start site; IGFBP3 mRNA is enriched in polysomes enabling continued cap-dependent translation under hypoxia, despite global protein synthesis suppression.","method":"RNA interference (HIF-1α/HIF-2α siRNA), chromatin immunoprecipitation (ChIP), transfection/luciferase assays, metabolic labeling, 7-methyl GTP-cap binding assay, mTOR inhibitors, bicistronic RNA reporter, polysome fractionation","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP + mutagenesis/reporter + polysome fractionation, multiple orthogonal methods in one study, single lab","pmids":["22415309"],"is_preprint":false},{"year":2005,"finding":"EGF suppresses IGFBP-3 mRNA and protein expression through MAPK activation in an EGFR-tyrosine kinase-dependent manner; secreted IGFBP-3 neutralizes IGFs and prevents IGF-I receptor activation; wild-type but not IGF-binding-deficient (I56G/L80G/L81G) IGFBP-3 prevents IGF-I from activating IGF-IR and Akt, demonstrating that IGFBP-3's anti-proliferative effect on IGF signaling is IGF-binding dependent.","method":"Stable overexpression of wild-type vs. GGG mutant IGFBP-3, EGFR inhibitors, Western blot for IGF-IR and Akt phosphorylation, cell proliferation assays","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — side-by-side mutagenesis (GGG mutant) with functional readouts, EGFR inhibitor controls, single lab","pmids":["16210470"],"is_preprint":false},{"year":2013,"finding":"TGF-β1 induces IGFBP-3 expression in osteosarcoma cells, and IGFBP-3 in turn attenuates TGF-β1 activation of ERK1/2 and Akt, inhibits TGF-β1-induced cell cycle progression and proliferation; blocking IGF1R signaling abolishes IGFBP-3's effect, and blocking IGFBP-3 induction enhances nuclear Smad2 phosphorylation — establishing a negative-feedback loop.","method":"IGFBP-3 knockdown/overexpression, IGF1R inhibition, Western blot for ERK1/2, Akt, pSmad2, cell cycle and proliferation assays","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway dissection using multiple inhibitors and KD, single lab, multiple readouts","pmids":["23831640"],"is_preprint":false},{"year":2016,"finding":"IGFBP-3 inhibits Wnt signaling in metastatic melanoma cells by entering the cell, binding the Wnt signalosome component GSK-3β, dissociating the β-catenin destruction complex from the LRP6 receptor, activating GSK-3β through dephosphorylation, and targeting cytoplasmic β-catenin for proteasomal degradation; this effect depends on CD44.","method":"Recombinant IGFBP-3 treatment of cultured melanoma cells, co-immunoprecipitation with GSK-3β, β-catenin immunofluorescence/Western blot, proteasome inhibition, CD44 dependency assay, mouse xenograft","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of IGFBP-3 with GSK-3β, proteasome inhibitor rescue, CD44 dependency demonstrated, single lab","pmids":["27377812"],"is_preprint":false},{"year":2017,"finding":"Nuclear FAK cooperates with Runx1 to regulate IGFBP3 transcription in squamous cell carcinoma; FAK forms a molecular complex with Runx1 and interacts with Sin3a and other epigenetic modifiers that alter Runx1 transcriptional function, thereby controlling IGFBP3-dependent cell-cycle progression and tumor growth.","method":"Co-immunoprecipitation (FAK-Runx1 nuclear complex), genetic FAK nuclear localization models, luciferase reporter, in vivo tumor growth assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of nuclear FAK-Runx1 complex, in vivo tumor model, single lab","pmids":["28807942"],"is_preprint":false},{"year":2015,"finding":"Humanin binds directly to IGFBP3 (Kd ~5.05 µM) and both humanin and its analogue HN 3-19 interfere with the binding of importin-β1 to IGFBP3 in vitro (IC50 ~18.1 µM and ~10.3 µM respectively), thereby blocking IGFBP3 nuclear translocation and reducing apoptosis in lung adenocarcinoma cells.","method":"Competitive ligand dot blotting, co-immunoprecipitation, ELISA-based binding assay, apoptosis assay in lung adenocarcinoma cells","journal":"Protein and peptide letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with Kd determination, competitive inhibition of importin-β1, functional apoptosis rescue, single lab","pmids":["26216267"],"is_preprint":false},{"year":2001,"finding":"IGFBP-3 can be transported to the nucleus by an importin-β-mediated mechanism where it interacts with retinoid X receptor alpha (RXRα); IGFBP-3 antiproliferative signaling requires an active TGF-β signaling pathway and stimulates phosphorylation of TGF-β signaling intermediates Smad2 and Smad3.","method":"Transfection, nuclear transport assays, co-immunoprecipitation/interaction studies (review citing primary experimental data)","journal":"Molecular pathology : MP","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — review synthesizing multiple experimental observations (importin-β transport, RXRα interaction, Smad2/3 phosphorylation) from primary experimental reports; moderate confidence due to review format","pmids":["11376125"],"is_preprint":false},{"year":2007,"finding":"In oxygen-induced retinopathy, IGFBP3 acts independently of IGF-1 to prevent vessel loss and promote vascular regrowth; IGFBP3-deficient mice showed dose-dependent increase in retinal vessel loss and 31% decrease in vessel regrowth, while exogenous IGFBP3 increased vessel regrowth correlating with a 30% increase in endothelial progenitor cells in the retina.","method":"IGFBP3 knockout mice, exogenous IGFBP3 administration, oxygen-induced retinopathy model, retinal vessel quantification, endothelial progenitor cell quantification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus exogenous rescue in the same model, IGF-1 independence established (no serum IGF-1 difference), replicated with clinical data","pmids":["17567756"],"is_preprint":false},{"year":2013,"finding":"IGFBP-3 and TNF-α work antagonistically in retinal endothelial cells: IGFBP-3 inhibits apoptosis while TNF-α promotes it; loss of IGFBP-3 signaling (IGFBP-3 KO mice) results in increased retinal apoptosis, decreased B-wave and oscillatory potential amplitudes, reduced retinal thickness, and elevated TNF-α levels.","method":"IGFBP-3 knockout mice, electroretinogram, retinal cell counting, treatment of retinal endothelial cells with IGFBP-3 and TNF-α","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple functional readouts, antagonism demonstrated by direct cell treatment, single lab","pmids":["23868984"],"is_preprint":false},{"year":2013,"finding":"IGFBP-3 inhibits retinal endothelial cell (REC) death through activation of a specific IGFBP-3 receptor; siRNA knockdown of the IGFBP-3 receptor increased cell death, and IGFBP-3 overexpression upregulated IGFBP-3 receptor protein levels; co-immunoprecipitation confirmed IGFBP-3 and receptor binding; IGFBP-3 modulated Bcl-xL, Bax, cytochrome C and Akt in a receptor-dependent manner.","method":"IGFBP-3 receptor siRNA knockdown, IGFBP-3 plasmid overexpression (non-IGF-binding mutant), co-immunoprecipitation, cell death ELISA, caspase-3 ELISA, Western blot","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of IGFBP-3 with its receptor, siRNA rescue experiment, multiple downstream markers, single lab","pmids":["23291901"],"is_preprint":false},{"year":2009,"finding":"IGFBP3 co-localizes with and regulates hypocretin (orexin) in hypothalamic neurons; transgenic mice overexpressing human IGFBP3 show decreased hypocretin mRNA, peptide content, and increased sleep, possibly mediated through decreased hypocretin promoter activity in the presence of excess IGFBP3.","method":"Gene expression profiling (microarray), in vivo transgenic overexpression, hypocretin mRNA and peptide quantification, sleep phenotyping, promoter activity assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic overexpression with functional (sleep) and molecular (mRNA/peptide) readouts, promoter activity data, single lab","pmids":["19158946"],"is_preprint":false},{"year":2020,"finding":"IGFBP3 mediates lipid droplet formation and triglyceride accumulation in hepatocytes; recombinant IGFBP3 (secreted by activated hepatic stellate cells) induced lipid droplets and lipogenic genes in hepatocytes in vitro; NRP-1 deletion from HSCs reduced IGFBP3 secretion and protected hepatocytes from ethanol-induced steatosis.","method":"HSC-selective NRP-1 knockout (ColCre/Nrp1loxP mice), adipokine/inflammatory protein array, recombinant Igfbp3 treatment of hepatocytes, in vitro lipid droplet/triglyceride measurement, alcohol feeding model","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic HSC KO model plus recombinant protein treatment, direct hepatocyte readout, single lab","pmids":["32087348"],"is_preprint":false},{"year":2014,"finding":"miR-21 directly targets IGFBP3 mRNA and downregulates IGFBP3 expression in glioblastoma; IGFBP3 overexpression inhibited tumor cell proliferation in vitro and xenograft growth in vivo; IGFBP3 knockdown in miR-21-knockdown cells restored tumorigenesis, placing IGFBP3 as a downstream effector of miR-21.","method":"Microarray, 3'-UTR luciferase reporter (miR-21 target validation), overexpression and knockdown of IGFBP3, rescue/epistasis experiment, xenograft mouse model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated miR-21→IGFBP3 targeting with reporter assay and epistasis rescue experiment, in vivo xenograft, single lab","pmids":["25059666"],"is_preprint":false},{"year":2017,"finding":"IGFBP3 modulates lung tumor progression through IGF1 signaling; Igfbp3-null mice combined with Kras showed >2-fold increased lung tumor burden; overexpression of IGFBP3 in NSCLC cells induced apoptosis (10-fold increase in cleaved caspase-3) and inactivated IGF1 and MAPK signaling; IGF-binding-deficient IGFBP3 mutant partially retained activity, indicating both IGF-dependent and -independent mechanisms.","method":"Igfbp3-null mouse model crossed with Kras, overexpression of WT vs. IGF-binding-deficient mutant IGFBP3 in NSCLC cells, cleaved caspase-3 measurement, IGF1/MAPK signaling Western blot, cisplatin response assay","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — genetic KO mouse model plus mutagenesis (IGF-binding-deficient mutant), multiple functional readouts, in vivo and in vitro, single lab","pmids":["28330997"],"is_preprint":false},{"year":2016,"finding":"Pancreatic cancer cell-derived IGFBP-3 causes muscle wasting via IGF signaling inhibition; IGFBP-3 treatment of C2C12 muscle cells impaired myogenesis and enhanced muscle protein degradation; IGFBP3 knockdown in pancreatic cancer cells or antibody neutralization of IGFBP-3 in conditioned medium alleviated wasting.","method":"Conditioned medium from Capan-1 pancreatic cancer cells, IGFBP3 knockdown (siRNA), anti-IGFBP-3 antibody neutralization, myogenesis and protein degradation assays in C2C12 cells","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody neutralization and KD rescue in same experimental system, direct IGF signaling readout, single lab","pmids":["26975989"],"is_preprint":false},{"year":1995,"finding":"IGFBP-3 has three N-glycosylation sites (Asn89, Asn109, Asn172); site mutagenesis shows ~4, 5, and 6 kDa of carbohydrate at sites 1, 2, and 3 respectively; glycosylation is not required for secretion or IGF-I binding; the two native IGFBP-3 forms represent protein glycosylated at all three sites vs. only at Asn89/Asn109; glycosylation does not significantly affect acid-labile subunit (ALS) binding.","method":"Site-directed mutagenesis of N-glycosylation sites, ligand blotting with [125I]IGF-I, radioimmunoassay, ALS binding assay, expression in CHO cells","journal":"Progress in growth factor research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic site-directed mutagenesis of all three glycosylation sites with quantitative biochemical characterization, single lab","pmids":["8817665"],"is_preprint":false},{"year":1995,"finding":"IGFBP-3 in serum undergoes proteolytic degradation by the tissue plasminogen activator (tPA)-plasminogen-plasmin system, providing an additional mechanism for regulation of IGF bioavailability.","method":"Serum proteolysis assays with tPA-plasminogen-plasmin pathway identification","journal":"Progress in growth factor research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single biochemical assay described in a short review-format paper, limited methodological detail in abstract","pmids":["8817671"],"is_preprint":false},{"year":2018,"finding":"IGFBP-3 mediates nuclear translocation of IGF-1R in corneal epithelial cells in response to growth factor withdrawal via SUMOylation by SUMO 2/3; IGF-1R and IGFBP-3 undergo reciprocal regulation independent of PI3K/Akt signaling; under growth conditions IGFBP-3 arrests the cell cycle in G0/G1, while under stress it maintains nuclear IGF-1R levels.","method":"Growth factor withdrawal model, SUMOylation assays (SUMO 2/3), nuclear fractionation, cell cycle analysis, PI3K/Akt inhibition","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SUMOylation mechanism established, nuclear translocation functionally characterized, PI3K-independence shown, single lab","pmids":["30078228"],"is_preprint":false},{"year":2022,"finding":"IGFBP-3 regulates mitochondrial homeostasis in corneal epithelial cells through control of the sBNIP3L/NIX mitophagy receptor; both loss and gain of IGFBP-3 function increase mitochondrial respiration; nuclear accumulation of IGFBP-3 is associated with increased respiration; IGFBP-3 also regulates lamellar cristae morphology and mitochondrial dynamics.","method":"Loss-of-function (siRNA/KD) and gain-of-function (overexpression) of IGFBP-3, Seahorse metabolic flux analysis, mitochondrial morphology imaging, sBNIP3L/NIX assays, nuclear fractionation","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complementary gain and loss of function, metabolic flux analysis, identification of mitophagy receptor as downstream effector, single lab","pmids":["34918377"],"is_preprint":false},{"year":2021,"finding":"IGFBP-3 mediates metabolic homeostasis in corneal epithelial cells under hyperosmolar stress; hyperosmolarity decreases IGFBP-3 expression; supplementation with recombinant IGFBP-3 abrogates metabolic and mitochondrial changes (altered calcium, depolarization, decreased ATP and mtDNA) induced by hyperosmolar stress.","method":"hTCEpi cell hyperosmolar stress model, Seahorse metabolic flux analysis, mitochondrial calcium/polarization/mtDNA assays, ELISA for IGFBP-3 and cytokines, recombinant IGFBP-3 supplementation, LDH cytotoxicity assay","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein rescue with multiple metabolic/mitochondrial readouts, single lab","pmids":["34100890"],"is_preprint":false},{"year":2019,"finding":"ROS- and HIF1α-dependent IGFBP3 upregulation under hyperglycemia leads to IGFBP3 secretion, sequestration of extracellular IGF1, blockade of IGF1 pro-survival signaling, and cardiomyocyte apoptosis; siRNA against IGFBP3 or anti-IGFBP3 antibody rescued cardiac apoptosis; HIF1α inhibition downregulated IGFBP3; PHD regulates HIF1α stability upstream of IGFBP3.","method":"Co-IP (IGF1-IGFBP3 extracellular association), Western blot, siRNA (IGFBP3, HIF1α), anti-IGFBP3 antibody, ROS scavenger, diabetic rat model, echocardiography","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of IGF1-IGFBP3 extracellular complex, siRNA and antibody rescue in parallel, in vivo cardiac functional readout, single lab","pmids":["30659610"],"is_preprint":false},{"year":2023,"finding":"METTL3 promotes IGFBP3 expression via N6-methyladenosine (m6A) mRNA modification in cardiac fibroblasts; METTL3 silencing downregulates IGFBP3 and inhibits cardiac fibroblast activation; IGFBP3 knockdown inhibits migration and proliferation of cardiac fibroblasts.","method":"MeRIP-seq (m6A sequencing), METTL3 silencing, IGFBP3 knockdown, transverse aortic constriction and isoproterenol cardiac fibrosis models, migration/proliferation assays","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq established METTL3→m6A→IGFBP3 axis, KD in vivo and in vitro, single lab","pmids":["36657656"],"is_preprint":false},{"year":2012,"finding":"IGFBP3 promoter methylation epigenetically silences IGFBP3 expression in hepatoblastoma (HB) cell lines; treatment with 5-aza-2'-deoxycytidine restored IGFBP3 expression; restoring IGFBP3 in HB cells reduced colony formation, migration, and invasion; IGFBP3 promoter methylation predominantly occurred in metastatic HB with vascular invasion.","method":"Bisulfite sequencing of IGFBP3 promoter CpGs, 5-aza-2'-deoxycytidine demethylation, IGFBP3 re-expression in cell lines, colony formation, migration and invasion assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic mechanism (bisulfite sequencing) plus functional rescue, single lab","pmids":["22401581"],"is_preprint":false},{"year":2009,"finding":"IGFBP-3 contains a 22-amino acid metal-binding domain (MBD) that selectively targets cancer cells via cell surface cross-linking to transferrin receptor, caveolin 1, and integrin-β; MBD uptake rate correlates with gene expression of stress-response pathways (NF-κB, Hsp-70B); MBD-tagged cytotoxic peptides show selective cytotoxicity to cancer vs. normal cells and reduce tumor burden in mouse models.","method":"MBD cross-linking to cell surface receptors, correlation with NCI-60 gene array data, cytotoxicity assays, in vivo biodistribution, mouse leukemia/melanoma dissemination models","journal":"Anti-cancer drugs","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical cross-linking to multiple cell surface receptors with in vivo biodistribution confirmation, single lab","pmids":["19342998"],"is_preprint":false},{"year":2020,"finding":"IGFBP3 inhibits angiogenesis by activating THBS1 (thrombospondin-1) transcription through intracellular signaling; IGFBP3 induction increased THBS1 in epithelial ovarian cancer cells; THBS1 silencing reversed IGFBP3-induced inhibition of capillary tube formation (HUVEC assay) and chick CAM vessel development; luciferase assay showed intracellular IGFBP3 more potently activated THBS1 promoter than extracellular IGFBP3.","method":"Inducible IGFBP3 expression system, THBS1 siRNA, HUVEC tube formation assay, chick CAM assay, xenograft, luciferase promoter assay","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter luciferase assay distinguishes intracellular vs. extracellular function, THBS1 siRNA rescue, multiple angiogenesis readouts, single lab","pmids":["32642286"],"is_preprint":false},{"year":2020,"finding":"BMP2 upregulates IGFBP3 expression in human endometrial stromal cells via ALK3 receptor and the transcription factor ID1; IGFBP3 in turn promotes MMP2 expression and cell migration; knockdown of IGFBP3 or ID1 suppressed BMP2-induced MMP2 upregulation and cell migration.","method":"Immortalized and primary human endometrial stromal cells, BMP2 dose-response, ALK3 knockdown, ID1 knockdown, IGFBP3 knockdown, MMP2 measurement, migration assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ALK3→ID1→IGFBP3→MMP2 pathway established by sequential KD, single lab","pmids":["32975335"],"is_preprint":false},{"year":1998,"finding":"Insulin increases IGFBP-3 gene transcription in hepatic nonparenchymal cells via an insulin-responsive element that recruits insulin-responsive nuclear factors (demonstrated by gel mobility shift assay and southwestern blot); IGF-I increases IGFBP-3 mRNA stability (post-transcriptional regulation).","method":"In vitro transcription assays, gel mobility shift assay, southwestern blot, mRNA stability analysis","journal":"Progress in nucleic acid research and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gel shift and southwestern blot identify nuclear factors binding insulin-responsive element, multiple regulatory mechanisms established, single lab review","pmids":["9594576"],"is_preprint":false},{"year":2018,"finding":"ADAM28 promotes IGF-I-induced leukemia cell proliferation by degrading IGFBP-3, thereby increasing free IGF-I availability; ADAM28 knockout reduced leukemic cell growth and dissemination in a xenotransplantation model.","method":"ADAM28 knockdown/knockout in leukemic cells, IGFBP-3 degradation assay, IGF-I proliferation assay, xenotransplantation mouse model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protease-substrate relationship established with in vivo xenotransplantation validation, single lab","pmids":["30429106"],"is_preprint":false},{"year":2023,"finding":"TGF-β and EGFRvIII transactivation in glioblastoma cells activates c-Jun transcription factor via Smad2/3 and ERK1/2 pathways, which binds the IGFBP3 promoter to promote IGFBP3 production and secretion; IGFBP3 knockdown inhibited TGF-β/EGFRvIII signaling and malignant behaviors, revealing a positive feedback loop.","method":"TGF-β treatment of GBM cells, co-immunoprecipitation (Smad2/3, ERK1/2), ChIP (c-Jun binding to IGFBP3 promoter), IGFBP3 knockdown, in vitro/in vivo tumor assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates c-Jun binding to IGFBP3 promoter, pathway dissection with Smad/ERK inhibitors, single lab","pmids":["37192967"],"is_preprint":false},{"year":2024,"finding":"IGFBP3 promotes resistance to the PARP inhibitor olaparib in prostate cancer by enhancing DNA repair capacity through activation of EGFR and DNA-PKcs; IGFBP3 depletion reduces EGFR/DNA-PKcs activity, increases DNA damage accumulation, and re-sensitizes resistant cells to olaparib; gefitinib (EGFR inhibitor) phenocopies IGFBP3 inhibition.","method":"Olaparib-resistant cell line development, IGFBP3 siRNA knockdown, EGFR inhibition (gefitinib), DNA-PKcs assay, γH2AX foci, cell viability assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by phenocopy (IGFBP3 KD vs. gefitinib), DNA repair mechanistic readouts, single lab","pmids":["38327800"],"is_preprint":false},{"year":2013,"finding":"SND1 knockdown in hepatocellular carcinoma cells increases IGFBP3 expression; increased IGFBP3 negatively regulates IGF pathway activation by restricting IGF-receptor interactions; conversely, IGFBP3 knockdown promotes cell proliferation, placing IGFBP3 downstream of SND1 as a negative regulator of IGF signaling in HCC.","method":"Stable SND1 shRNA knockdown, IGFBP3 stable knockdown, real-time PCR screening of IGF pathway genes, proliferation and tumor formation assays","journal":"Anatomical record","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway ordering by expression analysis and KD, no direct binding or biochemical assay for IGFBP3-receptor interaction, single lab","pmids":["23878061"],"is_preprint":false},{"year":2022,"finding":"IGFBP3 knockdown in aged corpus cavernosum smooth muscle cells (CCSMCs) increased cell viability and proliferation while decreasing apoptosis, oxidative stress, and fibrosis, identifying IGFBP3 upregulation with aging as a driver of these pathological processes in erectile dysfunction.","method":"siRNA knockdown of IGFBP3 in primary aged CCSMCs, flow cytometry (apoptosis), EdU/CCK-8 (proliferation), ROS assay, Western blot, immunofluorescence","journal":"Oxidative medicine and cellular longevity","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single KD approach in primary cells, multiple readouts but no mechanistic pathway placement beyond signaling markers, single lab","pmids":["35154570"],"is_preprint":false}],"current_model":"IGFBP3 is a multifunctional secreted protein that acts both as an extracellular IGF-sequestering carrier (binding >75% of circulating IGF-1 in a 150-kDa ternary complex with ALS) and as an intracellular/nuclear signaling molecule with IGF-independent activities: it is transcriptionally induced by p53 and HIF-1α (via a distal HRE), transported to the nucleus by importin-β, where it interacts with RXRα, cooperates with nuclear FAK/Runx1, and promotes DNA repair through complexes containing EGFR, DNA-PKcs, NONO, and SFPQ; extracellularly it signals through the death receptor TMEM219 to regulate pancreatic beta-cell homeostasis and colonic stem cells, inhibits Wnt/GSK-3β/β-catenin signaling in melanoma cells, promotes vascular regrowth in the retina, activates STAT-1-dependent apoptosis in chondrocytes, suppresses IGF1R signaling via THBS1 and direct IGF sequestration, and undergoes proteolytic regulation by ADAM28 and plasmin; its expression is epigenetically silenced by promoter methylation and is post-transcriptionally regulated by m6A modification via METTL3."},"narrative":{"mechanistic_narrative":"IGFBP3 is a secreted, multifunctional protein that controls insulin-like growth factor (IGF) bioavailability and executes IGF-independent signaling programs governing apoptosis, DNA repair, and tissue homeostasis [PMID:16210470, PMID:28330997]. As a carrier, it sequesters extracellular IGF-I and prevents IGF-IR and downstream Akt/MAPK activation; this anti-proliferative effect requires intact IGF binding, as an IGF-binding-deficient mutant fails to block IGF-I signaling, and IGFBP3 levels feed back negatively on TGF-β1- and SND1-driven IGF pathway activation [PMID:16210470, PMID:23831640, PMID:28330997]. IGFBP3 carbohydrate occupancy at three N-glycosylation sites (Asn89, Asn109, Asn172) is dispensable for secretion, IGF-I binding, and ALS association [PMID:8817665], and IGF availability is further tuned by proteolysis through ADAM28 and the plasmin system [PMID:30429106, PMID:8817671]. Independently of IGF, IGFBP3 is imported to the nucleus by importin-β, where it engages RXRα and stimulates Smad2/3 phosphorylation, and assembles repair complexes with EGFR, DNA-PKcs, NONO and SFPQ that promote non-homologous end-joining — a function that drives resistance to PARP inhibition in prostate cancer [PMID:11376125, PMID:30725116, PMID:38327800]. As an apoptosis effector it transduces p53-induced death and drives chondrocyte apoptosis via IGF-independent STAT-1 induction [PMID:12118329, PMID:11886859]. Extracellularly, IGFBP3 signals through the death receptor TMEM219 to regulate colonic stem cells and pancreatic beta-cell homeostasis [PMID:26431183, PMID:35115561], inhibits Wnt/GSK-3β/β-catenin signaling in melanoma in a CD44-dependent manner [PMID:27377812], transcriptionally activates the anti-angiogenic factor THBS1 [PMID:32642286], and promotes retinal vascular regrowth and endothelial survival [PMID:17567756, PMID:23868984]. Its own expression is induced by hypoxia/HIF-1α via a distal HRE, by p53, insulin, TGF-β/EGFRvIII, and BMP2 pathways, and is restrained by promoter methylation, miR-21, and METTL3-dependent m6A modification [PMID:22415309, PMID:22401581, PMID:25059666, PMID:36657656].","teleology":[{"year":1995,"claim":"Established the post-translational architecture of IGFBP-3 by mapping which modifications and proteolytic events govern its carrier behavior, clarifying that glycosylation is structurally tolerated rather than functionally required.","evidence":"Site-directed mutagenesis of three N-glycosylation sites with ligand blotting and ALS binding assays; serum proteolysis assays identifying the tPA-plasminogen-plasmin pathway","pmids":["8817665","8817671"],"confidence":"High","gaps":["Does not address how glycosylation affects nuclear import or non-IGF functions","Proteolysis finding rests on a single biochemical assay in review format"]},{"year":1998,"claim":"Answered how IGFBP3 transcription and mRNA stability are hormonally controlled, linking metabolic signals to IGF-binding capacity.","evidence":"In vitro transcription, gel mobility shift, southwestern blot, and mRNA stability analysis in hepatic nonparenchymal cells","pmids":["9594576"],"confidence":"Medium","gaps":["Insulin-responsive nuclear factors not molecularly identified","Review-format synthesis"]},{"year":2001,"claim":"Defined a nuclear, IGF-independent mode of action by showing importin-β imports IGFBP-3 to the nucleus where it binds RXRα and engages TGF-β/Smad signaling.","evidence":"Nuclear transport and co-immunoprecipitation studies synthesized in a review","pmids":["11376125"],"confidence":"Medium","gaps":["Review-format synthesis of primary data","Functional consequence of RXRα binding not resolved here"]},{"year":2002,"claim":"Connected IGFBP-3 to two distinct apoptotic programs — as the effector of p53-induced apoptosis and as an inducer of IGF-independent STAT-1-mediated death.","evidence":"Inducible p53 cell models with antibody/antisense neutralization; cDNA microarray and IGF-binding-deficient mutant plus antisense STAT-1 knockdown in chondrogenic cells","pmids":["12118329","11886859"],"confidence":"High","gaps":["Mechanism linking nuclear IGFBP-3 to STAT-1 transcription not defined","Cell-type generality of p53 axis untested"]},{"year":2005,"claim":"Resolved that IGFBP-3's anti-proliferative effect on IGF signaling is IGF-binding dependent, using a binding-deficient mutant to separate sequestration from receptor-level control.","evidence":"Stable WT vs. GGG (I56G/L80G/L81G) mutant overexpression with IGF-IR/Akt phosphorylation readouts and EGFR inhibitors","pmids":["16210470"],"confidence":"High","gaps":["Does not address IGF-independent functions of the same protein","EGF→MAPK suppression mechanism of IGFBP3 not detailed"]},{"year":2007,"claim":"Demonstrated IGF-independent tissue protection in vivo by showing IGFBP3 promotes retinal vascular regrowth and endothelial progenitor recruitment.","evidence":"IGFBP3 knockout mice plus exogenous IGFBP3 rescue in an oxygen-induced retinopathy model with vessel and EPC quantification","pmids":["17567756"],"confidence":"High","gaps":["Receptor mediating retinal effect not identified in this study","Molecular signaling downstream unresolved"]},{"year":2009,"claim":"Identified a cancer-cell-targeting metal-binding domain and a neural regulatory role, broadening IGFBP3 functions beyond IGF biology.","evidence":"MBD cross-linking to transferrin receptor, caveolin-1, integrin-β with cytotoxicity and biodistribution assays; transgenic IGFBP3 overexpression with hypocretin/sleep phenotyping","pmids":["19342998","19158946"],"confidence":"Medium","gaps":["MBD surface partners not validated as physiological signaling receptors","Hypocretin promoter regulation mechanism incomplete"]},{"year":2012,"claim":"Established hypoxia/HIF-1α and promoter methylation as opposing inducible and silencing controls of IGFBP3 expression in cancer.","evidence":"ChIP, reporter assays and polysome fractionation mapping a -57 kb HRE; bisulfite sequencing and 5-aza demethylation rescue in hepatoblastoma","pmids":["22415309","22401581"],"confidence":"Medium","gaps":["Functional output of hypoxia-induced IGFBP3 not assayed in the HRE study","Methylation causality in vivo not established"]},{"year":2013,"claim":"Defined IGFBP3 as a node in negative-feedback and survival circuits across osteosarcoma, retina, and HCC, restraining TGF-β1 and IGF signaling while protecting endothelial cells from apoptosis.","evidence":"Knockdown/overexpression with IGF1R inhibitors (osteosarcoma); IGFBP-3 KO mice with ERG/retinal readouts; receptor siRNA and Co-IP in retinal endothelial cells; SND1 and IGFBP3 knockdown in HCC","pmids":["23831640","23868984","23291901","23878061"],"confidence":"Medium","gaps":["The retinal IGFBP-3 receptor was not molecularly cloned/identified","SND1→IGFBP3 ordering rests on expression analysis without direct binding data"]},{"year":2015,"claim":"Identified TMEM219 as a bona fide IGFBP3 death receptor on stem cells and a humanin-importinβ1 axis controlling nuclear entry, defining distinct receptor-dependent and nuclear signaling routes.","evidence":"Organoid assays with recombinant ecto-TMEM219 in diabetic enteropathy models; competitive binding and importin-β1 displacement assays with humanin","pmids":["26431183","26216267"],"confidence":"High","gaps":["TMEM219 downstream signaling not fully mapped","Humanin study confidence Medium and single lab"]},{"year":2016,"claim":"Extended IGFBP3 signaling to intracellular Wnt suppression and cancer cachexia, showing it can enter cells to activate GSK-3β and that tumor-derived IGFBP3 drives muscle wasting.","evidence":"Recombinant IGFBP-3, Co-IP with GSK-3β, proteasome inhibition and CD44 dependency in melanoma; conditioned medium with knockdown/antibody neutralization in C2C12 cells","pmids":["27377812","26975989"],"confidence":"Medium","gaps":["Mechanism of IGFBP3 cell entry via CD44 not biochemically defined","Cachexia receptor mediating muscle effect not identified"]},{"year":2017,"claim":"Clarified transcriptional control of IGFBP3 by nuclear FAK/Runx1 and dissected its dual IGF-dependent/-independent tumor-suppressive activity in lung cancer.","evidence":"FAK-Runx1 Co-IP and reporter assays with nuclear localization models; Igfbp3-null x Kras mice and WT vs. binding-deficient mutant overexpression in NSCLC","pmids":["28807942","28330997"],"confidence":"Medium","gaps":["IGF-independent component of the lung effect not mechanistically pinpointed","FAK/Runx1 epigenetic partners only partially defined"]},{"year":2018,"claim":"Established proteolytic and SUMOylation-based control points: ADAM28 degrades IGFBP-3 to release IGF-I, and SUMO2/3 directs IGFBP-3-dependent nuclear translocation of IGF-1R under stress.","evidence":"ADAM28 knockdown/knockout with degradation and xenotransplantation assays; SUMOylation assays and nuclear fractionation in corneal epithelial cells","pmids":["30429106","30078228"],"confidence":"Medium","gaps":["SUMO sites on IGFBP-3/IGF-1R not mapped","Physiological scope of nuclear IGF-1R unclear"]},{"year":2019,"claim":"Defined the DNA-repair complex and a hyperglycemia-driven cardiac apoptosis circuit, showing IGFBP-3 promotes NHEJ via NONO/SFPQ/EGFR/DNA-PKcs and mediates HIF1α/ROS-dependent IGF sequestration in cardiomyocytes.","evidence":"LC-MS/MS interactome, reciprocal Co-IP, PLA, cell-free binding and end-joining assays with PARP/EGFR/DNA-PKcs inhibitors; Co-IP, siRNA/antibody rescue and diabetic rat echocardiography","pmids":["30725116","30659610"],"confidence":"High","gaps":["How nuclear IGFBP-3 nucleates the repair complex structurally is unknown","Cardiac axis is Medium-confidence single lab"]},{"year":2020,"claim":"Mapped additional inducers (BMP2/ALK3/ID1) and effectors (THBS1, MMP2, hepatic lipid droplets), positioning IGFBP3 in angiogenesis, stromal migration, and steatosis.","evidence":"Inducible IGFBP3 with THBS1 siRNA and angiogenesis assays distinguishing intracellular vs. extracellular promoter activation; sequential BMP2/ALK3/ID1/IGFBP3 knockdowns; HSC-selective NRP-1 KO with recombinant IGFBP3 hepatocyte treatment","pmids":["32642286","32975335","32087348"],"confidence":"Medium","gaps":["Intracellular signaling activating THBS1 transcription not defined","Receptor mediating hepatocyte lipid response unidentified"]},{"year":2022,"claim":"Confirmed TMEM219 as a beta-cell death receptor for IGFBP3 and uncovered roles in mitochondrial homeostasis and aging-related smooth muscle pathology.","evidence":"TMEM219 KO mice plus pharmacological IGFBP3/TMEM219 blockade with patient validation; gain/loss-of-function with Seahorse flux and sBNIP3L/NIX assays in corneal cells; IGFBP3 knockdown in aged CCSMCs","pmids":["35115561","34918377","35154570"],"confidence":"High","gaps":["TMEM219 intracellular signaling cascade incompletely defined","Mitochondrial and CCSMC mechanisms are Medium/Low confidence single lab"]},{"year":2023,"claim":"Identified m6A/METTL3 post-transcriptional control and a c-Jun-driven TGF-β/EGFRvIII positive feedback loop driving IGFBP3 in fibrosis and glioblastoma.","evidence":"MeRIP-seq with METTL3/IGFBP3 knockdown in cardiac fibrosis models; ChIP for c-Jun binding to the IGFBP3 promoter with Smad/ERK pathway dissection","pmids":["36657656","37192967"],"confidence":"Medium","gaps":["m6A reader mediating IGFBP3 stabilization not identified","Feedback loop receptor/ligand stoichiometry unresolved"]},{"year":2024,"claim":"Demonstrated that IGFBP3-driven EGFR/DNA-PKcs DNA repair confers PARP inhibitor resistance, giving therapeutic relevance to its nuclear repair function.","evidence":"Olaparib-resistant prostate cancer cells with IGFBP3 siRNA, gefitinib phenocopy, γH2AX and viability assays","pmids":["38327800"],"confidence":"Medium","gaps":["Direct molecular link between IGFBP3 and EGFR activation not biochemically resolved","In vivo resistance reversal not shown"]},{"year":null,"claim":"The molecular identity and signaling logic of the non-TMEM219 'IGFBP-3 receptor' (e.g., the retinal endothelial receptor) and the structural basis by which nuclear IGFBP-3 nucleates transcription and DNA-repair complexes remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Retinal IGFBP-3 receptor not molecularly cloned","No structure of nuclear IGFBP-3 in complex with RXRα or NONO/SFPQ","Mechanism of cell entry for intracellular functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[6,18,25,32]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,7,8,35]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,14]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,6,25]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11,4,10,22]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,8,1]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3,18,1]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4,34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[17,18,34,32]}],"complexes":["IGF-1/IGFBP3/ALS ternary complex","Nuclear IGFBP3-NONO-SFPQ-EGFR-DNA-PKcs DNA-repair complex"],"partners":["TMEM219","IGF1","RXRA","NONO","SFPQ","GSK3B","EGFR","IGF1R"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P17936","full_name":"Insulin-like growth factor-binding protein 3","aliases":[],"length_aa":291,"mass_kda":31.7,"function":"Multifunctional protein that plays a critical role in regulating the availability of IGFs such as IGF1 and IGF2 to their receptors and thereby regulates IGF-mediated cellular processes including proliferation, differentiation, and apoptosis in a cell-type specific manner (PubMed:10874028, PubMed:19556345). Also exhibits IGF-independent antiproliferative and apoptotic effects mediated by its receptor TMEM219/IGFBP-3R (PubMed:20353938). Inhibits the positive effect of humanin on insulin sensitivity (PubMed:19623253). Promotes testicular germ cell apoptosis (PubMed:19952275). Acts via LRP-1/alpha2M receptor, also known as TGF-beta type V receptor, to mediate cell growth inhibition independent of IGF1 (PubMed:9252371). Mechanistically, induces serine-specific dephosphorylation of IRS1 or IRS2 upon ligation to its receptor, leading to the inhibitory cascade (PubMed:15371331). In the nucleus, interacts with transcription factors such as retinoid X receptor-alpha/RXRA to regulate transcriptional signaling and apoptosis (PubMed:10874028)","subcellular_location":"Secreted; Nucleus","url":"https://www.uniprot.org/uniprotkb/P17936/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IGFBP3","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IGFBP3","total_profiled":1310},"omim":[{"mim_id":"620290","title":"TRANSMEMBRANE PROTEIN 219; TMEM219","url":"https://www.omim.org/entry/620290"},{"mim_id":"619489","title":"SHORT STATURE, DAUBER-ARGENTE TYPE; SSDA","url":"https://www.omim.org/entry/619489"},{"mim_id":"619485","title":"PAPPALYSIN 2; PAPPA2","url":"https://www.omim.org/entry/619485"},{"mim_id":"618907","title":"SILVER-RUSSELL SYNDROME 4; SRS4","url":"https://www.omim.org/entry/618907"},{"mim_id":"618905","title":"SILVER-RUSSELL SYNDROME 2; SRS2","url":"https://www.omim.org/entry/618905"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"placenta","ntpm":1748.7}],"url":"https://www.proteinatlas.org/search/IGFBP3"},"hgnc":{"alias_symbol":["IBP3","BP-53"],"prev_symbol":[]},"alphafold":{"accession":"P17936","domains":[{"cath_id":"4.10.40.20","chopping":"44-126","consensus_level":"high","plddt":90.75,"start":44,"end":126},{"cath_id":"4.10.800.10","chopping":"208-278","consensus_level":"medium","plddt":81.2162,"start":208,"end":278}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P17936","model_url":"https://alphafold.ebi.ac.uk/files/AF-P17936-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P17936-F1-predicted_aligned_error_v6.png","plddt_mean":68.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IGFBP3","jax_strain_url":"https://www.jax.org/strain/search?query=IGFBP3"},"sequence":{"accession":"P17936","fasta_url":"https://rest.uniprot.org/uniprotkb/P17936.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P17936/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P17936"}},"corpus_meta":[{"pmid":"20472501","id":"PMC_20472501","title":"Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies.","date":"2010","source":"The Lancet. Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20472501","citation_count":520,"is_preprint":false},{"pmid":"17567756","id":"PMC_17567756","title":"IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17567756","citation_count":143,"is_preprint":false},{"pmid":"19279229","id":"PMC_19279229","title":"Perspectives in mammalian IGFBP-3 biology: local vs. systemic action.","date":"2009","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19279229","citation_count":140,"is_preprint":false},{"pmid":"11376125","id":"PMC_11376125","title":"Signalling pathways involved in antiproliferative effects of IGFBP-3: a review.","date":"2001","source":"Molecular pathology : MP","url":"https://pubmed.ncbi.nlm.nih.gov/11376125","citation_count":139,"is_preprint":false},{"pmid":"16306136","id":"PMC_16306136","title":"IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer.","date":"2005","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16306136","citation_count":137,"is_preprint":false},{"pmid":"25059666","id":"PMC_25059666","title":"MicroRNA-21 promotes glioblastoma tumorigenesis by down-regulating insulin-like growth factor-binding protein-3 (IGFBP3).","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25059666","citation_count":136,"is_preprint":false},{"pmid":"26522455","id":"PMC_26522455","title":"Insulin-like growth factor binding-protein-3 (IGFBP-3).","date":"2015","source":"Best practice & research. Clinical endocrinology & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26522455","citation_count":130,"is_preprint":false},{"pmid":"15979304","id":"PMC_15979304","title":"Essential roles of IGFBP-3 and IGFBP-rP1 in breast cancer.","date":"2005","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/15979304","citation_count":120,"is_preprint":false},{"pmid":"15247132","id":"PMC_15247132","title":"Associations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer.","date":"2004","source":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15247132","citation_count":94,"is_preprint":false},{"pmid":"32500027","id":"PMC_32500027","title":"Insulin Growth Factor Binding Protein 7 (IGFBP7)-Related Cancer and IGFBP3 and IGFBP7 Crosstalk.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32500027","citation_count":85,"is_preprint":false},{"pmid":"10873390","id":"PMC_10873390","title":"P53 and IGFBP-3: apoptosis and cancer protection.","date":"2000","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/10873390","citation_count":85,"is_preprint":false},{"pmid":"9594576","id":"PMC_9594576","title":"Molecular regulation of insulin-like growth factor-I and its principal binding protein, IGFBP-3.","date":"1998","source":"Progress in nucleic acid research and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9594576","citation_count":82,"is_preprint":false},{"pmid":"16723126","id":"PMC_16723126","title":"Characterization of the expression of the hypoxia-induced genes neuritin, TXNIP and IGFBP3 in cancer.","date":"2006","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/16723126","citation_count":80,"is_preprint":false},{"pmid":"18753603","id":"PMC_18753603","title":"Progesterone regulates FGF10, MET, IGFBP1, and IGFBP3 in the endometrium of the ovine uterus.","date":"2008","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/18753603","citation_count":79,"is_preprint":false},{"pmid":"31982427","id":"PMC_31982427","title":"Salvianolic acid B improves myocardial function in diabetic cardiomyopathy by suppressing IGFBP3.","date":"2020","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/31982427","citation_count":77,"is_preprint":false},{"pmid":"30725116","id":"PMC_30725116","title":"IGFBP-3 interacts with NONO and SFPQ in PARP-dependent DNA damage repair in triple-negative breast cancer.","date":"2019","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/30725116","citation_count":71,"is_preprint":false},{"pmid":"27329260","id":"PMC_27329260","title":"Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits.","date":"2016","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/27329260","citation_count":70,"is_preprint":false},{"pmid":"26431183","id":"PMC_26431183","title":"Circulating IGF-I and IGFBP3 Levels Control Human Colonic Stem Cell Function and Are Disrupted in Diabetic Enteropathy.","date":"2015","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/26431183","citation_count":69,"is_preprint":false},{"pmid":"27736013","id":"PMC_27736013","title":"IGFBP3 and MAPK/ERK signaling mediates melatonin-induced antitumor activity in prostate cancer.","date":"2016","source":"Journal of pineal research","url":"https://pubmed.ncbi.nlm.nih.gov/27736013","citation_count":63,"is_preprint":false},{"pmid":"19158946","id":"PMC_19158946","title":"IGFBP3 colocalizes with and regulates hypocretin (orexin).","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19158946","citation_count":61,"is_preprint":false},{"pmid":"24953254","id":"PMC_24953254","title":"IGFBP-3: a cell fate pivot in cancer and disease.","date":"2014","source":"Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society","url":"https://pubmed.ncbi.nlm.nih.gov/24953254","citation_count":59,"is_preprint":false},{"pmid":"34502376","id":"PMC_34502376","title":"IGF-1 and IGFBP-3 in Inflammatory Cachexia.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34502376","citation_count":58,"is_preprint":false},{"pmid":"32087348","id":"PMC_32087348","title":"Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12.","date":"2020","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/32087348","citation_count":58,"is_preprint":false},{"pmid":"17724372","id":"PMC_17724372","title":"IGF-1 and IGFBP-3 gene variants influence on serum levels and prostate cancer risk in African-Americans.","date":"2007","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/17724372","citation_count":53,"is_preprint":false},{"pmid":"35115561","id":"PMC_35115561","title":"The IGFBP3/TMEM219 pathway regulates beta cell homeostasis.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35115561","citation_count":49,"is_preprint":false},{"pmid":"28807942","id":"PMC_28807942","title":"Nuclear FAK and Runx1 Cooperate to Regulate IGFBP3, Cell-Cycle Progression, and Tumor Growth.","date":"2017","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28807942","citation_count":49,"is_preprint":false},{"pmid":"21932422","id":"PMC_21932422","title":"Serum IGF1, IGF2 and IGFBP3 and risk of advanced colorectal adenoma.","date":"2011","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21932422","citation_count":48,"is_preprint":false},{"pmid":"28330997","id":"PMC_28330997","title":"IGFBP3 Modulates Lung Tumorigenesis and Cell Growth through IGF1 Signaling.","date":"2017","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/28330997","citation_count":47,"is_preprint":false},{"pmid":"19784788","id":"PMC_19784788","title":"Association of IGF1 and IGFBP3 polymorphisms with colorectal polyps and colorectal cancer risk.","date":"2009","source":"Cancer causes & control : CCC","url":"https://pubmed.ncbi.nlm.nih.gov/19784788","citation_count":46,"is_preprint":false},{"pmid":"22415309","id":"PMC_22415309","title":"Hypoxia induces IGFBP3 in esophageal squamous cancer cells through HIF-1α-mediated mRNA transcription and continuous protein synthesis.","date":"2012","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/22415309","citation_count":46,"is_preprint":false},{"pmid":"26975989","id":"PMC_26975989","title":"Pancreatic cancer cell-derived IGFBP-3 contributes to muscle wasting.","date":"2016","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/26975989","citation_count":45,"is_preprint":false},{"pmid":"11886859","id":"PMC_11886859","title":"Identification of STAT-1 as a molecular target of IGFBP-3 in the process of chondrogenesis.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11886859","citation_count":45,"is_preprint":false},{"pmid":"32703944","id":"PMC_32703944","title":"Hsa_circ_0046263 functions as a ceRNA to promote nasopharyngeal carcinoma progression by upregulating IGFBP3.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32703944","citation_count":44,"is_preprint":false},{"pmid":"30641835","id":"PMC_30641835","title":"Suppression of tumor growth via IGFBP3 depletion as a potential treatment in glioma.","date":"2019","source":"Journal of neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/30641835","citation_count":43,"is_preprint":false},{"pmid":"19858071","id":"PMC_19858071","title":"Common genetic variation in IGF1, IGFBP1 and IGFBP3 and ovarian cancer risk.","date":"2009","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/19858071","citation_count":40,"is_preprint":false},{"pmid":"23868984","id":"PMC_23868984","title":"IGFBP-3 and TNF-α regulate retinal endothelial cell apoptosis.","date":"2013","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/23868984","citation_count":40,"is_preprint":false},{"pmid":"24668606","id":"PMC_24668606","title":"Aflatoxin exposure is inversely associated with IGF1 and IGFBP3 levels in vitro and in Kenyan schoolchildren.","date":"2014","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/24668606","citation_count":39,"is_preprint":false},{"pmid":"22401581","id":"PMC_22401581","title":"IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors.","date":"2012","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22401581","citation_count":39,"is_preprint":false},{"pmid":"36657656","id":"PMC_36657656","title":"IGFBP3 epigenetic promotion induced by METTL3 boosts cardiac fibroblast activation and fibrosis.","date":"2023","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36657656","citation_count":38,"is_preprint":false},{"pmid":"12118329","id":"PMC_12118329","title":"IGFBP-3 mediates p53-induced apoptosis during serum starvation.","date":"2002","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12118329","citation_count":38,"is_preprint":false},{"pmid":"22004906","id":"PMC_22004906","title":"IGF1 and IGFBP3 in acute respiratory distress syndrome.","date":"2011","source":"European journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/22004906","citation_count":37,"is_preprint":false},{"pmid":"24824313","id":"PMC_24824313","title":"Insulin-like growth factor pathway genetic polymorphisms, circulating IGF1 and IGFBP3, and prostate cancer survival.","date":"2014","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/24824313","citation_count":36,"is_preprint":false},{"pmid":"12150629","id":"PMC_12150629","title":"The effects of tonsillectomy and adenoidectomy on serum IGF-I and IGFBP3 levels in children.","date":"2002","source":"The Laryngoscope","url":"https://pubmed.ncbi.nlm.nih.gov/12150629","citation_count":35,"is_preprint":false},{"pmid":"23831640","id":"PMC_23831640","title":"TGF-β-induced expression of IGFBP-3 regulates IGF1R signaling in human osteosarcoma cells.","date":"2013","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23831640","citation_count":35,"is_preprint":false},{"pmid":"8817665","id":"PMC_8817665","title":"The role of glycosylation in the action of IGFBP-3.","date":"1995","source":"Progress in growth factor research","url":"https://pubmed.ncbi.nlm.nih.gov/8817665","citation_count":34,"is_preprint":false},{"pmid":"29772705","id":"PMC_29772705","title":"B-Myb Mediates Proliferation and Migration of Non-Small-Cell Lung Cancer via Suppressing IGFBP3.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29772705","citation_count":33,"is_preprint":false},{"pmid":"30659610","id":"PMC_30659610","title":"ROS- and HIF1α-dependent IGFBP3 upregulation blocks IGF1 survival signaling and thereby mediates high-glucose-induced cardiomyocyte apoptosis.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30659610","citation_count":32,"is_preprint":false},{"pmid":"34349117","id":"PMC_34349117","title":"TRAIP modulates the IGFBP3/AKT pathway to enhance the invasion and proliferation of osteosarcoma by promoting KANK1 degradation.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34349117","citation_count":32,"is_preprint":false},{"pmid":"33041662","id":"PMC_33041662","title":"Circ_0000285 regulates proliferation, migration, invasion and apoptosis of osteosarcoma by miR-409-3p/IGFBP3 axis.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33041662","citation_count":32,"is_preprint":false},{"pmid":"32742448","id":"PMC_32742448","title":"Graphene Oxide Nanoparticles Induce Apoptosis in wild-type and CRISPR/Cas9-IGF/IGFBP3 knocked-out Osteosarcoma Cells.","date":"2020","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32742448","citation_count":32,"is_preprint":false},{"pmid":"20003326","id":"PMC_20003326","title":"Promoter methylation of IGFBP-3 and p53 expression in ovarian endometrioid carcinoma.","date":"2009","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20003326","citation_count":31,"is_preprint":false},{"pmid":"16210470","id":"PMC_16210470","title":"EGF-mediated regulation of IGFBP-3 determines esophageal epithelial cellular response to IGF-I.","date":"2005","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16210470","citation_count":31,"is_preprint":false},{"pmid":"32975335","id":"PMC_32975335","title":"The regulation of IGFBP3 by BMP2 has a role in human endometrial remodeling.","date":"2020","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/32975335","citation_count":30,"is_preprint":false},{"pmid":"21195059","id":"PMC_21195059","title":"IGFBP3 and BAG1 enhance radiation-induced apoptosis in squamous esophageal cancer cells.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21195059","citation_count":30,"is_preprint":false},{"pmid":"26216267","id":"PMC_26216267","title":"Humanin Peptide Binds to Insulin-Like Growth Factor-Binding Protein 3 (IGFBP3) and Regulates Its Interaction with Importin-β.","date":"2015","source":"Protein and peptide letters","url":"https://pubmed.ncbi.nlm.nih.gov/26216267","citation_count":28,"is_preprint":false},{"pmid":"33378445","id":"PMC_33378445","title":"IGF-I/IGFBP3/ALS Deficiency in Sarcopenia: Low GHBP Suggests GH Resistance in a Subgroup of Geriatric Patients.","date":"2021","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/33378445","citation_count":28,"is_preprint":false},{"pmid":"25277046","id":"PMC_25277046","title":"Targeted mass spectrometry analysis of the proteins IGF1, IGF2, IBP2, IBP3 and A2GL by blood protein precipitation.","date":"2014","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/25277046","citation_count":25,"is_preprint":false},{"pmid":"34094948","id":"PMC_34094948","title":"XBP1- IGFBP3 Signaling Pathway Promotes NSCLC Invasion and Metastasis.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34094948","citation_count":25,"is_preprint":false},{"pmid":"8817671","id":"PMC_8817671","title":"Serum proteolysis of IGFBP-3.","date":"1995","source":"Progress in growth factor research","url":"https://pubmed.ncbi.nlm.nih.gov/8817671","citation_count":24,"is_preprint":false},{"pmid":"29579543","id":"PMC_29579543","title":"IGFBP-3 plays an important role in senescence as an aging marker.","date":"2018","source":"Environmental toxicology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29579543","citation_count":24,"is_preprint":false},{"pmid":"29522154","id":"PMC_29522154","title":"RSRC1 mutation affects intellect and behaviour through aberrant splicing and transcription, downregulating IGFBP3.","date":"2018","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/29522154","citation_count":22,"is_preprint":false},{"pmid":"35294528","id":"PMC_35294528","title":"BMI and Contraceptives Affect New Age-, Sex-, and Puberty-adjusted IGF-I and IGFBP-3 Reference Ranges Across Life Span.","date":"2022","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/35294528","citation_count":22,"is_preprint":false},{"pmid":"34100890","id":"PMC_34100890","title":"IGFBP-3 Mediates Metabolic Homeostasis During Hyperosmolar Stress in the Corneal Epithelium.","date":"2021","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/34100890","citation_count":22,"is_preprint":false},{"pmid":"23878061","id":"PMC_23878061","title":"SND1 affects proliferation of hepatocellular carcinoma cell line SMMC-7721 by regulating IGFBP3 expression.","date":"2013","source":"Anatomical record (Hoboken, N.J. : 2007)","url":"https://pubmed.ncbi.nlm.nih.gov/23878061","citation_count":22,"is_preprint":false},{"pmid":"35154570","id":"PMC_35154570","title":"Upregulated IGFBP3 with Aging Is Involved in Modulating Apoptosis, Oxidative Stress, and Fibrosis: A Target of Age-Related Erectile Dysfunction.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/35154570","citation_count":22,"is_preprint":false},{"pmid":"30078228","id":"PMC_30078228","title":"Mutual regulation between IGF-1R and IGFBP-3 in human corneal epithelial cells.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30078228","citation_count":22,"is_preprint":false},{"pmid":"17210081","id":"PMC_17210081","title":"IGFBP3 mRNA expression in benign and malignant breast tumors.","date":"2007","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/17210081","citation_count":21,"is_preprint":false},{"pmid":"30815935","id":"PMC_30815935","title":"Testis-specific protein, Y-linked 1 activates PI3K/AKT and RAS signaling pathways through suppressing IGFBP3 expression during tumor progression.","date":"2019","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/30815935","citation_count":21,"is_preprint":false},{"pmid":"39232384","id":"PMC_39232384","title":"METTL3 inhibitor suppresses the progression of prostate cancer via IGFBP3/AKT pathway and synergizes with PARP inhibitor.","date":"2024","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/39232384","citation_count":20,"is_preprint":false},{"pmid":"32642286","id":"PMC_32642286","title":"IGFBP3 inhibits angiogenesis through intracellular regulation of THBS1 expression.","date":"2020","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32642286","citation_count":20,"is_preprint":false},{"pmid":"26304028","id":"PMC_26304028","title":"The association between circulating IGF1, IGFBP3, and calcium: results from NHANES III.","date":"2015","source":"Endocrine connections","url":"https://pubmed.ncbi.nlm.nih.gov/26304028","citation_count":20,"is_preprint":false},{"pmid":"38177295","id":"PMC_38177295","title":"Elevated expression of WSB2 degrades p53 and activates the IGFBP3-AKT-mTOR-dependent pathway to drive hepatocellular carcinoma.","date":"2024","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38177295","citation_count":19,"is_preprint":false},{"pmid":"19449212","id":"PMC_19449212","title":"IGFBP3 polymorphisms and risk of cancer: a meta-analysis.","date":"2009","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/19449212","citation_count":19,"is_preprint":false},{"pmid":"27377812","id":"PMC_27377812","title":"IGFBP-3 inhibits Wnt signaling in metastatic melanoma cells.","date":"2016","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/27377812","citation_count":19,"is_preprint":false},{"pmid":"20350746","id":"PMC_20350746","title":"Influence of IGFBP3 gene polymorphisms on IGFBP3 serum levels and the risk of prostate cancer in low-risk Korean men.","date":"2010","source":"Urology","url":"https://pubmed.ncbi.nlm.nih.gov/20350746","citation_count":19,"is_preprint":false},{"pmid":"33188835","id":"PMC_33188835","title":"IGFBP-3 stimulates human osteosarcoma cell migration by upregulating VCAM-1 expression.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33188835","citation_count":18,"is_preprint":false},{"pmid":"34918377","id":"PMC_34918377","title":"IGFBP-3 functions as a molecular switch that mediates mitochondrial and metabolic homeostasis.","date":"2022","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/34918377","citation_count":18,"is_preprint":false},{"pmid":"30335898","id":"PMC_30335898","title":"Investigation of IGF1, IGF2BP2, and IGFBP3 variants with lymph node status and esophagogastric junction adenocarcinoma risk.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30335898","citation_count":17,"is_preprint":false},{"pmid":"31317059","id":"PMC_31317059","title":"Predictive and targeting value of IGFBP-3 in therapeutically resistant prostate cancer.","date":"2019","source":"American journal of clinical and experimental urology","url":"https://pubmed.ncbi.nlm.nih.gov/31317059","citation_count":17,"is_preprint":false},{"pmid":"30429106","id":"PMC_30429106","title":"ADAM28 promotes tumor growth and dissemination of acute myeloid leukemia through IGFBP-3 degradation and IGF-I-induced cell proliferation.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30429106","citation_count":17,"is_preprint":false},{"pmid":"36602546","id":"PMC_36602546","title":"Doxorubicin induced ROS-dependent HIF1α activation mediates blockage of IGF1R survival signaling by IGFBP3 promotes cardiac apoptosis.","date":"2023","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/36602546","citation_count":16,"is_preprint":false},{"pmid":"23291901","id":"PMC_23291901","title":"Regulation of retinal endothelial cell apoptosis through activation of the IGFBP-3 receptor.","date":"2013","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/23291901","citation_count":16,"is_preprint":false},{"pmid":"35798794","id":"PMC_35798794","title":"Roles of IGFBP-3 in cell migration and growth in an endophytic tongue squamous cell carcinoma cell line.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35798794","citation_count":15,"is_preprint":false},{"pmid":"38186306","id":"PMC_38186306","title":"CDK12 regulates angiogenesis of advanced prostate cancer by IGFBP3.","date":"2024","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38186306","citation_count":15,"is_preprint":false},{"pmid":"31400542","id":"PMC_31400542","title":"Regulation of IGF-I by IGFBP3 and IGFBP5 during odontoblast differentiation in mice.","date":"2019","source":"Journal of oral biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/31400542","citation_count":15,"is_preprint":false},{"pmid":"32129151","id":"PMC_32129151","title":"MiR-384 Inhibits Malignant Biological Behavior Such as Proliferation and Invasion of Osteosarcoma by Regulating IGFBP3.","date":"2020","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/32129151","citation_count":15,"is_preprint":false},{"pmid":"38327800","id":"PMC_38327800","title":"IGFBP3 promotes resistance to Olaparib via modulating EGFR signaling in advanced prostate cancer.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38327800","citation_count":14,"is_preprint":false},{"pmid":"19846909","id":"PMC_19846909","title":"The expression and function of IGFBP-3 in normal and malignant breast tissue.","date":"2009","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19846909","citation_count":14,"is_preprint":false},{"pmid":"19342998","id":"PMC_19342998","title":"The metal-binding domain of IGFBP-3 selectively delivers therapeutic molecules into cancer cells.","date":"2009","source":"Anti-cancer drugs","url":"https://pubmed.ncbi.nlm.nih.gov/19342998","citation_count":14,"is_preprint":false},{"pmid":"25947142","id":"PMC_25947142","title":"Circulating IGF1 and IGFBP3 in relation to the development of β-cell autoimmunity in young children.","date":"2015","source":"European journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/25947142","citation_count":13,"is_preprint":false},{"pmid":"17451653","id":"PMC_17451653","title":"Epigenetic and functional analysis of IGFBP3 and IGFBPrP1 in cellular immortalization.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17451653","citation_count":13,"is_preprint":false},{"pmid":"25556430","id":"PMC_25556430","title":"Induction of apoptosis by IGFBP3 overexpression in hepatocellular carcinoma cells.","date":"2014","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/25556430","citation_count":13,"is_preprint":false},{"pmid":"20039319","id":"PMC_20039319","title":"IGF1, IGFBP1, and IGFBP3 genes and mammographic density: the Multiethnic Cohort.","date":"2010","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20039319","citation_count":13,"is_preprint":false},{"pmid":"31658437","id":"PMC_31658437","title":"Associations of plasma IGF1, IGFBP3 and estradiol with leucocyte telomere length, a marker of biological age, in men.","date":"2020","source":"European journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/31658437","citation_count":13,"is_preprint":false},{"pmid":"37192967","id":"PMC_37192967","title":"IGFBP3 induced by the TGF-β/EGFRvIII transactivation contributes to the malignant phenotype of glioblastoma.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37192967","citation_count":12,"is_preprint":false},{"pmid":"31866567","id":"PMC_31866567","title":"Igfbp3 in grass carp (Ctenopharyngodon idellus): Molecular identification and mRNA expression under glucose, insulin and glucagon.","date":"2019","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/31866567","citation_count":12,"is_preprint":false},{"pmid":"20084546","id":"PMC_20084546","title":"IGFBP3 A-202C polymorphism and breast cancer susceptibility: a meta-analysis involving 33,557 cases and 45,254 controls.","date":"2010","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/20084546","citation_count":12,"is_preprint":false},{"pmid":"30370550","id":"PMC_30370550","title":"Effects of IGFBP3 gene silencing mediated inhibition of ERK/MAPK signaling pathway on proliferation, apoptosis, autophagy, and cell senescence in rats nucleus pulposus cells.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30370550","citation_count":12,"is_preprint":false},{"pmid":"32929656","id":"PMC_32929656","title":"IGFBP3 gene promoter methylation analysis and its association with clinicopathological characteristics of colorectal carcinoma.","date":"2020","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/32929656","citation_count":11,"is_preprint":false},{"pmid":"35871161","id":"PMC_35871161","title":"SALIS transcriptionally represses IGFBP3/Caspase-7-mediated apoptosis by associating with STAT5A to promote hepatocellular carcinoma.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35871161","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56307,"output_tokens":10341,"usd":0.162018,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20764,"output_tokens":6456,"usd":0.13261,"stage2_stop_reason":"end_turn"},"total_usd":0.294628,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"IGFBP3 binds its receptor TMEM219 on colonic stem cells (CoSCs) in an IGF-I-independent manner, leading to disruption of CoSC function and prevention of organoid growth in vitro; restoration of normal IGFBP3/IGF-I levels rescued CoSC homeostasis.\",\n      \"method\": \"In vitro organoid growth assay, recombinant ecto-TMEM219 protein treatment, preclinical diabetic enteropathy model, proteomic profiling of patient serum\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal in vitro and in vivo experiments with receptor identification, multiple orthogonal methods (organoids, recombinant protein rescue, preclinical model), replicated in patient cohorts\",\n      \"pmids\": [\"26431183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGFBP3 signals through the death receptor TMEM219 on pancreatic beta cells, causing beta cell loss and dysfunction; genetic ablation of TMEM219 or pharmacological blockade of IGFBP3/TMEM219 preserved beta cell mass and prevented/delayed diabetes onset in preclinical models.\",\n      \"method\": \"TMEM219 knockout mice, in vitro beta cell treatment, in vivo IGFBP3/TMEM219 inhibition, patient cohort validation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with pharmacological inhibition and patient data, multiple orthogonal methods in one study\",\n      \"pmids\": [\"35115561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IGFBP3 (using an IGF-binding-deficient mutant) upregulates STAT-1 mRNA and protein expression, induces STAT-1 phosphorylation and nuclear localization, and this IGF-independent STAT-1 induction mediates IGFBP3-induced apoptosis in chondrogenic cells; antisense STAT-1 oligonucleotides abolished IGFBP3-induced apoptosis.\",\n      \"method\": \"cDNA microarray, Northern blot, transfection with IGFBP3 mutant unable to bind IGFs, antisense oligonucleotide knockdown, immunolocalization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis (IGF-binding deficient mutant) plus functional rescue (antisense abolishes apoptosis), single lab but multiple orthogonal methods\",\n      \"pmids\": [\"11886859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IGFBP-3 mediates p53-induced apoptosis during serum starvation; inhibition of IGFBP-3 with antibody or antisense oligomers reduced apoptosis to levels comparable to p53 degradation, and IGF-I co-treatment blocked IGFBP-3-dependent apoptosis.\",\n      \"method\": \"Doxycycline-inducible p53 model (p53-negative PC-3 cells), stable E6-transfected H460 cells to degrade p53, anti-IGFBP-3 antibody neutralization, IGFBP-3 antisense oligomers\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two complementary cell models (gain and loss of p53), multiple inhibitory tools (antibody + antisense), single lab\",\n      \"pmids\": [\"12118329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IGFBP-3 forms nuclear complexes with NONO and SFPQ (DNA/RNA-binding proteins) in a PARP-dependent and EGFR/DNA-PKcs-dependent manner in triple-negative breast cancer cells, promoting DNA double-strand break repair by non-homologous end-joining; PARP inhibitors and LINP1 siRNA blocked these interactions.\",\n      \"method\": \"LC-MS/MS interactome analysis, co-immunoprecipitation, proximity ligation assay, cell-free biochemical binding assay, DNA end-joining in vitro assay, γH2AX foci measurement, EGFR/DNA-PKcs inhibitors, PARP inhibitors, siRNA\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal Co-IP confirmed by cell-free assay and proximity ligation, functional end-joining assay, multiple inhibitor controls, single lab\",\n      \"pmids\": [\"30725116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Hypoxia induces IGFBP3 mRNA transcription in esophageal squamous cancer cells via HIF-1α binding to a novel hypoxia-responsive element (HRE) at -57 kb upstream of the transcription start site; IGFBP3 mRNA is enriched in polysomes enabling continued cap-dependent translation under hypoxia, despite global protein synthesis suppression.\",\n      \"method\": \"RNA interference (HIF-1α/HIF-2α siRNA), chromatin immunoprecipitation (ChIP), transfection/luciferase assays, metabolic labeling, 7-methyl GTP-cap binding assay, mTOR inhibitors, bicistronic RNA reporter, polysome fractionation\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP + mutagenesis/reporter + polysome fractionation, multiple orthogonal methods in one study, single lab\",\n      \"pmids\": [\"22415309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EGF suppresses IGFBP-3 mRNA and protein expression through MAPK activation in an EGFR-tyrosine kinase-dependent manner; secreted IGFBP-3 neutralizes IGFs and prevents IGF-I receptor activation; wild-type but not IGF-binding-deficient (I56G/L80G/L81G) IGFBP-3 prevents IGF-I from activating IGF-IR and Akt, demonstrating that IGFBP-3's anti-proliferative effect on IGF signaling is IGF-binding dependent.\",\n      \"method\": \"Stable overexpression of wild-type vs. GGG mutant IGFBP-3, EGFR inhibitors, Western blot for IGF-IR and Akt phosphorylation, cell proliferation assays\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — side-by-side mutagenesis (GGG mutant) with functional readouts, EGFR inhibitor controls, single lab\",\n      \"pmids\": [\"16210470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TGF-β1 induces IGFBP-3 expression in osteosarcoma cells, and IGFBP-3 in turn attenuates TGF-β1 activation of ERK1/2 and Akt, inhibits TGF-β1-induced cell cycle progression and proliferation; blocking IGF1R signaling abolishes IGFBP-3's effect, and blocking IGFBP-3 induction enhances nuclear Smad2 phosphorylation — establishing a negative-feedback loop.\",\n      \"method\": \"IGFBP-3 knockdown/overexpression, IGF1R inhibition, Western blot for ERK1/2, Akt, pSmad2, cell cycle and proliferation assays\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissection using multiple inhibitors and KD, single lab, multiple readouts\",\n      \"pmids\": [\"23831640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IGFBP-3 inhibits Wnt signaling in metastatic melanoma cells by entering the cell, binding the Wnt signalosome component GSK-3β, dissociating the β-catenin destruction complex from the LRP6 receptor, activating GSK-3β through dephosphorylation, and targeting cytoplasmic β-catenin for proteasomal degradation; this effect depends on CD44.\",\n      \"method\": \"Recombinant IGFBP-3 treatment of cultured melanoma cells, co-immunoprecipitation with GSK-3β, β-catenin immunofluorescence/Western blot, proteasome inhibition, CD44 dependency assay, mouse xenograft\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of IGFBP-3 with GSK-3β, proteasome inhibitor rescue, CD44 dependency demonstrated, single lab\",\n      \"pmids\": [\"27377812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nuclear FAK cooperates with Runx1 to regulate IGFBP3 transcription in squamous cell carcinoma; FAK forms a molecular complex with Runx1 and interacts with Sin3a and other epigenetic modifiers that alter Runx1 transcriptional function, thereby controlling IGFBP3-dependent cell-cycle progression and tumor growth.\",\n      \"method\": \"Co-immunoprecipitation (FAK-Runx1 nuclear complex), genetic FAK nuclear localization models, luciferase reporter, in vivo tumor growth assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of nuclear FAK-Runx1 complex, in vivo tumor model, single lab\",\n      \"pmids\": [\"28807942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Humanin binds directly to IGFBP3 (Kd ~5.05 µM) and both humanin and its analogue HN 3-19 interfere with the binding of importin-β1 to IGFBP3 in vitro (IC50 ~18.1 µM and ~10.3 µM respectively), thereby blocking IGFBP3 nuclear translocation and reducing apoptosis in lung adenocarcinoma cells.\",\n      \"method\": \"Competitive ligand dot blotting, co-immunoprecipitation, ELISA-based binding assay, apoptosis assay in lung adenocarcinoma cells\",\n      \"journal\": \"Protein and peptide letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with Kd determination, competitive inhibition of importin-β1, functional apoptosis rescue, single lab\",\n      \"pmids\": [\"26216267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IGFBP-3 can be transported to the nucleus by an importin-β-mediated mechanism where it interacts with retinoid X receptor alpha (RXRα); IGFBP-3 antiproliferative signaling requires an active TGF-β signaling pathway and stimulates phosphorylation of TGF-β signaling intermediates Smad2 and Smad3.\",\n      \"method\": \"Transfection, nuclear transport assays, co-immunoprecipitation/interaction studies (review citing primary experimental data)\",\n      \"journal\": \"Molecular pathology : MP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — review synthesizing multiple experimental observations (importin-β transport, RXRα interaction, Smad2/3 phosphorylation) from primary experimental reports; moderate confidence due to review format\",\n      \"pmids\": [\"11376125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In oxygen-induced retinopathy, IGFBP3 acts independently of IGF-1 to prevent vessel loss and promote vascular regrowth; IGFBP3-deficient mice showed dose-dependent increase in retinal vessel loss and 31% decrease in vessel regrowth, while exogenous IGFBP3 increased vessel regrowth correlating with a 30% increase in endothelial progenitor cells in the retina.\",\n      \"method\": \"IGFBP3 knockout mice, exogenous IGFBP3 administration, oxygen-induced retinopathy model, retinal vessel quantification, endothelial progenitor cell quantification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus exogenous rescue in the same model, IGF-1 independence established (no serum IGF-1 difference), replicated with clinical data\",\n      \"pmids\": [\"17567756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IGFBP-3 and TNF-α work antagonistically in retinal endothelial cells: IGFBP-3 inhibits apoptosis while TNF-α promotes it; loss of IGFBP-3 signaling (IGFBP-3 KO mice) results in increased retinal apoptosis, decreased B-wave and oscillatory potential amplitudes, reduced retinal thickness, and elevated TNF-α levels.\",\n      \"method\": \"IGFBP-3 knockout mice, electroretinogram, retinal cell counting, treatment of retinal endothelial cells with IGFBP-3 and TNF-α\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple functional readouts, antagonism demonstrated by direct cell treatment, single lab\",\n      \"pmids\": [\"23868984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IGFBP-3 inhibits retinal endothelial cell (REC) death through activation of a specific IGFBP-3 receptor; siRNA knockdown of the IGFBP-3 receptor increased cell death, and IGFBP-3 overexpression upregulated IGFBP-3 receptor protein levels; co-immunoprecipitation confirmed IGFBP-3 and receptor binding; IGFBP-3 modulated Bcl-xL, Bax, cytochrome C and Akt in a receptor-dependent manner.\",\n      \"method\": \"IGFBP-3 receptor siRNA knockdown, IGFBP-3 plasmid overexpression (non-IGF-binding mutant), co-immunoprecipitation, cell death ELISA, caspase-3 ELISA, Western blot\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of IGFBP-3 with its receptor, siRNA rescue experiment, multiple downstream markers, single lab\",\n      \"pmids\": [\"23291901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IGFBP3 co-localizes with and regulates hypocretin (orexin) in hypothalamic neurons; transgenic mice overexpressing human IGFBP3 show decreased hypocretin mRNA, peptide content, and increased sleep, possibly mediated through decreased hypocretin promoter activity in the presence of excess IGFBP3.\",\n      \"method\": \"Gene expression profiling (microarray), in vivo transgenic overexpression, hypocretin mRNA and peptide quantification, sleep phenotyping, promoter activity assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic overexpression with functional (sleep) and molecular (mRNA/peptide) readouts, promoter activity data, single lab\",\n      \"pmids\": [\"19158946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IGFBP3 mediates lipid droplet formation and triglyceride accumulation in hepatocytes; recombinant IGFBP3 (secreted by activated hepatic stellate cells) induced lipid droplets and lipogenic genes in hepatocytes in vitro; NRP-1 deletion from HSCs reduced IGFBP3 secretion and protected hepatocytes from ethanol-induced steatosis.\",\n      \"method\": \"HSC-selective NRP-1 knockout (ColCre/Nrp1loxP mice), adipokine/inflammatory protein array, recombinant Igfbp3 treatment of hepatocytes, in vitro lipid droplet/triglyceride measurement, alcohol feeding model\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic HSC KO model plus recombinant protein treatment, direct hepatocyte readout, single lab\",\n      \"pmids\": [\"32087348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-21 directly targets IGFBP3 mRNA and downregulates IGFBP3 expression in glioblastoma; IGFBP3 overexpression inhibited tumor cell proliferation in vitro and xenograft growth in vivo; IGFBP3 knockdown in miR-21-knockdown cells restored tumorigenesis, placing IGFBP3 as a downstream effector of miR-21.\",\n      \"method\": \"Microarray, 3'-UTR luciferase reporter (miR-21 target validation), overexpression and knockdown of IGFBP3, rescue/epistasis experiment, xenograft mouse model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated miR-21→IGFBP3 targeting with reporter assay and epistasis rescue experiment, in vivo xenograft, single lab\",\n      \"pmids\": [\"25059666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IGFBP3 modulates lung tumor progression through IGF1 signaling; Igfbp3-null mice combined with Kras showed >2-fold increased lung tumor burden; overexpression of IGFBP3 in NSCLC cells induced apoptosis (10-fold increase in cleaved caspase-3) and inactivated IGF1 and MAPK signaling; IGF-binding-deficient IGFBP3 mutant partially retained activity, indicating both IGF-dependent and -independent mechanisms.\",\n      \"method\": \"Igfbp3-null mouse model crossed with Kras, overexpression of WT vs. IGF-binding-deficient mutant IGFBP3 in NSCLC cells, cleaved caspase-3 measurement, IGF1/MAPK signaling Western blot, cisplatin response assay\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — genetic KO mouse model plus mutagenesis (IGF-binding-deficient mutant), multiple functional readouts, in vivo and in vitro, single lab\",\n      \"pmids\": [\"28330997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pancreatic cancer cell-derived IGFBP-3 causes muscle wasting via IGF signaling inhibition; IGFBP-3 treatment of C2C12 muscle cells impaired myogenesis and enhanced muscle protein degradation; IGFBP3 knockdown in pancreatic cancer cells or antibody neutralization of IGFBP-3 in conditioned medium alleviated wasting.\",\n      \"method\": \"Conditioned medium from Capan-1 pancreatic cancer cells, IGFBP3 knockdown (siRNA), anti-IGFBP-3 antibody neutralization, myogenesis and protein degradation assays in C2C12 cells\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody neutralization and KD rescue in same experimental system, direct IGF signaling readout, single lab\",\n      \"pmids\": [\"26975989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"IGFBP-3 has three N-glycosylation sites (Asn89, Asn109, Asn172); site mutagenesis shows ~4, 5, and 6 kDa of carbohydrate at sites 1, 2, and 3 respectively; glycosylation is not required for secretion or IGF-I binding; the two native IGFBP-3 forms represent protein glycosylated at all three sites vs. only at Asn89/Asn109; glycosylation does not significantly affect acid-labile subunit (ALS) binding.\",\n      \"method\": \"Site-directed mutagenesis of N-glycosylation sites, ligand blotting with [125I]IGF-I, radioimmunoassay, ALS binding assay, expression in CHO cells\",\n      \"journal\": \"Progress in growth factor research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic site-directed mutagenesis of all three glycosylation sites with quantitative biochemical characterization, single lab\",\n      \"pmids\": [\"8817665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"IGFBP-3 in serum undergoes proteolytic degradation by the tissue plasminogen activator (tPA)-plasminogen-plasmin system, providing an additional mechanism for regulation of IGF bioavailability.\",\n      \"method\": \"Serum proteolysis assays with tPA-plasminogen-plasmin pathway identification\",\n      \"journal\": \"Progress in growth factor research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single biochemical assay described in a short review-format paper, limited methodological detail in abstract\",\n      \"pmids\": [\"8817671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IGFBP-3 mediates nuclear translocation of IGF-1R in corneal epithelial cells in response to growth factor withdrawal via SUMOylation by SUMO 2/3; IGF-1R and IGFBP-3 undergo reciprocal regulation independent of PI3K/Akt signaling; under growth conditions IGFBP-3 arrests the cell cycle in G0/G1, while under stress it maintains nuclear IGF-1R levels.\",\n      \"method\": \"Growth factor withdrawal model, SUMOylation assays (SUMO 2/3), nuclear fractionation, cell cycle analysis, PI3K/Akt inhibition\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SUMOylation mechanism established, nuclear translocation functionally characterized, PI3K-independence shown, single lab\",\n      \"pmids\": [\"30078228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGFBP-3 regulates mitochondrial homeostasis in corneal epithelial cells through control of the sBNIP3L/NIX mitophagy receptor; both loss and gain of IGFBP-3 function increase mitochondrial respiration; nuclear accumulation of IGFBP-3 is associated with increased respiration; IGFBP-3 also regulates lamellar cristae morphology and mitochondrial dynamics.\",\n      \"method\": \"Loss-of-function (siRNA/KD) and gain-of-function (overexpression) of IGFBP-3, Seahorse metabolic flux analysis, mitochondrial morphology imaging, sBNIP3L/NIX assays, nuclear fractionation\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complementary gain and loss of function, metabolic flux analysis, identification of mitophagy receptor as downstream effector, single lab\",\n      \"pmids\": [\"34918377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IGFBP-3 mediates metabolic homeostasis in corneal epithelial cells under hyperosmolar stress; hyperosmolarity decreases IGFBP-3 expression; supplementation with recombinant IGFBP-3 abrogates metabolic and mitochondrial changes (altered calcium, depolarization, decreased ATP and mtDNA) induced by hyperosmolar stress.\",\n      \"method\": \"hTCEpi cell hyperosmolar stress model, Seahorse metabolic flux analysis, mitochondrial calcium/polarization/mtDNA assays, ELISA for IGFBP-3 and cytokines, recombinant IGFBP-3 supplementation, LDH cytotoxicity assay\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein rescue with multiple metabolic/mitochondrial readouts, single lab\",\n      \"pmids\": [\"34100890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ROS- and HIF1α-dependent IGFBP3 upregulation under hyperglycemia leads to IGFBP3 secretion, sequestration of extracellular IGF1, blockade of IGF1 pro-survival signaling, and cardiomyocyte apoptosis; siRNA against IGFBP3 or anti-IGFBP3 antibody rescued cardiac apoptosis; HIF1α inhibition downregulated IGFBP3; PHD regulates HIF1α stability upstream of IGFBP3.\",\n      \"method\": \"Co-IP (IGF1-IGFBP3 extracellular association), Western blot, siRNA (IGFBP3, HIF1α), anti-IGFBP3 antibody, ROS scavenger, diabetic rat model, echocardiography\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of IGF1-IGFBP3 extracellular complex, siRNA and antibody rescue in parallel, in vivo cardiac functional readout, single lab\",\n      \"pmids\": [\"30659610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL3 promotes IGFBP3 expression via N6-methyladenosine (m6A) mRNA modification in cardiac fibroblasts; METTL3 silencing downregulates IGFBP3 and inhibits cardiac fibroblast activation; IGFBP3 knockdown inhibits migration and proliferation of cardiac fibroblasts.\",\n      \"method\": \"MeRIP-seq (m6A sequencing), METTL3 silencing, IGFBP3 knockdown, transverse aortic constriction and isoproterenol cardiac fibrosis models, migration/proliferation assays\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq established METTL3→m6A→IGFBP3 axis, KD in vivo and in vitro, single lab\",\n      \"pmids\": [\"36657656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IGFBP3 promoter methylation epigenetically silences IGFBP3 expression in hepatoblastoma (HB) cell lines; treatment with 5-aza-2'-deoxycytidine restored IGFBP3 expression; restoring IGFBP3 in HB cells reduced colony formation, migration, and invasion; IGFBP3 promoter methylation predominantly occurred in metastatic HB with vascular invasion.\",\n      \"method\": \"Bisulfite sequencing of IGFBP3 promoter CpGs, 5-aza-2'-deoxycytidine demethylation, IGFBP3 re-expression in cell lines, colony formation, migration and invasion assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic mechanism (bisulfite sequencing) plus functional rescue, single lab\",\n      \"pmids\": [\"22401581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IGFBP-3 contains a 22-amino acid metal-binding domain (MBD) that selectively targets cancer cells via cell surface cross-linking to transferrin receptor, caveolin 1, and integrin-β; MBD uptake rate correlates with gene expression of stress-response pathways (NF-κB, Hsp-70B); MBD-tagged cytotoxic peptides show selective cytotoxicity to cancer vs. normal cells and reduce tumor burden in mouse models.\",\n      \"method\": \"MBD cross-linking to cell surface receptors, correlation with NCI-60 gene array data, cytotoxicity assays, in vivo biodistribution, mouse leukemia/melanoma dissemination models\",\n      \"journal\": \"Anti-cancer drugs\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical cross-linking to multiple cell surface receptors with in vivo biodistribution confirmation, single lab\",\n      \"pmids\": [\"19342998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IGFBP3 inhibits angiogenesis by activating THBS1 (thrombospondin-1) transcription through intracellular signaling; IGFBP3 induction increased THBS1 in epithelial ovarian cancer cells; THBS1 silencing reversed IGFBP3-induced inhibition of capillary tube formation (HUVEC assay) and chick CAM vessel development; luciferase assay showed intracellular IGFBP3 more potently activated THBS1 promoter than extracellular IGFBP3.\",\n      \"method\": \"Inducible IGFBP3 expression system, THBS1 siRNA, HUVEC tube formation assay, chick CAM assay, xenograft, luciferase promoter assay\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter luciferase assay distinguishes intracellular vs. extracellular function, THBS1 siRNA rescue, multiple angiogenesis readouts, single lab\",\n      \"pmids\": [\"32642286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BMP2 upregulates IGFBP3 expression in human endometrial stromal cells via ALK3 receptor and the transcription factor ID1; IGFBP3 in turn promotes MMP2 expression and cell migration; knockdown of IGFBP3 or ID1 suppressed BMP2-induced MMP2 upregulation and cell migration.\",\n      \"method\": \"Immortalized and primary human endometrial stromal cells, BMP2 dose-response, ALK3 knockdown, ID1 knockdown, IGFBP3 knockdown, MMP2 measurement, migration assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ALK3→ID1→IGFBP3→MMP2 pathway established by sequential KD, single lab\",\n      \"pmids\": [\"32975335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Insulin increases IGFBP-3 gene transcription in hepatic nonparenchymal cells via an insulin-responsive element that recruits insulin-responsive nuclear factors (demonstrated by gel mobility shift assay and southwestern blot); IGF-I increases IGFBP-3 mRNA stability (post-transcriptional regulation).\",\n      \"method\": \"In vitro transcription assays, gel mobility shift assay, southwestern blot, mRNA stability analysis\",\n      \"journal\": \"Progress in nucleic acid research and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gel shift and southwestern blot identify nuclear factors binding insulin-responsive element, multiple regulatory mechanisms established, single lab review\",\n      \"pmids\": [\"9594576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADAM28 promotes IGF-I-induced leukemia cell proliferation by degrading IGFBP-3, thereby increasing free IGF-I availability; ADAM28 knockout reduced leukemic cell growth and dissemination in a xenotransplantation model.\",\n      \"method\": \"ADAM28 knockdown/knockout in leukemic cells, IGFBP-3 degradation assay, IGF-I proliferation assay, xenotransplantation mouse model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protease-substrate relationship established with in vivo xenotransplantation validation, single lab\",\n      \"pmids\": [\"30429106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TGF-β and EGFRvIII transactivation in glioblastoma cells activates c-Jun transcription factor via Smad2/3 and ERK1/2 pathways, which binds the IGFBP3 promoter to promote IGFBP3 production and secretion; IGFBP3 knockdown inhibited TGF-β/EGFRvIII signaling and malignant behaviors, revealing a positive feedback loop.\",\n      \"method\": \"TGF-β treatment of GBM cells, co-immunoprecipitation (Smad2/3, ERK1/2), ChIP (c-Jun binding to IGFBP3 promoter), IGFBP3 knockdown, in vitro/in vivo tumor assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates c-Jun binding to IGFBP3 promoter, pathway dissection with Smad/ERK inhibitors, single lab\",\n      \"pmids\": [\"37192967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGFBP3 promotes resistance to the PARP inhibitor olaparib in prostate cancer by enhancing DNA repair capacity through activation of EGFR and DNA-PKcs; IGFBP3 depletion reduces EGFR/DNA-PKcs activity, increases DNA damage accumulation, and re-sensitizes resistant cells to olaparib; gefitinib (EGFR inhibitor) phenocopies IGFBP3 inhibition.\",\n      \"method\": \"Olaparib-resistant cell line development, IGFBP3 siRNA knockdown, EGFR inhibition (gefitinib), DNA-PKcs assay, γH2AX foci, cell viability assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by phenocopy (IGFBP3 KD vs. gefitinib), DNA repair mechanistic readouts, single lab\",\n      \"pmids\": [\"38327800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SND1 knockdown in hepatocellular carcinoma cells increases IGFBP3 expression; increased IGFBP3 negatively regulates IGF pathway activation by restricting IGF-receptor interactions; conversely, IGFBP3 knockdown promotes cell proliferation, placing IGFBP3 downstream of SND1 as a negative regulator of IGF signaling in HCC.\",\n      \"method\": \"Stable SND1 shRNA knockdown, IGFBP3 stable knockdown, real-time PCR screening of IGF pathway genes, proliferation and tumor formation assays\",\n      \"journal\": \"Anatomical record\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway ordering by expression analysis and KD, no direct binding or biochemical assay for IGFBP3-receptor interaction, single lab\",\n      \"pmids\": [\"23878061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGFBP3 knockdown in aged corpus cavernosum smooth muscle cells (CCSMCs) increased cell viability and proliferation while decreasing apoptosis, oxidative stress, and fibrosis, identifying IGFBP3 upregulation with aging as a driver of these pathological processes in erectile dysfunction.\",\n      \"method\": \"siRNA knockdown of IGFBP3 in primary aged CCSMCs, flow cytometry (apoptosis), EdU/CCK-8 (proliferation), ROS assay, Western blot, immunofluorescence\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single KD approach in primary cells, multiple readouts but no mechanistic pathway placement beyond signaling markers, single lab\",\n      \"pmids\": [\"35154570\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IGFBP3 is a multifunctional secreted protein that acts both as an extracellular IGF-sequestering carrier (binding >75% of circulating IGF-1 in a 150-kDa ternary complex with ALS) and as an intracellular/nuclear signaling molecule with IGF-independent activities: it is transcriptionally induced by p53 and HIF-1α (via a distal HRE), transported to the nucleus by importin-β, where it interacts with RXRα, cooperates with nuclear FAK/Runx1, and promotes DNA repair through complexes containing EGFR, DNA-PKcs, NONO, and SFPQ; extracellularly it signals through the death receptor TMEM219 to regulate pancreatic beta-cell homeostasis and colonic stem cells, inhibits Wnt/GSK-3β/β-catenin signaling in melanoma cells, promotes vascular regrowth in the retina, activates STAT-1-dependent apoptosis in chondrocytes, suppresses IGF1R signaling via THBS1 and direct IGF sequestration, and undergoes proteolytic regulation by ADAM28 and plasmin; its expression is epigenetically silenced by promoter methylation and is post-transcriptionally regulated by m6A modification via METTL3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IGFBP3 is a secreted, multifunctional protein that controls insulin-like growth factor (IGF) bioavailability and executes IGF-independent signaling programs governing apoptosis, DNA repair, and tissue homeostasis [#6, #18]. As a carrier, it sequesters extracellular IGF-I and prevents IGF-IR and downstream Akt/MAPK activation; this anti-proliferative effect requires intact IGF binding, as an IGF-binding-deficient mutant fails to block IGF-I signaling, and IGFBP3 levels feed back negatively on TGF-\\u03b21- and SND1-driven IGF pathway activation [#6, #7, #18]. IGFBP3 carbohydrate occupancy at three N-glycosylation sites (Asn89, Asn109, Asn172) is dispensable for secretion, IGF-I binding, and ALS association [#20], and IGF availability is further tuned by proteolysis through ADAM28 and the plasmin system [#32, #21]. Independently of IGF, IGFBP3 is imported to the nucleus by importin-\\u03b2, where it engages RXR\\u03b1 and stimulates Smad2/3 phosphorylation, and assembles repair complexes with EGFR, DNA-PKcs, NONO and SFPQ that promote non-homologous end-joining \\u2014 a function that drives resistance to PARP inhibition in prostate cancer [#11, #4, #34]. As an apoptosis effector it transduces p53-induced death and drives chondrocyte apoptosis via IGF-independent STAT-1 induction [#3, #2]. Extracellularly, IGFBP3 signals through the death receptor TMEM219 to regulate colonic stem cells and pancreatic beta-cell homeostasis [#0, #1], inhibits Wnt/GSK-3\\u03b2/\\u03b2-catenin signaling in melanoma in a CD44-dependent manner [#8], transcriptionally activates the anti-angiogenic factor THBS1 [#29], and promotes retinal vascular regrowth and endothelial survival [#12, #13]. Its own expression is induced by hypoxia/HIF-1\\u03b1 via a distal HRE, by p53, insulin, TGF-\\u03b2/EGFRvIII, and BMP2 pathways, and is restrained by promoter methylation, miR-21, and METTL3-dependent m6A modification [#5, #27, #17, #26].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the post-translational architecture of IGFBP-3 by mapping which modifications and proteolytic events govern its carrier behavior, clarifying that glycosylation is structurally tolerated rather than functionally required.\",\n      \"evidence\": \"Site-directed mutagenesis of three N-glycosylation sites with ligand blotting and ALS binding assays; serum proteolysis assays identifying the tPA-plasminogen-plasmin pathway\",\n      \"pmids\": [\"8817665\", \"8817671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address how glycosylation affects nuclear import or non-IGF functions\", \"Proteolysis finding rests on a single biochemical assay in review format\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Answered how IGFBP3 transcription and mRNA stability are hormonally controlled, linking metabolic signals to IGF-binding capacity.\",\n      \"evidence\": \"In vitro transcription, gel mobility shift, southwestern blot, and mRNA stability analysis in hepatic nonparenchymal cells\",\n      \"pmids\": [\"9594576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Insulin-responsive nuclear factors not molecularly identified\", \"Review-format synthesis\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined a nuclear, IGF-independent mode of action by showing importin-\\u03b2 imports IGFBP-3 to the nucleus where it binds RXR\\u03b1 and engages TGF-\\u03b2/Smad signaling.\",\n      \"evidence\": \"Nuclear transport and co-immunoprecipitation studies synthesized in a review\",\n      \"pmids\": [\"11376125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review-format synthesis of primary data\", \"Functional consequence of RXR\\u03b1 binding not resolved here\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected IGFBP-3 to two distinct apoptotic programs \\u2014 as the effector of p53-induced apoptosis and as an inducer of IGF-independent STAT-1-mediated death.\",\n      \"evidence\": \"Inducible p53 cell models with antibody/antisense neutralization; cDNA microarray and IGF-binding-deficient mutant plus antisense STAT-1 knockdown in chondrogenic cells\",\n      \"pmids\": [\"12118329\", \"11886859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking nuclear IGFBP-3 to STAT-1 transcription not defined\", \"Cell-type generality of p53 axis untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved that IGFBP-3's anti-proliferative effect on IGF signaling is IGF-binding dependent, using a binding-deficient mutant to separate sequestration from receptor-level control.\",\n      \"evidence\": \"Stable WT vs. GGG (I56G/L80G/L81G) mutant overexpression with IGF-IR/Akt phosphorylation readouts and EGFR inhibitors\",\n      \"pmids\": [\"16210470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address IGF-independent functions of the same protein\", \"EGF\\u2192MAPK suppression mechanism of IGFBP3 not detailed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated IGF-independent tissue protection in vivo by showing IGFBP3 promotes retinal vascular regrowth and endothelial progenitor recruitment.\",\n      \"evidence\": \"IGFBP3 knockout mice plus exogenous IGFBP3 rescue in an oxygen-induced retinopathy model with vessel and EPC quantification\",\n      \"pmids\": [\"17567756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating retinal effect not identified in this study\", \"Molecular signaling downstream unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified a cancer-cell-targeting metal-binding domain and a neural regulatory role, broadening IGFBP3 functions beyond IGF biology.\",\n      \"evidence\": \"MBD cross-linking to transferrin receptor, caveolin-1, integrin-\\u03b2 with cytotoxicity and biodistribution assays; transgenic IGFBP3 overexpression with hypocretin/sleep phenotyping\",\n      \"pmids\": [\"19342998\", \"19158946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MBD surface partners not validated as physiological signaling receptors\", \"Hypocretin promoter regulation mechanism incomplete\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established hypoxia/HIF-1\\u03b1 and promoter methylation as opposing inducible and silencing controls of IGFBP3 expression in cancer.\",\n      \"evidence\": \"ChIP, reporter assays and polysome fractionation mapping a -57 kb HRE; bisulfite sequencing and 5-aza demethylation rescue in hepatoblastoma\",\n      \"pmids\": [\"22415309\", \"22401581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional output of hypoxia-induced IGFBP3 not assayed in the HRE study\", \"Methylation causality in vivo not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined IGFBP3 as a node in negative-feedback and survival circuits across osteosarcoma, retina, and HCC, restraining TGF-\\u03b21 and IGF signaling while protecting endothelial cells from apoptosis.\",\n      \"evidence\": \"Knockdown/overexpression with IGF1R inhibitors (osteosarcoma); IGFBP-3 KO mice with ERG/retinal readouts; receptor siRNA and Co-IP in retinal endothelial cells; SND1 and IGFBP3 knockdown in HCC\",\n      \"pmids\": [\"23831640\", \"23868984\", \"23291901\", \"23878061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The retinal IGFBP-3 receptor was not molecularly cloned/identified\", \"SND1\\u2192IGFBP3 ordering rests on expression analysis without direct binding data\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified TMEM219 as a bona fide IGFBP3 death receptor on stem cells and a humanin-importin\\u03b21 axis controlling nuclear entry, defining distinct receptor-dependent and nuclear signaling routes.\",\n      \"evidence\": \"Organoid assays with recombinant ecto-TMEM219 in diabetic enteropathy models; competitive binding and importin-\\u03b21 displacement assays with humanin\",\n      \"pmids\": [\"26431183\", \"26216267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TMEM219 downstream signaling not fully mapped\", \"Humanin study confidence Medium and single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended IGFBP3 signaling to intracellular Wnt suppression and cancer cachexia, showing it can enter cells to activate GSK-3\\u03b2 and that tumor-derived IGFBP3 drives muscle wasting.\",\n      \"evidence\": \"Recombinant IGFBP-3, Co-IP with GSK-3\\u03b2, proteasome inhibition and CD44 dependency in melanoma; conditioned medium with knockdown/antibody neutralization in C2C12 cells\",\n      \"pmids\": [\"27377812\", \"26975989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of IGFBP3 cell entry via CD44 not biochemically defined\", \"Cachexia receptor mediating muscle effect not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Clarified transcriptional control of IGFBP3 by nuclear FAK/Runx1 and dissected its dual IGF-dependent/-independent tumor-suppressive activity in lung cancer.\",\n      \"evidence\": \"FAK-Runx1 Co-IP and reporter assays with nuclear localization models; Igfbp3-null x Kras mice and WT vs. binding-deficient mutant overexpression in NSCLC\",\n      \"pmids\": [\"28807942\", \"28330997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IGF-independent component of the lung effect not mechanistically pinpointed\", \"FAK/Runx1 epigenetic partners only partially defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established proteolytic and SUMOylation-based control points: ADAM28 degrades IGFBP-3 to release IGF-I, and SUMO2/3 directs IGFBP-3-dependent nuclear translocation of IGF-1R under stress.\",\n      \"evidence\": \"ADAM28 knockdown/knockout with degradation and xenotransplantation assays; SUMOylation assays and nuclear fractionation in corneal epithelial cells\",\n      \"pmids\": [\"30429106\", \"30078228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO sites on IGFBP-3/IGF-1R not mapped\", \"Physiological scope of nuclear IGF-1R unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the DNA-repair complex and a hyperglycemia-driven cardiac apoptosis circuit, showing IGFBP-3 promotes NHEJ via NONO/SFPQ/EGFR/DNA-PKcs and mediates HIF1\\u03b1/ROS-dependent IGF sequestration in cardiomyocytes.\",\n      \"evidence\": \"LC-MS/MS interactome, reciprocal Co-IP, PLA, cell-free binding and end-joining assays with PARP/EGFR/DNA-PKcs inhibitors; Co-IP, siRNA/antibody rescue and diabetic rat echocardiography\",\n      \"pmids\": [\"30725116\", \"30659610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nuclear IGFBP-3 nucleates the repair complex structurally is unknown\", \"Cardiac axis is Medium-confidence single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped additional inducers (BMP2/ALK3/ID1) and effectors (THBS1, MMP2, hepatic lipid droplets), positioning IGFBP3 in angiogenesis, stromal migration, and steatosis.\",\n      \"evidence\": \"Inducible IGFBP3 with THBS1 siRNA and angiogenesis assays distinguishing intracellular vs. extracellular promoter activation; sequential BMP2/ALK3/ID1/IGFBP3 knockdowns; HSC-selective NRP-1 KO with recombinant IGFBP3 hepatocyte treatment\",\n      \"pmids\": [\"32642286\", \"32975335\", \"32087348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular signaling activating THBS1 transcription not defined\", \"Receptor mediating hepatocyte lipid response unidentified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed TMEM219 as a beta-cell death receptor for IGFBP3 and uncovered roles in mitochondrial homeostasis and aging-related smooth muscle pathology.\",\n      \"evidence\": \"TMEM219 KO mice plus pharmacological IGFBP3/TMEM219 blockade with patient validation; gain/loss-of-function with Seahorse flux and sBNIP3L/NIX assays in corneal cells; IGFBP3 knockdown in aged CCSMCs\",\n      \"pmids\": [\"35115561\", \"34918377\", \"35154570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TMEM219 intracellular signaling cascade incompletely defined\", \"Mitochondrial and CCSMC mechanisms are Medium/Low confidence single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified m6A/METTL3 post-transcriptional control and a c-Jun-driven TGF-\\u03b2/EGFRvIII positive feedback loop driving IGFBP3 in fibrosis and glioblastoma.\",\n      \"evidence\": \"MeRIP-seq with METTL3/IGFBP3 knockdown in cardiac fibrosis models; ChIP for c-Jun binding to the IGFBP3 promoter with Smad/ERK pathway dissection\",\n      \"pmids\": [\"36657656\", \"37192967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A reader mediating IGFBP3 stabilization not identified\", \"Feedback loop receptor/ligand stoichiometry unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that IGFBP3-driven EGFR/DNA-PKcs DNA repair confers PARP inhibitor resistance, giving therapeutic relevance to its nuclear repair function.\",\n      \"evidence\": \"Olaparib-resistant prostate cancer cells with IGFBP3 siRNA, gefitinib phenocopy, \\u03b3H2AX and viability assays\",\n      \"pmids\": [\"38327800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between IGFBP3 and EGFR activation not biochemically resolved\", \"In vivo resistance reversal not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular identity and signaling logic of the non-TMEM219 'IGFBP-3 receptor' (e.g., the retinal endothelial receptor) and the structural basis by which nuclear IGFBP-3 nucleates transcription and DNA-repair complexes remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Retinal IGFBP-3 receptor not molecularly cloned\", \"No structure of nuclear IGFBP-3 in complex with RXR\\u03b1 or NONO/SFPQ\", \"Mechanism of cell entry for intracellular functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [6, 18, 25, 32]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 7, 8, 35]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 6, 25]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11, 4, 10, 22]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 8, 1]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3, 18, 1]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4, 34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [17, 18, 34, 32]}\n    ],\n    \"complexes\": [\n      \"IGF-1/IGFBP3/ALS ternary complex\",\n      \"Nuclear IGFBP3-NONO-SFPQ-EGFR-DNA-PKcs DNA-repair complex\"\n    ],\n    \"partners\": [\n      \"TMEM219\",\n      \"IGF1\",\n      \"RXRA\",\n      \"NONO\",\n      \"SFPQ\",\n      \"GSK3B\",\n      \"EGFR\",\n      \"IGF1R\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}