Affinage

IGFBP2

Insulin-like growth factor-binding protein 2 · UniProt P18065

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

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IGFBP2 is a secreted, multifunctional modulator of IGF signaling, integrin-mediated adhesion, and intranuclear transcriptional regulation that governs cell proliferation, survival, metabolism, and tissue remodeling across diverse contexts. Extracellularly, IGFBP2 sequesters IGF-I and IGF-II to inhibit IGF receptor activation—a complex cleavable by MMP-9 and MMP-1 to release free IGFs—and simultaneously engages integrin α5β1 and receptor tyrosine phosphatase β (RTPTβ) to activate FAK/ERK and PI3K/AKT signaling while suppressing PTEN, thereby driving proliferation, invasion, EMT (via NF-κB/ZEB1), vasculogenic mimicry, and depot-specific inhibition of adipogenesis (PMID:30368528, PMID:25787077, PMID:27659045, PMID:25370576, PMID:18563800). Intracellularly, IGFBP2 translocates to the nucleus via a defined NLS to transactivate the VEGF promoter, promote nuclear EGFR accumulation and EGFR-STAT3 signaling, facilitate NF-κB p65 nuclear translocation, and stabilize cytoplasmic p21 against ubiquitin-dependent degradation, linking it to angiogenesis, immune evasion (PD-L1 upregulation, M2 macrophage polarization via IL-10), and apoptosis resistance (PMID:21750048, PMID:29885520, PMID:32302288, PMID:33309859, PMID:32120023). Systemically, IGFBP2 functions as a leptin-regulated insulin sensitizer that improves hepatic glucose metabolism, protects alveolar epithelial cells from senescence and fibrosis, and modulates neuronal excitability and dendritic spine plasticity in the brain (PMID:20074524, PMID:36787736, PMID:39117630, PMID:28158790).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2003 High

    The discovery that IIp45 binds the RGD-containing C-terminus of IGFBP2 and antagonizes glioma invasion established that IGFBP2 has a direct, IGF-independent pro-invasive function mediated through its integrin-binding domain and linked to NF-κB signaling.

    Evidence Yeast two-hybrid, co-immunoprecipitation, invasion assays, and xenograft models in glioma cells

    PMID:14617774

    Open questions at the time
    • Identity of integrin receptor(s) not determined in this study
    • Structural basis of IIp45-IGFBP2 interaction unresolved
  2. 2005 High

    Retroviral IGFBP2 overexpression in chick embryos demonstrated that IGFBP2 inhibits IGF-I/II-mediated chondrocyte proliferation in vivo, establishing its classical role as an extracellular IGF sequestrant in skeletal development.

    Evidence RCAS retroviral overexpression in chick wing, skeletal morphometry, in vitro chondrocyte assays

    PMID:16183342

    Open questions at the time
    • Relative contribution of IGF-I vs IGF-II sequestration not dissected
    • Whether IGFBP2 also acts via integrins in this skeletal context not tested
  3. 2008 High

    Demonstrating that MMP-9 cleaves the IGFBP2–IGF-II complex to release bioactive IGF-II revealed a protease-dependent mechanism for local IGF bioavailability regulation, and showed that complex formation itself curtails IGFBP2's autonomous motility-promoting activity.

    Evidence In vitro protease cleavage assay with functional motility and proliferation readouts in astrocytoma cells

    PMID:18563800

    Open questions at the time
    • In vivo relevance of MMP-9 cleavage not confirmed at this point
    • Cleavage site(s) not precisely mapped
  4. 2010 High

    Adenoviral IGFBP2 overexpression reversed diabetes across multiple insulin-resistant mouse models, establishing IGFBP2 as a systemic metabolic regulator that improves hepatic insulin sensitivity downstream of leptin signaling.

    Evidence Adenoviral overexpression in ob/ob, Ay/a, DIO, and STZ mice; hyperinsulinemic-euglycemic clamp

    PMID:20074524

    Open questions at the time
    • Receptor and signaling pathway mediating hepatic insulin sensitization not identified
    • Whether circulating vs. locally produced IGFBP2 is the active species unclear
  5. 2011 High

    Demonstrating that IGFBP2 localizes to the nucleus and transactivates the VEGF promoter established a paradigm-shifting intracellular/nuclear function beyond its classical secreted IGF-binding role.

    Evidence VEGF promoter luciferase reporter, nuclear fractionation, immunofluorescence, CAM xenograft angiogenesis assay in neuroblastoma cells

    PMID:21750048

    Open questions at the time
    • Nuclear import mechanism (NLS requirements) not defined in this study
    • DNA-binding domain or cofactors for transactivation not identified
  6. 2013 High

    Multiple studies converged to show that extracellular IGFBP2 acts through integrin receptors to suppress PTEN, activate PI3K/AKT, and promote survival/chemoresistance, while also functioning as an inhibitor of IGF1R signaling in distinct cellular contexts, revealing context-dependent dual roles.

    Evidence Integrin-blocking and PI3K-inhibitor studies in breast epithelial cells; exogenous IGFBP2 supplementation reversing IGF1R-antibody resistance in rhabdomyosarcoma

    PMID:23515291 PMID:24292683

    Open questions at the time
    • How the same protein switches between pro-survival (integrin/PTEN) and IGF-inhibitory modes not resolved
    • Integrin subunit specificity not yet fully defined
  7. 2014 High

    IGFBP2 was shown to inhibit adipogenesis in visceral but not subcutaneous adipocytes via its heparin-binding domain and integrin/FAK/PTEN signaling, establishing depot-specific metabolic regulation independent of IGF-I.

    Evidence HBD-mutant IGFBP2, echistatin integrin blockade, dose-response in human adipocytes

    PMID:25370576

    Open questions at the time
    • Heparan sulfate proteoglycan co-receptors mediating depot specificity not identified
    • In vivo depot-specific effects not directly tested
  8. 2015 High

    Three parallel advances defined key signaling nodes: IGFBP2 binding to RPTPβ drives PKCζ-mediated vimentin phosphorylation and PTEN inactivation in vascular smooth muscle; IGFBP2 augments nuclear EGFR accumulation and EGFR-STAT3 signaling in glioblastoma; and IGFBP2 with IGF-I coordinately activates AMPK/autophagy required for osteoblast differentiation.

    Evidence Proteomic co-IP and inhibitory peptides in diabetic mice (RPTPβ); nuclear fractionation in GBM cells (EGFR-STAT3); AMPK inhibitors and autophagy readouts in osteoblasts

    PMID:25787077 PMID:25893308 PMID:26556533

    Open questions at the time
    • Whether RPTPβ and integrin pathways converge or are independent not tested
    • Nuclear EGFR mechanism relies on correlation in a single lab
    • AMPK-autophagy link established only in osteoblast lineage
  9. 2016 High

    IGFBP2 was shown to drive EMT in pancreatic cancer through PI3K/Akt/IKKβ-mediated NF-κB p65 nuclear translocation, with PTEN rescue fully blocking this axis, placing IGFBP2 as an upstream orchestrator of NF-κB-dependent mesenchymal programs.

    Evidence Overexpression/knockdown with PTEN rescue, p65 translocation by immunofluorescence, in vivo metastasis assays

    PMID:27659045

    Open questions at the time
    • Whether IGFBP2's extracellular (integrin) or intracellular pool activates NF-κB not dissected
    • Epigenetic regulation of IGFBP2 in pancreatic cancer not addressed
  10. 2016 High

    Site-specific intronic CpG methylation was shown to suppress hepatic IGFBP2 transcription, and this epigenetic silencing precedes obesity and hepatosteatosis, establishing DNA methylation as a causal upstream regulator of IGFBP2 expression with metabolic consequences.

    Evidence In vitro site-specific methylation reporter assay, bisulfite sequencing, mouse dietary model

    PMID:27126637

    Open questions at the time
    • Methyltransferases responsible not identified
    • Whether demethylation therapy could restore IGFBP2 in vivo not tested
  11. 2017 Medium

    MMP-1 was identified as a second protease cleaving IGFBP2-IGF-II complexes, and IGFBP2 was found to exert IGF1R-independent anxiolytic effects by increasing dendritic spine density in brain, broadening its functional repertoire to neuroplasticity.

    Evidence In vitro MMP-1 cleavage of IGFBP2-IGF-II complex with MSC migration assays; in vivo PTSD models with IGF1R antagonist JB1 and dendritic spine analysis

    PMID:28158790 PMID:29321953

    Open questions at the time
    • MMP-1 cleavage site not mapped
    • Receptor and signaling mechanism for IGFBP2's neuroplasticity effects unknown
    • Behavioral studies from single lab
  12. 2018 High

    Two studies defined critical domain requirements: IGFBP2 interacts with integrin α5β1 to activate FAK/ERK/SP1 and drive CD144/MMP2-dependent vasculogenic mimicry in glioma, and its NLS is required for nuclear translocation of NF-κB p65 and ZEB1-dependent EMT and metastasis.

    Evidence Co-IP for integrin binding, ChIP for SP1 binding to CD144 promoter, orthotopic glioma model; NLS mutant with nuclear fractionation and xenograft metastasis assays in salivary ACC

    PMID:29885520 PMID:30368528

    Open questions at the time
    • Structural basis of IGFBP2-integrin α5β1 interaction not resolved
    • Whether NLS-dependent and integrin-dependent functions are coupled or independent unclear
  13. 2020 Medium

    Intracellular IGFBP2 was shown to stabilize cytoplasmic p21 against ubiquitin-mediated degradation, regulate PD-L1 expression through nuclear EGFR/STAT3, drive IL-10-mediated M2 macrophage polarization via STAT3, and modulate β-catenin/Oct4 stemness via integrin-TRIM33, revealing a broad intracellular signaling hub.

    Evidence Co-IP of IGFBP2-p21, ubiquitination assays in keratinocytes; EGFR nuclear fractionation in melanoma; in vivo macrophage depletion in PDAC; RNA immunoprecipitation for β-catenin-Oct4 mRNA in GBM

    PMID:32120023 PMID:32302288 PMID:32803659 PMID:33309859

    Open questions at the time
    • p21 stabilization confirmed in one cell type (psoriatic keratinocytes)
    • β-catenin RNA-binding function is unconventional and lacks independent replication
    • Relative contribution of secreted vs intracellular IGFBP2 to immune modulation not resolved
  14. 2021 High

    COL11A1-ERK-SP1-NF-κB was identified as an upstream transcriptional circuit driving IGFBP2 expression, and secreted IGFBP2 activates TGF-β3 to promote cancer-associated fibroblast activation, establishing IGFBP2 as a paracrine mediator of tumor-stroma crosstalk in ovarian cancer.

    Evidence ChIP for p65 binding to IGFBP2 promoter, co-culture experiments, in vivo TGF-β3 antibody blockade

    PMID:34117361

    Open questions at the time
    • Direct IGFBP2-TGF-β3 molecular interaction not characterized
    • Whether this paracrine axis operates in other tumor types unknown
  15. 2022 High

    DNA hypomethylation of a proximal enhancer was shown to drive IGFBP2 expression in ovarian cancer precursor lesions, where IGFBP2 sustains tubal epithelial growth via AKT, linking epigenetic derepression to early tumorigenesis.

    Evidence Spatial transcriptomics, pyrosequencing, 5-azacytidine treatment, IGFBP2 knockdown with AKT readout

    PMID:36206311

    Open questions at the time
    • Whether enhancer hypomethylation is a driver or passenger event in serous tumorigenesis not established
    • AKT-dependent mechanism downstream of IGFBP2 not fully dissected
  16. 2023 High

    Loss of IGFBP2 in alveolar type 2 cells was shown to promote cellular senescence and lung fibrosis, and intranasal recombinant IGFBP2 or transgenic overexpression attenuated these phenotypes, establishing IGFBP2 as an anti-senescence factor in the lung.

    Evidence Aged IGFBP2 transgenic mice, recombinant protein delivery, bleomycin fibrosis model, AEC2 senescence marker quantification

    PMID:36787736

    Open questions at the time
    • Receptor and signaling pathway mediating anti-senescence effect in AEC2 cells not identified
    • Whether systemic IGFBP2 levels decline with aging and contribute to fibrosis susceptibility not addressed
  17. 2024 High

    IGFBP2's integrin α5/FAK axis was extended to podocyte apoptosis via mitochondrial dysfunction in diabetic kidney disease, and astrocyte-derived IGFBP2 was identified as a paracrine excitatory signal increasing neuronal calcium and hyperexcitability in epilepsy and stroke models.

    Evidence IGFBP2 KO in diabetic mice with ITGA5 knockdown and FAK inhibition; astrocyte-specific P2Y1R transgenic mice with IGFBP2 knockdown and neuronal Ca2+ imaging

    PMID:38796567 PMID:39117630

    Open questions at the time
    • Whether neuronal excitability effects are integrin-mediated not tested
    • Specific IGFBP2 receptor on neurons unknown
    • Whether podocyte effects are IGF-dependent or independent not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the identity of the neuronal receptor mediating IGFBP2's excitatory effects; the structural basis for IGFBP2's dual extracellular/nuclear functions and how NLS-dependent and integrin-dependent activities are coordinated; the receptor mediating hepatic insulin sensitization; and whether intracellular functions such as p21 stabilization and β-catenin RNA binding generalize beyond single cell-type observations.
  • No crystal structure of full-length IGFBP2 or its receptor complexes
  • Hepatic insulin sensitization receptor unknown
  • Neuronal receptor unknown
  • Generalizability of intracellular p21 and β-catenin functions untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0060090 molecular adaptor activity 4 GO:0008289 lipid binding 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005576 extracellular region 9 GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1430728 Metabolism 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2
Partners
CDKN1AEGFRIGF1IGF2IIP45ITGA5ITGB1PTPRB

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 Adenoviral overexpression of IGFBP2 reversed diabetes in insulin-resistant ob/ob, Ay/a, diet-induced obese, and streptozotocin-treated mice; hyperinsulinemic clamp studies showed a 3-fold improvement in hepatic insulin sensitivity, establishing IGFBP2 as a regulator of glucose metabolism downstream of leptin signaling. Adenoviral overexpression in mouse models, hyperinsulinemic clamp studies, liver microarray profiling Cell metabolism High 20074524
2003 IIp45, identified by yeast two-hybrid screening, binds to IGFBP2 through the thyroglobulin-RGD region of IGFBP2's C-terminus, and this interaction antagonizes IGFBP2-stimulated glioma cell invasion both in vitro and in xenograft models, partly by suppressing NF-κB and ICAM-1 expression. Yeast two-hybrid, co-immunoprecipitation, invasion assays, xenograft model, gene expression profiling Proceedings of the National Academy of Sciences of the United States of America High 14617774
2011 IGFBP2 overexpression in neuroblastoma cells transactivates the VEGF gene promoter; cell fractionation and immunofluorescence demonstrated nuclear localization of IGFBP2, and transactivation of VEGF promoter required intracellular IGFBP2, leading to proangiogenic activity in chick chorioallantoic membrane xenografts. VEGF promoter luciferase reporter cotransfection, cell fractionation, immunofluorescence, CAM xenograft assay Endocrinology High 21750048
2015 IGFBP2 binding to receptor tyrosine phosphatase β (RPTPβ) together with IGF-I receptor stimulation induces PKCζ-mediated vimentin serine phosphorylation, which drives RPTPβ polymerization, PTEN inactivation, and AKT activation to stimulate vascular smooth muscle cell proliferation during hyperglycemia. Proteomic co-immunoprecipitation, siRNA knockdown, cell-permeable inhibitory peptides, in vivo diabetic mouse model with pharmacological inhibitors The Journal of biological chemistry High 25787077
2015 IGFBP2 augments nuclear accumulation of EGFR and potentiates EGFR-STAT3 signaling, promoting invasion and migration of glioblastoma cells; both exogenous IGFBP2 treatment and intracellular IGFBP2 overexpression activated this nuclear EGFR/STAT3 axis. Nuclear fractionation, invasion/migration assays, siRNA knockdown, TCGA data correlation Oncogene Medium 25893308
2016 IGFBP2 drives NF-κB-dependent epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma by inducing nuclear translocation and phosphorylation of the p65 NF-κB subunit through the PI3K/Akt/IKKβ pathway; enforced PTEN expression blocked this pathway and restored epithelial phenotype. Overexpression/knockdown, invasion and metastasis assays in vitro and in vivo, immunofluorescence for p65 translocation, PTEN rescue experiments Cancer research High 27659045
2018 IGFBP2 interacts with integrin α5 and β1 subunits, activating FAK/ERK signaling to increase SP1 transcriptional activity, which binds the CD144 promoter and upregulates CD144 and MMP2, thereby promoting vasculogenic mimicry formation in glioma cells. Co-immunoprecipitation (integrin interaction), luciferase reporter assay, ChIP assay, stable knockdown orthotopic mouse model Oncogene High 30368528
2015 IGF-I and IGFBP-2 coordinately stimulate AMPK activation through their respective receptors in osteoblasts; early AMPK induction drives ULK-1 phosphorylation, beclin-1 and LC3II induction (autophagy), which is required for osteoblast differentiation, while sustained AMPK activation inhibits differentiation. Primary calvarial osteoblast culture, MC-3T3 cells, AMPK inhibitors, constitutively active AMPK expression, autophagy inhibitors, receptor-blocking antibodies Endocrinology High 26556533
2008 MMP-9 proteolytically cleaves the IGFBP2-IGFII complex in vitro, releasing free IGFII that enhances astrocytoma cell motility and growth; formation of the IGFBP2-IGFII complex also reduces the pool of free IGFBP2 and thereby inhibits IGFBP2's own cell motility-promoting effect. In vitro protease cleavage assay, cell motility and proliferation assays using LN229 cells, conditioned medium experiments Glia High 18563800
2013 Exogenous IGFBP2 acting via integrin receptors reduces PTEN levels in breast epithelial cells, protecting them from apoptosis and conferring chemoresistance; this survival function requires functional estrogen receptor-α, and conversely IGFBP2 upregulates ER-α expression via integrin receptors through IGF-IR and PI3K activation in cancer cells. siRNA knockdown, exogenous IGFBP2 treatment, integrin receptor blocking, PI3K inhibitors, ER-α silencing, cell survival assays Endocrinology High 23515291
2014 IGFBP2 inhibits adipogenesis and lipogenesis specifically in visceral (not subcutaneous) human adipocytes via its heparin-binding domain mediating cell-surface association and integrin signaling, leading to FAK phosphorylation and decreased PTEN levels, independent of IGF-I. siRNA knockdown, exogenous IGFBP2 dose-response, HBD-mutant IGFBP2, echistatin (integrin blocker), Western blotting, lipid staining International journal of obesity High 25370576
2013 IGFBP2 is inhibitory to IGF1R phosphorylation and downstream signaling; in rhabdomyosarcoma, downregulation of IGFBP2 confers resistance to IGF1R antibody therapy, and adding exogenous IGFBP2 potentiates IGF1R antibody activity and reverses resistance in vitro and in vivo. In vivo resistance model, exogenous IGFBP2 supplementation, expression analysis, IGF1R phosphorylation assays Oncogene Medium 24292683
2013 Hyperglycemia induces IGFBP2 expression in prostate cancer cells via increased acetylation of histones H3 and H4 at the IGFBP2 gene promoter (epigenetic mechanism); elevated IGFBP2 reduces docetaxel-induced apoptosis, and silencing IGFBP2 negates the glucose-mediated survival advantage. siRNA knockdown, chromatin immunoprecipitation (ChIP) for histone acetylation, DNA methylation analysis, ELISA, cell death assay Endocrine-related cancer Medium 23959956
2016 Intronic CpG methylation of IGFBP2 (CpG2605) suppresses its hepatic expression; selective methylation of this site in vitro reduced reporter activity by ~85%, and this epigenetic silencing precedes diet-induced obesity and hepatosteatosis in mice. Bisulfite sequencing, in vitro methylation reporter assay, mouse dietary model with epigenetic profiling Human molecular genetics High 27126637
2017 MMP-1 cleaves the IGF-2/IGFBP2 complex, releasing free IGF-2 that facilitates mesenchymal stem cell migration toward tumors; conditioned media from highly migrating MSCs expressing high MMP-1 cleaved the IGF-2/IGFBP2 complex in vitro. In vitro cleavage assay with conditioned media, exogenous recombinant protein addition, migration assays FEBS open bio Medium 29321953
2018 In salivary adenoid cystic carcinoma, IGFBP2 nuclear localization signal is required for nuclear translocation of NF-κB p65; nuclear IGFBP2 enhances p65-dependent ZEB1 expression to promote EMT; IGFBP2 NLS mutant failed to translocate p65, reduced ZEB1, and abrogated EMT and metastasis in xenograft models. IGFBP2 NLS mutant transfection, nuclear fractionation, invasion assays, xenograft metastasis model Cancer letters High 29885520
2020 IGFBP2 activates STAT3 in pancreatic ductal adenocarcinoma cells to augment IL-10 secretion, which drives tumor-associated macrophage polarization toward an M2 immunosuppressive phenotype, increasing Treg infiltration and impairing antitumor T-cell immunity. In vivo mouse model (macrophage depletion), STAT3 signaling analysis, IL-10 ELISA, flow cytometry for immune cell populations Cancer letters Medium 33309859
2020 Intracellular IGFBP2 stabilizes cytoplasmic p21 by protecting it from ubiquitin-dependent degradation in psoriatic keratinocytes; cytoplasmic p21 in turn inhibits pro-caspase 3 cleavage and JNK phosphorylation to resist apoptosis; silencing IGFBP2 destabilizes p21 and restores apoptosis. IGFBP2 overexpression/silencing in psoriatic keratinocytes, co-immunoprecipitation (IGFBP2-p21 interaction), ubiquitin-mediated degradation assays, caspase and JNK activity assays Aging High 32302288
2020 IGFBP2 regulates PD-L1 expression in melanoma by facilitating nuclear accumulation of EGFR and activating the EGFR/STAT3 signaling pathway, confirmed both in vitro and in vivo. IGFBP2 knockdown/overexpression, nuclear EGFR fractionation, STAT3 phosphorylation assays, in vivo melanoma models Cancer letters Medium 32120023
2020 IGFBP2 in glioblastoma cells induces TRIM33 (an E3 ubiquitin ligase) expression via integrin signaling, which depletes nuclear β-catenin; simultaneously, IGFBP2-stabilized cytoplasmic β-catenin binds the 3' UTR of Oct4 RNA, enhancing stemness of glioma cells. RT-PCR, Western blot, shRNA knockdown, RNA immunoprecipitation (RNAIP), luciferase reporter, neurosphere assay Journal of neuro-oncology Medium 32803659
2017 IGFBP2 exerts anxiolytic and antistress effects in rat PTSD models via an IGF-1 receptor-independent mechanism (not blocked by IGF1R antagonist JB1 or AMPA receptor antagonist NBQX); IGFBP2 increases mature dendritic spine density in medial prefrontal cortex and hippocampus 24 hours post-dosing, suggesting structural plasticity as the underlying mechanism. Porsolt test, contextual fear conditioning, chronic unpredictable stress model; selective receptor antagonists; dendritic spine morphology analysis in vivo The international journal of neuropsychopharmacology Medium 28158790
2005 IGFBP2 overexpression in chick embryo wing by RCAS retroviral vector inhibits IGF-I and IGF-II-mediated chondrocyte proliferation and matrix synthesis, resulting in shortened long bones; IGFBP2 excess also attenuates perichondrium/periosteum proliferation without affecting markers of chondrocyte maturation or osteoblast differentiation. RCAS retroviral overexpression in embryonic chick wing, in vivo skeletal morphometry, in vitro chondrocyte proliferation/matrix synthesis assays with IGF-I/II Bone High 16183342
2012 MDA-9/syntenin induces HIF-1α via ECM-Src-FAK-Akt signaling, which activates transcription of IGFBP2; secreted IGFBP2 promotes tumor angiogenesis and stimulates endothelial cells to produce and secrete VEGF-A. Gain/loss-of-function experiments, tube formation assay, CAM assay, xenograft tumor model Cancer research Medium 23233738
2023 Loss of IGFBP2 in alveolar type 2 (AEC2) cells promotes cellular senescence and lung fibrosis; intranasal recombinant IGFBP2 delivery and transgenic overexpression in aged mice reduced AEC2 senescence markers and SASP factors and ameliorated bleomycin-induced lung fibrosis. Aged human-IGFBP2 transgenic mice, intranasal recombinant protein delivery, bleomycin fibrosis model, AEC2 isolation with senescence marker quantification Cell reports. Medicine High 36787736
2024 IGFBP2 induces podocyte apoptosis by binding integrin α5 (ITGA5) and activating FAK phosphorylation, leading to mitochondrial dysfunction (membrane potential loss, ROS increase); ITGA5 knockdown or FAK inhibition attenuated podocyte apoptosis caused by high glucose or IGFBP2 overexpression. DKD mouse model (STZ), IGFBP2 knockout/knockdown, ITGA5 knockdown, FAK inhibitor, mitochondrial membrane potential assay, ROS measurement Apoptosis High 38796567
2024 Astrocyte-specific P2Y1R overexpression increases IGFBP2 secretion; secreted IGFBP2 acts as an excitatory signal causing neuronal hyperexcitability and increased neuronal Ca2+ signaling in mouse models of epilepsy and stroke. Astrocyte-specific P2Y1R transgenic mice, Ca2+ imaging, neuronal excitability recording, IGFBP2 knockdown experiments, epilepsy and stroke disease models Nature communications High 39117630
2022 In ovarian high-grade serous carcinoma precursor lesions, IGFBP2 expression is driven by DNA hypomethylation of its proximal enhancer; 5-azacytidine treatment increases IGFBP2 expression, and IGFBP2 knockdown suppresses tubal epithelial cell growth via AKT pathway inactivation. Spatial transcriptomics, pyrosequencing for methylation, 5-azacytidine treatment, IGFBP2 knockdown with AKT pathway analysis Cancer research High 36206311
2024 An omental-specific IGFBP2-high stromal population (mesothelial-mesenchymal transitioning) inhibits human adipose stem and progenitor cell adipogenesis through IGFBP2 secretion, identified by single-cell RNA sequencing and functional co-culture experiments. Single-cell RNA-seq, bulk RNA-seq of >30 SVF samples, functional co-culture adipogenesis assays with IGFBP2 knockdown Cell metabolism High 38729152
2021 COL11A1-mediated ERK activation increases p-SP1, which promotes p65 NF-κB binding to the IGFBP2 promoter, inducing IGFBP2 expression; IGFBP2 in turn activates TGF-β3, which promotes cancer-associated fibroblast (CAF) activation in ovarian cancer, driving IL-6 release, cancer cell proliferation, and invasiveness. Co-culture experiments, ChIP assay for p65 binding to IGFBP2 promoter, siRNA knockdown, in vivo mouse model with TGF-β3 antibody blockade Oncogene High 34117361

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Serum levels of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) in healthy infants, children, and adolescents: the relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index, and pubertal maturation. The Journal of clinical endocrinology and metabolism 392 7543116
2010 Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell metabolism 237 20074524
1990 Insulin differentially alters transcapillary movement of intravascular IGFBP-1, IGFBP-2 and endothelial cell IGF-binding proteins in the rat heart. Endocrinology 185 1694498
2002 Expression profiling of synovial sarcoma by cDNA microarrays: association of ERBB2, IGFBP2, and ELF3 with epithelial differentiation. The American journal of pathology 148 12414507
1999 Insulin-like growth factors (IGF-I, free IGF-I and IGF-II) and insulin-like growth factor binding proteins (IGFBP-2, IGFBP-3, IGFBP-6, and ALS) in blood circulation. Journal of clinical laboratory analysis 148 10414596
2020 IGFBP2: integrative hub of developmental and oncogenic signaling network. Oncogene 112 31925333
2006 Insulin-like growth factor binding protein-2 (IGFBP-2) is a marker for the metabolic syndrome. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 108 16915540
1997 Elevated serum insulin-like growth factor-binding protein 2 (IGFBP-2) and decreased IGFBP-3 in epithelial ovarian cancer: correlation with cancer antigen 125 and tumor-associated trypsin inhibitor. The Journal of clinical endocrinology and metabolism 102 9215312
2014 IGFBP-2: The dark horse in metabolism and cancer. Cytokine & growth factor reviews 96 25544066
2011 IGFBP-2 enhances VEGF gene promoter activity and consequent promotion of angiogenesis by neuroblastoma cells. Endocrinology 95 21750048
2018 IGFBP2 promotes vasculogenic mimicry formation via regulating CD144 and MMP2 expression in glioma. Oncogene 94 30368528
2016 IGFBP2 Activates the NF-κB Pathway to Drive Epithelial-Mesenchymal Transition and Invasive Character in Pancreatic Ductal Adenocarcinoma. Cancer research 94 27659045
1990 Production of insulin-like growth factor binding proteins (IGFBPs) by porcine granulosa cells: identification of IGFBP-2 and -3 and regulation by hormones and growth factors. Endocrinology 94 1699745
2005 Role of IGFBP2, IGF-I and IGF-II in regulating long bone growth. Bone 93 16183342
2016 Identification of IGFBP2 and IGFBP3 As Compensatory Biomarkers for CA19-9 in Early-Stage Pancreatic Cancer Using a Combination of Antibody-Based and LC-MS/MS-Based Proteomics. PloS one 82 27579675
2012 MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma. Cancer research 79 23233738
2003 IIp45, an insulin-like growth factor binding protein 2 (IGFBP-2) binding protein, antagonizes IGFBP-2 stimulation of glioma cell invasion. Proceedings of the National Academy of Sciences of the United States of America 76 14617774
2015 IGF-I and IGFBP-2 Stimulate AMPK Activation and Autophagy, Which Are Required for Osteoblast Differentiation. Endocrinology 75 26556533
1996 Expression of insulin-like growth factor-1 (IGF-1) and IGF-binding protein 2 (IGF-BP2) in the hippocampus following cytotoxic lesion of the dentate gyrus. The Journal of comparative neurology 75 8743420
2020 IGFBP2 promotes tumor progression by inducing alternative polarization of macrophages in pancreatic ductal adenocarcinoma through the STAT3 pathway. Cancer letters 74 33309859
2005 Significant expression of IGFBP2 in breast cancer compared with benign lesions. Journal of clinical pathology 73 15790698
2015 IGFBP2 potentiates nuclear EGFR-STAT3 signaling. Oncogene 71 25893308
2013 Hyperglycaemia-induced chemoresistance of prostate cancer cells due to IGFBP2. Endocrine-related cancer 71 23959956
2021 COL11A1 activates cancer-associated fibroblasts by modulating TGF-β3 through the NF-κB/IGFBP2 axis in ovarian cancer cells. Oncogene 69 34117361
2000 Ovarian follicular concentrations of activin, follistatin, inhibin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-2 (IGFBP-2), IGFBP-3, and vascular endothelial growth factor in spontaneous menstrual cycles of normal women of advanced reproductive age. The Journal of clinical endocrinology and metabolism 69 11134102
2020 IGFBP2 regulates PD-L1 expression by activating the EGFR-STAT3 signaling pathway in malignant melanoma. Cancer letters 66 32120023
2016 The miR-204-3p-targeted IGFBP2 pathway is involved in xanthohumol-induced glioma cell apoptotic death. Neuropharmacology 64 27487563
2018 Immune heterogeneity and clinicopathologic characterization of IGFBP2 in 2447 glioma samples. Oncoimmunology 61 29721393
1990 Identification of insulin-like growth factor-binding protein-3 (IGFBP-3) and IGFBP-2 in human follicular fluid. The Journal of clinical endocrinology and metabolism 61 1699963
2010 IGFBP2 promotes glioma tumor stem cell expansion and survival. Biochemical and biophysical research communications 60 20515648
2023 Loss of IGFBP2 mediates alveolar type 2 cell senescence and promotes lung fibrosis. Cell reports. Medicine 57 36787736
2005 DHT and testosterone, but not DHEA or E2, differentially modulate IGF-I, IGFBP-2, and IGFBP-3 in human prostatic stromal cells. American journal of physiology. Endocrinology and metabolism 57 16368782
1992 Triiodothyronine (T3) stimulates insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-2 production by rat osteoblasts in vitro. Acta endocrinologica 55 1377854
2013 IGFBP2/FAK pathway is causally associated with dasatinib resistance in non-small cell lung cancer cells. Molecular cancer therapeutics 54 24130049
2013 Insulin-like growth factor binding protein 2 (IGFBP-2) promotes growth and survival of breast epithelial cells: novel regulation of the estrogen receptor. Endocrinology 53 23515291
2002 Insulin-like growth factor-binding protein-2 (IGFBP-2) overexpression negatively regulates bone size and mass, but not density, in the absence and presence of growth hormone/IGF-I excess in transgenic mice. Anatomy and embryology 53 12478375
2015 Physiology and pathophysiology of IGFBP-1 and IGFBP-2 - consensus and dissent on metabolic control and malignant potential. Best practice & research. Clinical endocrinology & metabolism 52 26522454
2016 Early hypermethylation of hepatic Igfbp2 results in its reduced expression preceding fatty liver in mice. Human molecular genetics 51 27126637
2009 IGFBP2 is a candidate biomarker for Ink4a-Arf status and a therapeutic target for high-grade gliomas. Proceedings of the National Academy of Sciences of the United States of America 49 19805356
2020 IGFBP2 in cancer: Pathological role and clinical significance (Review). Oncology reports 47 33416173
2024 Proteomic Analysis of the Senescence-Associated Secretory Phenotype: GDF-15, IGFBP-2, and Cystatin-C Are Associated With Multiple Aging Traits. The journals of gerontology. Series A, Biological sciences and medical sciences 45 37982669
2011 Effects of cord serum insulin, IGF-II, IGFBP-2, IL-6 and cortisol concentrations on human birth weight and length: pilot study. PloS one 42 22242132
2008 Identification of Igf2, Igfbp2 and Enpp2 as estrogen-responsive genes in rat hippocampus. Endocrine journal 42 18946176
2007 Roles of insulin-like growth factor binding protein-2 (IGFBP-2) in glioblastoma. Anticancer research 41 17970029
2006 The effects of IGF-I on bovine follicle development and IGFBP-2 expression are dose and stage dependent. Reproduction (Cambridge, England) 41 16514194
2014 IGFBP-2 inhibits adipogenesis and lipogenesis in human visceral, but not subcutaneous, adipocytes. International journal of obesity (2005) 40 25370576
2000 Effects of IGFBP-2 overexpression in vitro and in vivo. Pediatric nephrology (Berlin, Germany) 40 10912521
2011 Circulating salmon 41-kDa insulin-like growth factor binding protein (IGFBP) is not IGFBP-3 but an IGFBP-2 subtype. General and comparative endocrinology 37 21354155
2002 Expression of IGF-II, IGFBP-2, -5, and -6 in meningiomas with different brain invasiveness. Journal of neuro-oncology 37 12125963
2011 High expression of IGFBP2 is associated with chemoresistance in adult acute myeloid leukemia. Leukemia research 36 21899885
2023 High baseline tumor burden-associated macrophages promote an immunosuppressive microenvironment and reduce the efficacy of immune checkpoint inhibitors through the IGFBP2-STAT3-PD-L1 pathway. Cancer communications (London, England) 35 37031362
2019 Novel serum markers HSP60, CHI3L1, and IGFBP-2 in metastatic colorectal cancer. Oncology letters 35 31788106
2008 Multidimensional reference regions for IGF-I, IGFBP-2 and IGFBP-3 concentrations in serum of healthy adults. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 35 18550406
2022 Spatial Transcriptomic Analysis of Ovarian Cancer Precursors Reveals Reactivation of IGFBP2 during Pathogenesis. Cancer research 34 36206311
2018 IGFBP2 promotes neural stem cell maintenance and proliferation differentially associated with glioblastoma subtypes. Brain research 34 30347220
1998 Retinoic acid stimulates IGF binding protein (IGFBP)-6 and depresses IGFBP-2 and IGFBP-4 in SK-N-SH human neuroblastoma cells. The Journal of endocrinology 33 9795362
2012 A cross-sectional analysis of the association between diet and insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (IGFBP)-2, and IGFBP-3 in men in the United Kingdom. Cancer causes & control : CCC 32 22527168
2010 Modulation of IGFBP2 mRNA expression in white adipose tissue upon aging and obesity. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 32 20730703
2020 Physiological Disturbance in Fatty Liver Energy Metabolism Converges on IGFBP2 Abundance and Regulation in Mice and Men. International journal of molecular sciences 30 32532003
2015 Novel anti IGFBP2 single chain variable fragment inhibits glioma cell migration and invasion. Journal of neuro-oncology 30 25944386
2020 Intracellular Insulin-like growth factor binding protein 2 (IGFBP2) contributes to the senescence of keratinocytes in psoriasis by stabilizing cytoplasmic p21. Aging 29 32302288
2016 IGFBP-2 and -3 co-ordinately regulate IGF1 induced matrix mineralisation of differentiating human dental pulp cells. Stem cell research 29 27776273
2015 Roles of miR-278-3p in IBP2 regulation and Bombyx mori cytoplasmic polyhedrosis virus replication. Gene 29 26348138
1996 Expression of IGFBP-2, -3, and -4 mRNA during differentiation of Caco-2 colon epithelial cells. The American journal of physiology 29 8944682
2021 SNAIL2 contributes to tumorigenicity and chemotherapy resistance in pancreatic cancer by regulating IGFBP2. Cancer science 28 34628696
2019 IGFBP2 promotes immunosuppression associated with its mesenchymal induction and FcγRIIB phosphorylation in glioblastoma. PloS one 28 31560714
2024 Icaritin-curcumol activates CD8+ T cells through regulation of gut microbiota and the DNMT1/IGFBP2 axis to suppress the development of prostate cancer. Journal of experimental & clinical cancer research : CR 27 38778379
2019 Silencing circular RNA VANGL1 inhibits progression of bladder cancer by regulating miR-1184/IGFBP2 axis. Cancer medicine 27 31758655
2023 Cancer-associated fibroblast-associated gene IGFBP2 promotes glioma progression through induction of M2 macrophage polarization. American journal of physiology. Cell physiology 26 37982173
2019 MiR-34b-5p Mediates the Proliferation and Differentiation of Myoblasts by Targeting IGFBP2. Cells 26 30999686
2022 Metastatic colorectal carcinoma-associated fibroblasts have immunosuppressive properties related to increased IGFBP2 expression. Cancer letters 25 35569697
2018 Potential Functions of IGFBP-2 for Ovarian Folliculogenesis and Steroidogenesis. Frontiers in endocrinology 25 29706932
2018 IGFBP2 promotes salivary adenoid cystic carcinoma metastasis by activating the NF-κB/ZEB1 signaling pathway. Cancer letters 25 29885520
2014 Targeted mass spectrometry analysis of the proteins IGF1, IGF2, IBP2, IBP3 and A2GL by blood protein precipitation. Journal of proteomics 25 25277046
2008 Matrix metalloproteinase-9 interplays with the IGFBP2-IGFII complex to promote cell growth and motility in astrocytomas. Glia 25 18563800
1996 The unique endometrial expression and genomic organization of the porcine IGFBP-2 gene. Molecular and cellular endocrinology 25 8832579
2019 BMSC-derived leptin and IGFBP2 promote erlotinib resistance in lung adenocarcinoma cells through IGF-1R activation in hypoxic environment. Cancer biology & therapy 24 31559898
2018 Trichostatin A reverses the chemoresistance of lung cancer with high IGFBP2 expression through enhancing autophagy. Scientific reports 24 29500455
2013 Downregulation of IGFBP2 is associated with resistance to IGF1R therapy in rhabdomyosarcoma. Oncogene 24 24292683
1998 Estradiol increases relative amounts of insulin-like growth factor binding protein (IGFBP)-3 in serum and expression of IGFBP-2 in anterior pituitaries of ewes. Biology of reproduction 24 9675002
2017 IGFBP2 plays an important role in heat shock protein 27-mediated cancer progression and metastasis. Oncotarget 23 28903396
2018 Downregulation of CD147 induces malignant melanoma cell apoptosis via the regulation of IGFBP2 expression. International journal of oncology 22 30272281
2019 The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 in a pooled analysis of 16,024 men from 22 studies. International journal of cancer 21 30873591
2017 IGFBP2 Produces Rapid-Acting and Long-Lasting Effects in Rat Models of Posttraumatic Stress Disorder via a Novel Mechanism Associated with Structural Plasticity. The international journal of neuropsychopharmacology 21 28158790
2015 The coordinate cellular response to insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-2 (IGFBP-2) is regulated through vimentin binding to receptor tyrosine phosphatase β (RPTPβ). The Journal of biological chemistry 21 25787077
2024 IGFBP2/ITGA5 promotes gefitinib resistance via activating STAT3/CXCL1 axis in non-small cell lung cancer. Cell death & disease 20 38918360
2020 Associations between IGF1, IGFBP2 and TGFß3 Genes Polymorphisms and Growth Performance of Broiler Chicken Lines. Animals : an open access journal from MDPI 20 32380764
2018 Insulin like growth factor binding protein 2 (IGFBP-2) for risk prediction in patients with severe aortic stenosis undergoing Transcatheter Aortic Valve Implantation (TAVI). International journal of cardiology 20 30309683
2003 Changes of serum growth factors (IGF-I,-II and IGFBP-2,-3) prior to and after stem cell transplantation in children with acute leukemia. Bone marrow transplantation 20 12900778
2019 IGFBP2 promotes the EMT of colorectal cancer cells by regulating E-cadherin expression. International journal of clinical and experimental pathology 19 31934083
2017 Silencing IGFBP-2 decreases pancreatic cancer metastasis and enhances chemotherapeutic sensitivity. Oncotarget 19 28977895
2017 Matrix metalloproteinase-1 facilitates MSC migration via cleavage of IGF-2/IGFBP2 complex. FEBS open bio 19 29321953
2011 High IGFBP2 expression correlates with tumor severity in pediatric rhabdomyosarcoma. The American journal of pathology 19 21924226
2024 Disease-relevant upregulation of P2Y1 receptor in astrocytes enhances neuronal excitability via IGFBP2. Nature communications 18 39117630
2021 ONC201 Shows Potent Anticancer Activity Against Medullary Thyroid Cancer via Transcriptional Inhibition of RET, VEGFR2, and IGFBP2. Molecular cancer therapeutics 18 33536187
2018 IGFBP2 is a potential biomarker in acute kidney injury (AKI) and resveratrol-loaded nanoparticles prevent AKI. Oncotarget 18 30564296
2024 A human omentum-specific mesothelial-like stromal population inhibits adipogenesis through IGFBP2 secretion. Cell metabolism 17 38729152
2024 IGFBP2 induces podocyte apoptosis promoted by mitochondrial damage via integrin α5/FAK in diabetic kidney disease. Apoptosis : an international journal on programmed cell death 17 38796567
2020 Regulation of β-catenin by IGFBP2 and its cytoplasmic actions in glioma. Journal of neuro-oncology 17 32803659
2014 IGF-I and IGFBP2 in peripheral artery disease: results of a prospective study. Scandinavian cardiovascular journal : SCJ 17 24548188