Affinage

IGFBP2

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

Length
325 aa
Mass
34.8 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IGFBP2 is a secreted and intracellular pleiotropic protein that governs IGF availability and engages cell-surface and nuclear signaling to control cell migration, survival, differentiation, and metabolism (PMID:16569642, PMID:37436978, PMID:16183342). Its canonical extracellular role is to bind and sequester IGF-II: adipocyte-derived IGFBP2 limits IGF-II autocrine signaling to suppress breast cancer invasion (PMID:37436978), and IGFBP2 excess inhibits IGF-I/IGF-II-driven chondrocyte proliferation during skeletal development (PMID:16183342); the IGFBP2-IGF-II complex is cleaved by MMP-9 to liberate active IGF-II (PMID:18563800). Beyond ligand sequestration, IGFBP2 acts as a signaling ligand through an RGD motif (D306) that binds integrin α5/β1, driving FAK/ERK and PI3K/Akt activation to promote migration, vasculogenic mimicry via SP1/CD144, survival through PTEN reduction, and—on podocytes—FAK-dependent mitochondrial injury and apoptosis (PMID:16569642, PMID:30368528, PMID:23515291, PMID:38796567). A separate heparin-binding domain (HBD-1) engages RPTPβ to activate AKT and stimulate osteoblast differentiation (PMID:24839202). IGFBP2 also translocates to the nucleus, where it potentiates EGFR nuclear accumulation and EGFR/STAT3 transactivation of targets including VEGF and PD-L1, and where it activates NF-κB (p65) through PI3K/Akt/IKKβ to drive ZEB1-dependent epithelial-mesenchymal transition and metastasis (PMID:25893308, PMID:21750048, PMID:32120023, PMID:29885520, PMID:31818638). Through STAT3-driven IL-10, IGFBP2 also reshapes the tumor immune microenvironment toward M2 macrophage polarization (PMID:33309859). In metabolism, IGFBP2 is a leptin-regulated hepatokine that improves hepatic insulin sensitivity and reverses hyperglycemia in vivo (PMID:20074524), and in the CNS it enhances NMDA receptor-dependent excitatory transmission, LTP, and structural plasticity through IGF1R-independent mechanisms (PMID:31832311, PMID:28158790, PMID:36481930). Its expression is controlled by p16(INK4a), HIF-1α, promoter histone acetylation, and intronic CpG methylation (PMID:19805356, PMID:34155347, PMID:23959956, PMID:27126637).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2006 High

    Established that IGFBP2 acts not merely as an IGF carrier but as an integrin ligand, defining the RGD motif as the structural basis for a direct cell-motility-promoting interaction.

    Evidence Co-IP, RGD-to-RGE (D306E) mutagenesis, integrin α5 siRNA, and migration assays

    PMID:16569642

    Open questions at the time
    • Did not resolve downstream kinase cascade from integrin engagement
    • Did not address β1 subunit contribution
  2. 2008 High

    Showed that proteolysis of the IGFBP2-IGF-II complex by MMP-9 controls bioavailable IGF-II, connecting matrix remodeling to IGF release and tumor cell motility.

    Evidence In vitro proteolysis with recombinant MMPs (negative controls MMP-2, MT1-MMP) and motility/growth assays

    PMID:18563800

    Open questions at the time
    • Cleavage sites not mapped
    • In vivo relevance of MMP-9 cleavage not established
  3. 2010 High

    Defined IGFBP2 as a leptin-regulated metabolic hepatokine, answering whether IGFBP2 has a systemic glucose-regulatory function distinct from IGF sequestration.

    Evidence Adenoviral IGFBP2 overexpression across multiple diabetic mouse models with hyperinsulinemic-euglycemic clamp

    PMID:20074524

    Open questions at the time
    • Molecular receptor/effector for hepatic insulin sensitization not identified
    • Direct hepatocyte target undefined
  4. 2011 Medium

    Demonstrated that intracellular/nuclear IGFBP2 has a transcriptional function, transactivating the VEGF promoter and driving angiogenesis.

    Evidence VEGF promoter luciferase reporter, cell fractionation, immunofluorescence, and chick CAM xenograft

    PMID:21750048

    Open questions at the time
    • DNA-binding partner mediating promoter activation not identified
    • Single lab, no structural validation
  5. 2014 High

    Identified a second receptor system—HBD-1 binding RPTPβ to activate AKT—explaining how IGFBP2 promotes osteoblast differentiation independently of the integrin/RGD axis.

    Evidence RPTPβ Co-IP, HBD-1 mutagenesis, IGFBP2-null osteoblast rescue, synthetic peptide rescue

    PMID:24839202

    Open questions at the time
    • Structural basis of HBD-1/RPTPβ interaction unresolved
    • How RPTPβ engagement activates AKT not detailed
  6. 2015 Medium

    Linked nuclear IGFBP2 to oncogenic receptor signaling by showing it potentiates EGFR nuclear accumulation and EGFR/STAT3 transactivation to drive glioblastoma invasion.

    Evidence Overexpression/exogenous treatment, nuclear fractionation, STAT3 reporter, invasion assays

    PMID:25893308

    Open questions at the time
    • Direct IGFBP2-EGFR binding mode not defined
    • Mechanism of EGFR nuclear import unknown
  7. 2016 Medium

    Defined a PI3K/Akt/IKKβ-NF-κB(p65) cascade by which IGFBP2 drives EMT, with PTEN as an opposing brake.

    Evidence Overexpression/knockdown, p65 fractionation, pathway inhibitors, PTEN rescue epistasis, in vivo metastasis

    PMID:27659045

    Open questions at the time
    • Upstream receptor coupling IGFBP2 to PI3K not specified here
    • Single lab
  8. 2018 High

    Showed the integrin-FAK/ERK axis feeds SP1-driven CD144 transcription to enable vasculogenic mimicry, and that NLS-dependent nuclear p65 translocation drives ZEB1-mediated EMT and metastasis.

    Evidence Co-IP (α5/β1), ChIP (SP1-CD144), reporter assays, NLS mutagenesis, orthotopic and xenograft models

    PMID:29885520 PMID:30368528

    Open questions at the time
    • Crosstalk between cytoplasmic integrin signaling and nuclear NF-κB function not unified
    • ZEB1 promoter occupancy by p65 mapped only in part
  9. 2019 High

    Extended nuclear EGFR signaling to immune evasion (PD-L1 via EGFR/STAT3) and immunosuppression (STAT3/IL-10-driven M2 macrophage polarization and Treg infiltration), and established CNS roles in neuronal excitability and synaptic potentiation.

    Evidence Knockdown with PD-L1/STAT3 readouts and xenografts; macrophage polarization with PDAC model; astrocytic P2Y1R overexpression with Ca2+ imaging; igfbp2-KO electrophysiology with rescue

    PMID:31818638 PMID:31832311 PMID:32120023 PMID:33309859 PMID:39117630

    Open questions at the time
    • Receptor mediating CNS excitability effects of IGFBP2 not defined
    • Whether nuclear and immune mechanisms operate in the same cells unclear
  10. 2020 Medium

    Identified intracellular protein-stabilization roles—protecting cytoplasmic p21 from ubiquitination to block apoptosis, and stabilizing cytoplasmic β-catenin via TRIM33 to regulate Oct4 and stemness.

    Evidence Co-IP and ubiquitination assays in keratinocytes; RNAIP, fractionation, and neurosphere assays in glioma

    PMID:32302288 PMID:32803659

    Open questions at the time
    • Direct binding interfaces (IGFBP2-p21) not mapped
    • How a secreted protein accesses cytoplasmic substrates not resolved
  11. 2022 High

    Mechanistically dissected the neuroplasticity activity using an IGFBP2-mimetic peptide, showing NMDA receptor- and IGF2R-dependent (IGF1R-independent) synaptic remodeling and rescue of Shank3 deficits.

    Evidence Peptide binding, IGF1R antagonism, phosphoproteomics, electrophysiology, behavior in Shank3+/- mice

    PMID:36481930

    Open questions at the time
    • The functional receptor on dendrites not definitively identified
    • Endogenous full-length IGFBP2 vs mimetic peptide equivalence not established
  12. 2024 High

    Showed context-dependent IGF-sequestration outcomes: adipocyte IGFBP2 restrains tumor invasion by binding cancer-derived IGF-II, while podocyte integrin α5/FAK signaling makes IGFBP2 pro-apoptotic in diabetic kidney disease.

    Evidence Patient-derived adipocyte CM with IGF-II siRNA/neutralizing antibody and invasion assays; ITGA5 knockdown and FAK inhibition with mitochondrial/apoptosis readouts and STZ-DKD model

    PMID:37436978 PMID:38796567

    Open questions at the time
    • Determinants of pro- vs anti-tumor IGFBP2 output not unified
    • Tissue factors switching IGFBP2 between sequestration and signaling unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IGFBP2 partitions among its mutually exclusive activities—extracellular IGF sequestration, integrin/RPTPβ signaling, and nuclear transcriptional functions—within a given cell, and what controls its nuclear import and access to cytoplasmic substrates, remains unresolved.
  • No structural model unifying ligand-binding, RGD, HBD-1, and NLS functions
  • Mechanism of nuclear translocation undefined
  • Receptor for IGF1R-independent CNS effects not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 3 GO:0140313 molecular sequestering activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005576 extracellular region 3 GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-1430728 Metabolism 2
Partners
CDKN1ACTNNB1DNAPKEGFRIGF2ITGA5ITGB1PTPRB

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 IGFBP2 promotes cell mobility through direct interaction with integrin α5 via its RGD domain (D306). An RGD→RGE point mutant (D306E) abolished co-immunoprecipitation with integrin α5 and eliminated the elevation in cell migration, demonstrating that the RGD domain is essential for this interaction and its functional consequence. Co-immunoprecipitation, RGD-to-RGE site-directed mutagenesis, siRNA knockdown of integrin α5, migration assays The Journal of biological chemistry High 16569642
2014 IGFBP2 stimulates osteoblast differentiation through its heparin-binding domain-1 (HBD-1), which interacts with receptor tyrosine phosphatase β (RPTPβ). Disruption of this interaction, overexpression of RPTPβ, or HBD-1 mutations all impaired AKT activation and differentiation; a synthetic HBD-1 peptide rescued differentiation in IGFBP-2-null calvarial osteoblasts. RPTPβ co-immunoprecipitation, HBD-1 domain mutagenesis, IGFBP-2 knockout osteoblast rescue, synthetic peptide addition, AKT activation assays Journal of bone and mineral research High 24839202
2015 IGFBP2 potentiates nuclear accumulation of EGFR and activates EGFR/STAT3 signaling, augmenting STAT3 transactivation. Both exogenous IGFBP2 treatment and cellular overexpression triggered aberrant EGFR activation and subsequent STAT3 signaling; nuclear IGFBP2 directly enhanced invasive and migratory capacities of glioblastoma cells. IGFBP2 overexpression and exogenous treatment, nuclear fractionation, STAT3 reporter assays, invasion/migration assays in glioblastoma cells Oncogene Medium 25893308
2011 IGFBP2 promotes transcriptional activation of the VEGF gene promoter through nuclear localization. Transactivation of VEGF promoter occurred only in the presence of intracellular IGFBP2; cell fractionation and immunofluorescence confirmed nuclear localization. IGFBP2-overexpressing neuroblastoma xenografts induced neomicrovascularization in vivo. VEGF promoter luciferase reporter co-transfection, cell fractionation, immunofluorescence, chick embryo chorioallantoic membrane xenograft assay Endocrinology Medium 21750048
2016 IGFBP2 induces NF-κB-dependent epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma by triggering nuclear translocation and phosphorylation of p65 NF-κB through the PI3K/Akt/IKKβ pathway. Enforced PTEN expression blocked this cascade and restored epithelial phenotype. IGFBP2 overexpression/knockdown, nuclear fractionation for p65, pathway inhibitors, PTEN overexpression epistasis, invasion and metastasis assays in vitro and in vivo Cancer research Medium 27659045
2018 IGFBP2 interacts with integrin α5 and β1 subunits and enhances vasculogenic mimicry in glioma through a FAK/ERK-dependent pathway that activates transcription factor SP1, which binds the CD144 promoter to upregulate CD144 expression. MMP2 expression was also augmented. Co-immunoprecipitation (integrin α5/β1), luciferase reporter assay, ChIP assay (SP1 binding to CD144 promoter), FAK/ERK pathway inhibition, orthotopic mouse model with IGFBP2 knockdown Oncogene High 30368528
2008 MMP-9 proteolyzes the IGFBP2-IGFII complex in vitro, releasing free IGFII that enhances motility and growth of astrocytoma cells. MMP-2 and MT1-MMP did not proteolyze this complex. Formation of the IGFBP2-IGFII complex also inhibited IGFBP2's own cell motility-promoting effect by reducing the pool of free IGFBP2. In vitro proteolysis assay with recombinant MMPs, cell motility and growth assays with liberated IGFII Glia High 18563800
2015 IGF-I and IGFBP-2 coordinately stimulate osteoblast differentiation by inducing AMPK activation through their respective receptors (IGF-IR and RPTPβ). Early AMPK activation stimulates autophagy via ULK-1 S555 phosphorylation and beclin-1/LC3II induction, which is required for differentiation; subsequent AMPK down-regulation after day 9 allows mTOR/AKT induction to suppress autophagy and complete differentiation. AMPK inhibitors/constitutively active AMPK overexpression, receptor blocking, autophagy component analysis (ULK-1, beclin-1, LC3II), time-course differentiation assays in MC-3T3 and calvarial osteoblasts Endocrinology Medium 26556533
2019 IGFBP2 activates STAT3 in PDAC cells to augment IL-10 expression and secretion, driving polarization of macrophages toward an immunosuppressive M2 phenotype, which in turn increases regulatory T-cell infiltration and impairs anti-tumor T-cell immunity in a mouse model. IGFBP2 overexpression/knockdown, STAT3 activation assays, IL-10 ELISA, macrophage polarization assays, mouse PDAC tumor model, flow cytometry Cancer letters Medium 33309859
2013 IGFBP2 acting via integrin receptors reduces PTEN levels in breast epithelial cells, thereby promoting survival and protecting against chemotherapy-induced death. This IGFBP2-integrin-PTEN axis also upregulates estrogen receptor-α (ERα) mRNA and protein; silencing ERα blocked IGFBP2-conferred survival. Silencing IGFBP2 increased PTEN and sensitized cells to chemotherapy. siRNA knockdown of IGFBP2 and ERα, exogenous IGFBP2 treatment, integrin receptor blocking, PTEN western blotting, cell viability assays, PI3K inhibition Endocrinology Medium 23515291
2013 IGFBP2 is causally associated with dasatinib resistance in NSCLC via focal adhesion kinase (FAK) activation. Ectopic overexpression or knockdown of IGFBP2 reversed the dasatinib susceptibility phenotype; FAK activation was associated with high IGFBP2 expression and partially mediated the resistance. Western blot/ELISA for IGFBP2 in 7 NSCLC lines, IGFBP2 overexpression/knockdown, cell viability assays, FAK inhibitor combination treatment in vitro and in vivo Molecular cancer therapeutics Medium 24130049
2019 IGFBP2 protects esophageal adenocarcinoma cells from acidic bile salts-induced DNA double-strand breaks by promoting nuclear accumulation and phosphorylation of EGFR and DNA-PKcs. Co-immunoprecipitation demonstrated co-localization of IGFBP2 with EGFR and DNA-PKcs after acidic bile salts treatment. IGFBP2 also stabilized EGFR protein (cycloheximide chase assay). Co-immunoprecipitation, nuclear fractionation, cycloheximide chase assay, IGFBP2 overexpression/knockdown, DNA damage assays (γH2AX), apoptosis assays Journal of experimental & clinical cancer research High 30626422
2020 Intracellular IGFBP2 stabilizes cytoplasmic p21 by protecting it from ubiquitin-dependent degradation in psoriatic keratinocytes, thereby inhibiting apoptosis. Cytoplasmic p21 suppresses pro-caspase 3 cleavage and JNK phosphorylation. Abrogation of IGFBP2 or p21 restored apoptosis. IGFBP2 overexpression/knockdown in psoriatic keratinocytes, co-immunoprecipitation (IGFBP2-p21), ubiquitination assay, caspase-3 cleavage assay, JNK phosphorylation Aging Medium 32302288
2020 IGFBP2 regulates PD-L1 expression in melanoma by facilitating nuclear accumulation of EGFR and activating the EGFR/STAT3/PD-L1 signaling pathway. IGFBP2 knockdown reduced nuclear EGFR, STAT3 activation, and PD-L1 levels both in vitro and in vivo. IGFBP2 overexpression/knockdown, nuclear fractionation, EGFR/STAT3 phosphorylation assays, PD-L1 expression, in vivo xenograft model Cancer letters Medium 32120023
2018 IGFBP2 promotes EMT in salivary adenoid cystic carcinoma by enhancing NF-κB (p65) nuclear translocation, which then drives ZEB1 transcription. Mutation of the nuclear localization signal of IGFBP2 impeded p65 nuclear translocation, lowered ZEB1 expression, and abrogated the EMT process and metastasis in xenograft models. IGFBP2 nuclear localization signal mutant, nuclear fractionation, NF-κB reporter, ZEB1 expression analysis, EMT markers, xenograft metastasis models Cancer letters Medium 29885520
2019 IGFBP2 upregulates ZEB1 in hepatocellular carcinoma via NF-κB signaling: IGFBP2 overexpression promotes nuclear localization of p65, which binds the ZEB1 promoter to drive transcription. Cell fractionation confirmed IGFBP2-induced p65 nuclear translocation. Dual-fluorescein reporter for NF-κB, cell fractionation for p65, IGFBP2 overexpression/knockdown, ZEB1/EMT marker measurement Digestive and liver disease Medium 31818638
2010 IGFBP2 overexpression reverses diabetes (lowers blood glucose and insulin) in insulin-resistant and insulin-deficient mouse models without significantly reducing body weight. Hyperinsulinemic clamp studies showed a 3-fold improvement in hepatic insulin sensitivity following IGFBP2 adenoviral treatment in ob/ob mice, establishing IGFBP2 as a leptin-regulated mediator of glucose metabolism. Adenoviral IGFBP2 overexpression in ob/ob, Ay/a, diet-induced obese, and STZ-treated mice; hyperinsulinemic-euglycemic clamp studies; liver microarray Cell metabolism High 20074524
2016 Methylation of a specific intronic CpG site (CpG2605) in the IGFBP2 gene suppresses its expression; in vitro selective methylation of CpG2605 reduced reporter activity by ~85%. This epigenetic inhibition of hepatic IGFBP2 occurs early in life (before obesity) and predicts later fatty liver development in mice. Combined bisulfite restriction analysis, luciferase reporter with selective CpG methylation, quantitative methylation-specific PCR, gene expression analysis Human molecular genetics Medium 27126637
2009 p16(INK4a) is a negative regulator of IGFBP2 expression; loss of Ink4a-Arf in a mouse glioma model elevated endogenous tumor cell IGFBP2 and bypassed the requirement for exogenous IGFBP2 for glioma progression. An inverse relationship between p16(INK4a) and IGFBP2 was confirmed in human glioma tissues and 90 cancer cell lines. RCAS/Ntv-a transgenic mouse model, Ink4a-Arf null background epistasis, antisense IGFBP2 RCAS vector, Western blotting, reverse-phase protein lysate arrays Proceedings of the National Academy of Sciences of the United States of America High 19805356
2008 IGFBP2 expression in the hippocampus is upregulated by estrogen in a brain region-specific manner (hippocampus but not hypothalamus) in ovariectomized rats. Time-dependent regulation in rat pituitary cell lines confirmed estrogen up-regulates IGFBP2 mRNA. Microarray analysis, quantitative RT-PCR in ovariectomized rat hippocampus and hypothalamus, cell line estrogen treatment Endocrine journal Low 18946176
2013 IGFBP2 downregulation inhibits IGF1R phosphorylation and signaling; exogenous IGFBP2 potentiates IGF1R antibody activity against rhabdomyosarcoma cells and reverses acquired resistance to IGF1R antibody therapy in vivo. Selection against IGFBP2 expression represents a mechanism of acquired resistance to IGF1R-targeted therapy. In vivo IGF1R antibody-resistant model generation, IGFBP2 expression analysis, exogenous IGFBP2 addition, IGF1R phosphorylation assays, PI3K/mTOR inhibitor combinations Oncogene Medium 24292683
2013 Hyperglycemia increases IGFBP2 expression in prostate cancer cells by increasing histone H3 and H4 acetylation at the IGFBP2 gene promoter; siRNA silencing of IGFBP2 abolished the glucose-induced resistance to docetaxel-induced apoptosis. Chromatin immunoprecipitation (ChIP) for histone acetylation at IGFBP2 promoter, siRNA knockdown, IGFBP2 ELISA, cell death assays (Trypan Blue), bisulfite restriction analysis Endocrine-related cancer Medium 23959956
2019 IGFBP2 is a downstream effector of P2Y1 receptor signaling in astrocytes that causes neuronal hyperexcitability. Genetic P2Y1R overexpression in astrocytes increased both astrocytic and neuronal Ca2+ signals; IGFBP2 was identified as the downstream molecule and acts as an excitatory signal causing neuronal excitation. In epilepsy and stroke models, reactive astrocytes upregulated P2Y1R and IGFBP2. Astrocyte-specific P2Y1R overexpression in mice, Ca2+ imaging, IGFBP2 identification as downstream mediator, neurological disease models (epilepsy, stroke) Nature communications Medium 39117630
2019 IGFBP2 enhances excitatory synaptic inputs onto CA1 pyramidal neurons, facilitates intrinsic excitability and long-term potentiation (LTP) by enhancing NMDA receptor-dependent EPSCs, and promotes neurite proliferation and elongation. Knockout of igfbp2 reduces pyramidal cell and interneuron numbers, impairs LTP and cognitive performance; these deficits are rescued by exogenous IGFBP2. Igfbp2 knockout mice, electrophysiology (LTP, EPSC, excitability), NMDA receptor-dependent current measurements, behavioral cognition tests, exogenous IGFBP2 rescue Advanced science High 31832311
2017 IGFBP2 exerts anxiolytic/antidepressant effects in rat PTSD models via an IGF-1 receptor-independent mechanism. Unlike IGF-1, effects were not blocked by the IGF1R antagonist JB1 or AMPA receptor antagonist NBQX. IGFBP2 increased mature dendritic spine densities in medial prefrontal cortex and hippocampus 24 hours post-dosing, suggesting structural plasticity as a mechanism. Porsolt, contextual fear conditioning, and chronic unpredictable stress models; selective receptor antagonists (JB1, NBQX); dendritic spine morphology measurement in dentate gyrus and mPFC The international journal of neuropsychopharmacology Medium 28158790
2022 An IGFBP2-mimetic peptide (JB2) promotes synaptic plasticity via NMDA receptor activation, gene transcription/translation, and IGF2 receptors (not IGF1 receptor-dependent). JB2 directly binds to dendrites/synapses and induces remodeling of the membrane phosphoproteome; it rescued synaptic, cognitive, and behavioral deficits in a Shank3 haploinsufficiency mouse model. Peptide binding assay, pharmacological receptor antagonism (IGF1R), phosphoproteomics, electrophysiology (synaptic plasticity), behavioral testing in Shank3+/- mice Molecular psychiatry High 36481930
2023 IGFBP2 secreted by mammary adipocytes limits breast cancer invasion through binding and sequestration of cancer-derived IGF-II (IGF2). IGF-II depletion by siRNA or neutralizing antibody abolished breast cancer invasion, establishing IGF-II autocrine signaling as the target of IGFBP2-mediated suppression. Patient-derived adipocyte conditioned medium, IGFBP2 loss-of-function, IGF-II siRNA knockdown, IGF-II neutralizing antibody, invasion assays Science advances High 37436978
2024 IGFBP2 induces podocyte apoptosis in diabetic kidney disease by binding integrin α5 (ITGA5) on podocytes and activating FAK phosphorylation, which causes mitochondrial injury (membrane potential decrease, ROS production). ITGA5 knockdown or FAK inhibition attenuated podocyte apoptosis caused by high glucose or IGFBP2 overexpression. IGFBP2 overexpression/knockdown, ITGA5 knockdown, FAK inhibitor, mitochondrial membrane potential and ROS assays, apoptosis assays, STZ-induced DKD mouse model Apoptosis Medium 38796567
2023 Loss of IGFBP2 mediates alveolar type 2 cell (AEC2) senescence. In aged human-IGFBP2 transgenic mice, IGFBP2 reduced senescence and SASP factors in AEC2 cells and ameliorated bleomycin-induced lung fibrosis. Intranasal recombinant IGFBP2 delivery protected aged mice from fibrosis. Human IGFBP2 transgenic mice, recombinant IGFBP2 intranasal delivery, bleomycin lung injury model, AEC2 senescence markers, SASP factor measurement Cell reports. Medicine Medium 36787736
2024 An omentum-specific high IGFBP2-expressing stromal population (transitioning between mesothelial and mesenchymal states) inhibits adipose stem/progenitor cell (hASPC) adipogenesis through IGFBP2 secretion. Single-cell RNA-seq identified this population and functional experiments confirmed secreted IGFBP2 as the anti-adipogenic effector. Single-cell and bulk RNA-seq of >30 human adipose SVF samples, conditioned medium/co-culture experiments, IGFBP2 functional blocking, adipogenesis assays Cell metabolism Medium 38729152
2021 In mice, Igfbp2 deficiency significantly impairs bariatric surgery-induced loss in adiposity and early improvement in insulin sensitivity (but not long-term glucose homeostasis), demonstrating that circulating IGFBP2 plays a causal role in the early metabolic improvements of bariatric surgery. Igfbp2 knockout mice, RYGB/BPD-DS/SG bariatric surgery models, insulin tolerance tests, adiposity measurements Cell reports. Medicine Medium 33948578
2020 IGFBP2 stabilizes cytoplasmic β-catenin (via TRIM33 induction that depletes nuclear β-catenin) and cytoplasmic β-catenin then binds the 3'UTR of Oct4 RNA, regulating Oct4 transcript levels and promoting stemness in glioma cells. IGFBP2 overexpression/treatment induces TRIM33, an E3 ubiquitin ligase that degrades nuclear β-catenin. IGFBP2 overexpression/treatment, shRNA knockdown of TRIM33/β-catenin, RNA immunoprecipitation (RNAIP) for β-catenin/Oct4 RNA interaction, luciferase reporter, nuclear/cytoplasmic fractionation, neurosphere assay Journal of neuro-oncology Medium 32803659
2005 IGFBP2 overexpression in developing chick long bones inhibits IGF-I- and IGF-II-mediated chondrocyte proliferation and matrix synthesis in vitro and in vivo, establishing IGFBP2 as an inhibitor of IGF action in skeletal development. IGFBP2 excess shortens long bones by inhibiting chondrocyte proliferation without affecting chondrocyte maturation markers. RCAS retroviral IGFBP2 overexpression in chick wing skeletal elements, in vitro chondrocyte proliferation/matrix synthesis assays with IGF-I, IGF-II, and long-R3-IGF-I (IGFBP-resistant analog) Bone High 16183342
2008 IGFBP2 upregulates DNA-PKcs expression in astrocytoma cells in a time- and dose-dependent manner following exogenous IGFBP2 stimulation. IGF-1 had no effect on DNA-PKcs induction, suggesting an IGF-1-independent mechanism for IGFBP2-driven DNA repair. Exogenous IGFBP2 stimulation of astrocytoma cells, time- and dose-response western blot for DNA-PKcs, comparison with IGF-1 treatment Journal of child neurology Low 18952587
2023 SARM1 in neurons promotes neuroinflammation and demyelination in experimental autoimmune encephalomyelitis by upregulating IGFBP2, which activates NF-κB signaling. SARM1 knockout reduced neuronal IGFBP2 levels; restoring NF-κB activation in SARM1 knockout EAE mice partially reversed the protective phenotype. SARM1 conditional KO in CNS (Nestin-CKO), RNA-seq, RT-PCR, immunostaining, NF-κB activation assay, NF-κB activator rescue experiment in SARM1-KO mice Acta physiologica Medium 37186158
2021 HIF-1α transcriptionally drives IGFBP2 expression in Wilms tumor, and IGFBP2 in turn supports constitutive IGF1-AKT signaling. Deficiency of either HIF-1α or IGFBP2 significantly impaired tumor growth and nearly abrogated metastasis in xenograft models; pharmacologic HIF-1α inhibition (echinomycin nanoliposomes) suppressed the HIF-1α-IGFBP2 axis. HIF-1α and IGFBP2 shRNA knockdown in xenografted Wilms tumor, patient-derived xenograft models, echinomycin nanoliposome treatment, AKT phosphorylation assays Oncogene Medium 34155347

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell metabolism 238 20074524
1993 Clinical studies of IGFBP-2 by radioimmunoassay. Growth regulation 160 7683512
2002 Expression profiling of synovial sarcoma by cDNA microarrays: association of ERBB2, IGFBP2, and ELF3 with epithelial differentiation. The American journal of pathology 149 12414507
2020 IGFBP2: integrative hub of developmental and oncogenic signaling network. Oncogene 115 31925333
2006 An interaction between insulin-like growth factor-binding protein 2 (IGFBP2) and integrin alpha5 is essential for IGFBP2-induced cell mobility. The Journal of biological chemistry 106 16569642
2014 IGFBP-2: The dark horse in metabolism and cancer. Cytokine & growth factor reviews 98 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
2005 Role of IGFBP2, IGF-I and IGF-II in regulating long bone growth. Bone 94 16183342
2020 IGFBP2 promotes tumor progression by inducing alternative polarization of macrophages in pancreatic ductal adenocarcinoma through the STAT3 pathway. Cancer letters 76 33309859
2015 IGF-I and IGFBP-2 Stimulate AMPK Activation and Autophagy, Which Are Required for Osteoblast Differentiation. Endocrinology 76 26556533
2005 Significant expression of IGFBP2 in breast cancer compared with benign lesions. Journal of clinical pathology 74 15790698
2013 Hyperglycaemia-induced chemoresistance of prostate cancer cells due to IGFBP2. Endocrine-related cancer 73 23959956
2015 IGFBP2 potentiates nuclear EGFR-STAT3 signaling. Oncogene 72 25893308
2021 COL11A1 activates cancer-associated fibroblasts by modulating TGF-β3 through the NF-κB/IGFBP2 axis in ovarian cancer cells. Oncogene 70 34117361
2020 IGFBP2 regulates PD-L1 expression by activating the EGFR-STAT3 signaling pathway in malignant melanoma. Cancer letters 69 32120023
2016 The miR-204-3p-targeted IGFBP2 pathway is involved in xanthohumol-induced glioma cell apoptotic death. Neuropharmacology 64 27487563
2023 Loss of IGFBP2 mediates alveolar type 2 cell senescence and promotes lung fibrosis. Cell reports. Medicine 63 36787736
2011 DNA hypermethylation profiles associated with glioma subtypes and EZH2 and IGFBP2 mRNA expression. Neuro-oncology 63 21339190
2019 IGFBP-2 Signaling in the Brain: From Brain Development to Higher Order Brain Functions. Frontiers in endocrinology 62 31824433
2018 Immune heterogeneity and clinicopathologic characterization of IGFBP2 in 2447 glioma samples. Oncoimmunology 61 29721393
2010 IGFBP2 promotes glioma tumor stem cell expansion and survival. Biochemical and biophysical research communications 60 20515648
2008 IGFBP2 and IGFBP5 overexpression correlates with the lymph node metastasis in T1 breast carcinomas. The breast journal 55 18373644
2014 IGFBP-2 directly stimulates osteoblast differentiation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 54 24839202
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
2016 Early hypermethylation of hepatic Igfbp2 results in its reduced expression preceding fatty liver in mice. Human molecular genetics 52 27126637
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
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 50 37982669
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 48 33416173
2014 Loss of PTEN expression is associated with IGFBP2 expression, younger age, and late stage in triple-negative breast cancer. American journal of clinical pathology 46 24515759
2019 Circulating IGFBP-2: a novel biomarker for incident dementia. Annals of clinical and translational neurology 45 31373442
1998 IGFBP-2 expression in a human cell line is associated with increased IGFBP-3 proteolysis, decreased IGFBP-1 expression and increased tumorigenicity. International journal of cancer 44 9714057
2016 Glioma progression is mediated by an addiction to aberrant IGFBP2 expression and can be blocked using anti-IGFBP2 strategies. The Journal of pathology 43 27125842
2008 Identification of Igf2, Igfbp2 and Enpp2 as estrogen-responsive genes in rat hippocampus. Endocrine journal 42 18946176
2006 The effects of IGF-I on bovine follicle development and IGFBP-2 expression are dose and stage dependent. Reproduction (Cambridge, England) 42 16514194
2000 Effects of IGFBP-2 overexpression in vitro and in vivo. Pediatric nephrology (Berlin, Germany) 40 10912521
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) 39 37031362
2011 High expression of IGFBP2 is associated with chemoresistance in adult acute myeloid leukemia. Leukemia research 36 21899885
2001 Roles of insulin-like growth factor-I (IGF-I) and IGF-I binding protein-2 (IGFBP2) and -5 (IGFBP5) in developing chick limbs. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 36 11914022
2022 Spatial Transcriptomic Analysis of Ovarian Cancer Precursors Reveals Reactivation of IGFBP2 during Pathogenesis. Cancer research 35 36206311
2021 IGFBP-2 partly mediates the early metabolic improvements caused by bariatric surgery. Cell reports. Medicine 35 33948578
2013 The role of insulin-like-growth factor binding protein 2 (IGFBP2) and phosphatase and tensin homologue (PTEN) in the regulation of myoblast differentiation and hypertrophy. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 35 23583027
2018 IGFBP2 promotes neural stem cell maintenance and proliferation differentially associated with glioblastoma subtypes. Brain research 34 30347220
2010 Patched1 inhibits epidermal progenitor cell expansion and basal cell carcinoma formation by limiting Igfbp2 activity. Cancer prevention research (Philadelphia, Pa.) 33 20858761
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
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 32 38778379
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 31 32532003
1995 Genetic ablation of IGFBP-2 suggests functional redundancy in the IGFBP family. Progress in growth factor research 31 8817688
2021 SNAIL2 contributes to tumorigenicity and chemotherapy resistance in pancreatic cancer by regulating IGFBP2. Cancer science 30 34628696
2017 IGFBP2 expression predicts IDH-mutant glioma patient survival. Oncotarget 30 27852048
2015 Novel anti IGFBP2 single chain variable fragment inhibits glioma cell migration and invasion. Journal of neuro-oncology 30 25944386
2015 Igfbp2 Deletion in Ovariectomized Mice Enhances Energy Expenditure but Accelerates Bone Loss. Endocrinology 30 26230658
2015 Roles of miR-278-3p in IBP2 regulation and Bombyx mori cytoplasmic polyhedrosis virus replication. Gene 30 26348138
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
2019 IGFBP2 promotes immunosuppression associated with its mesenchymal induction and FcγRIIB phosphorylation in glioblastoma. PloS one 29 31560714
2016 IGFBP-2 and -3 co-ordinately regulate IGF1 induced matrix mineralisation of differentiating human dental pulp cells. Stem cell research 29 27776273
1996 Expression of IGFBP-2, -3, and -4 mRNA during differentiation of Caco-2 colon epithelial cells. The American journal of physiology 29 8944682
2023 Cancer-associated fibroblast-associated gene IGFBP2 promotes glioma progression through induction of M2 macrophage polarization. American journal of physiology. Cell physiology 28 37982173
2019 Activation of EGFR-DNA-PKcs pathway by IGFBP2 protects esophageal adenocarcinoma cells from acidic bile salts-induced DNA damage. Journal of experimental & clinical cancer research : CR 28 30626422
2022 Metastatic colorectal carcinoma-associated fibroblasts have immunosuppressive properties related to increased IGFBP2 expression. Cancer letters 27 35569697
2019 MiR-34b-5p Mediates the Proliferation and Differentiation of Myoblasts by Targeting IGFBP2. Cells 27 30999686
2019 Silencing circular RNA VANGL1 inhibits progression of bladder cancer by regulating miR-1184/IGFBP2 axis. Cancer medicine 27 31758655
2019 IGFBP2 Plays an Essential Role in Cognitive Development during Early Life. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 27 31832311
2008 Matrix metalloproteinase-9 interplays with the IGFBP2-IGFII complex to promote cell growth and motility in astrocytomas. Glia 26 18563800
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
2006 Expression of IGFBP2 in gastric carcinoma and relationship with clinicopathologic parameters and cell proliferation. Digestive diseases and sciences 25 17171534
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
2019 IGFBP2 upregulates ZEB1 expression and promotes hepatocellular carcinoma progression through NF-κB signaling pathway. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 24 31818638
2018 Trichostatin A reverses the chemoresistance of lung cancer with high IGFBP2 expression through enhancing autophagy. Scientific reports 24 29500455
2017 IGFBP2 plays an important role in heat shock protein 27-mediated cancer progression and metastasis. Oncotarget 24 28903396
2013 Downregulation of IGFBP2 is associated with resistance to IGF1R therapy in rhabdomyosarcoma. Oncogene 24 24292683
2024 IGFBP2/ITGA5 promotes gefitinib resistance via activating STAT3/CXCL1 axis in non-small cell lung cancer. Cell death & disease 22 38918360
2018 Downregulation of CD147 induces malignant melanoma cell apoptosis via the regulation of IGFBP2 expression. International journal of oncology 22 30272281
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 22 28158790
2015 IGFBP2 modulates the chemoresistant phenotype in esophageal adenocarcinoma. Oncotarget 22 26317790
2024 Disease-relevant upregulation of P2Y1 receptor in astrocytes enhances neuronal excitability via IGFBP2. Nature communications 21 39117630
2020 Associations between IGF1, IGFBP2 and TGFß3 Genes Polymorphisms and Growth Performance of Broiler Chicken Lines. Animals : an open access journal from MDPI 21 32380764
2024 A human omentum-specific mesothelial-like stromal population inhibits adipogenesis through IGFBP2 secretion. Cell metabolism 19 38729152
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
2011 High IGFBP2 expression correlates with tumor severity in pediatric rhabdomyosarcoma. The American journal of pathology 19 21924226
2021 Targeting the HIF-1α-IGFBP2 axis therapeutically reduces IGF1-AKT signaling and blocks the growth and metastasis of relapsed anaplastic Wilms tumor. Oncogene 18 34155347
2018 IGFBP2 is a potential biomarker in acute kidney injury (AKI) and resveratrol-loaded nanoparticles prevent AKI. Oncotarget 18 30564296
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
2023 IGFBP2 secretion by mammary adipocytes limits breast cancer invasion. Science advances 17 37436978
2022 Gold Nanoparticles Disrupt the IGFBP2/mTOR/PTEN Axis to Inhibit Ovarian Cancer Growth. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 17 36104215
2020 Estrogen Stimulation of Pleiotrophin Enhances Osteoblast Differentiation and Maintains Bone Mass in IGFBP-2 Null Mice. Endocrinology 17 32168373
2020 Regulation of β-catenin by IGFBP2 and its cytoplasmic actions in glioma. Journal of neuro-oncology 17 32803659
2008 IGFBP2 is overexpressed by pediatric malignant astrocytomas and induces the repair enzyme DNA-PK. Journal of child neurology 17 18952587
2023 SARM1 promotes the neuroinflammation and demyelination through IGFBP2/NF-κB pathway in experimental autoimmune encephalomyelitis mice. Acta physiologica (Oxford, England) 16 37186158
2022 circSMARCA5 Is an Upstream Regulator of the Expression of miR-126-3p, miR-515-5p, and Their mRNA Targets, Insulin-like Growth Factor Binding Protein 2 (IGFBP2) and NRAS Proto-Oncogene, GTPase (NRAS) in Glioblastoma. International journal of molecular sciences 16 36430152
2022 An IGFBP2-derived peptide promotes neuroplasticity and rescues deficits in a mouse model of Phelan-McDermid syndrome. Molecular psychiatry 16 36481930
2020 Astrocytic IGFBP2 and CHI3L1 in cerebrospinal fluid drive cortical metastasis of HER2+breast cancer. Clinical & experimental metastasis 16 32279122

Missed literature

Know a paper Affinage missed for IGFBP2? Flag it for the maintainers and the community.

No submissions yet.