Affinage

IGFBP4

Insulin-like growth factor-binding protein 4 · UniProt P22692

Length
258 aa
Mass
27.9 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IGFBP-4 is a secreted modulator of growth factor signaling that operates through both IGF-dependent and IGF-independent mechanisms to regulate cell proliferation, differentiation, and tissue homeostasis. Its canonical function is sequestration of IGF-I and IGF-II, preventing their binding to the type I IGF receptor and thereby inhibiting IGF-driven proliferation in bone, smooth muscle, and other tissues (PMID:7544787, PMID:9564877). This inhibitory activity is regulated by proteolytic cleavage at Met135-Lys136 by the metalloproteinase PAPP-A, which requires prior IGF-II binding to IGFBP-4 to render it an efficient substrate, releasing bioavailable IGF (PMID:10620067, PMID:11522292, PMID:10898936). Independent of IGF binding, IGFBP-4 inhibits canonical Wnt/β-catenin signaling by physically engaging co-receptors LRP6 and Frizzled-8 to block Wnt3A, a mechanism that promotes cardiomyocyte differentiation and protects against ischemic cardiac injury, and its C-terminal thyroglobulin type-1 domain inhibits cathepsin B, conferring anti-angiogenic activity (PMID:18528331, PMID:27803037, PMID:23633927).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1995 High

    Establishing the core mechanism of action: IGFBP-4 was shown to inhibit IGF signaling by directly competing with the type I IGF receptor for IGF-I and IGF-II binding, resolving the question of whether IGFBP-4 acts at the receptor level or through other means.

    Evidence Radioligand binding assays using 125I-IGF-I/II and proliferation assays with IGF analogs of reduced IGFBP affinity in bone cells

    PMID:7544787

    Open questions at the time
    • Relative affinities for IGF-I vs. IGF-II not precisely quantified in this study
    • Whether IGFBP-4 has IGF-independent cellular effects was not addressed
  2. 1999 High

    Identifying the proteolytic switch: the specific PAPP-A cleavage site (Met135-Lys136) was mapped in human IGFBP-4, and deletion mutagenesis revealed that a distal region (residues 94-119) maintains the conformation necessary for substrate recognition, establishing that regulated proteolysis converts IGFBP-4 from an IGF inhibitor to a vehicle for IGF release.

    Evidence N-terminal sequencing, mass spectrometry of fragments, deletion mutagenesis, and protease-resistant mutants tested in osteoblast proliferation assays

    PMID:10620067 PMID:7538115

    Open questions at the time
    • Three-dimensional structure of the IGFBP-4/IGF/PAPP-A ternary complex not determined
    • Contribution of glycosylation to protease susceptibility not fully resolved
  3. 2001 High

    Identifying PAPP-A as the physiological IGFBP-4 protease and demonstrating that IGF-II binding to IGFBP-4 (not to PAPP-A) is the conformational trigger for efficient proteolysis resolved the long-standing question of what enzyme controlled IGFBP-4 turnover and how IGF-dependence operates.

    Evidence Immunodepletion/immunoinhibition of PAPP-A from pregnancy serum, trophoblast and osteoblast conditioned media; pre-incubation experiments with IGF-binding-deficient IGFBP-4 mutants

    PMID:10898936 PMID:11158056 PMID:11522292 PMID:11994388 PMID:15541345

    Open questions at the time
    • Whether other proteases (e.g., plasmin) contribute significantly to IGFBP-4 turnover in vivo remains unclear
    • Structural basis of IGF-II-induced conformational change in IGFBP-4 not resolved
  4. 1997 High

    A regulatory layer above PAPP-A was uncovered: basic C-terminal peptides of IGFBP-3, -5, and -6 inhibit IGFBP-4 proteolysis through heparin-reversible interactions, establishing that other IGFBPs modulate IGFBP-4 half-life and thus IGF bioavailability.

    Evidence Cell-free protease assay with 125I-IGFBP-4, synthetic peptide competition, and heparin reversal in osteoblast conditioned medium

    PMID:7499205 PMID:9165012

    Open questions at the time
    • In vivo relevance of cross-IGFBP regulation of proteolysis not demonstrated
    • Whether this inhibition targets PAPP-A specifically or the substrate was not resolved
  5. 2001 High

    In vivo functional validation showed that the IGFBP-4/protease axis controls IGF bioavailability in bone: systemic wild-type IGFBP-4 increased bone formation and serum free IGF-I, but protease-resistant IGFBP-4 did not, proving that proteolytic release of IGF is the mechanism by which circulating IGFBP-4 stimulates osteogenesis.

    Evidence Systemic administration of wild-type vs. protease-resistant IGFBP-4 in mice with measurement of serum osteocalcin, ALP, and free IGF-I

    PMID:11356715

    Open questions at the time
    • Tissue-specific contributions of endogenous PAPP-A to this effect not dissected
    • Whether other IGFBP-4-bound ligands contribute to the bone phenotype is unknown
  6. 2002 High

    Transgenic models demonstrated that IGFBP-4 is a physiological antagonist of IGF-I in smooth muscle: SMC-targeted overexpression caused smooth muscle hypoplasia that was epistatic to IGF-I overexpression, and protease-resistant IGFBP-4 transgenes produced more severe growth inhibition, confirming the protease-dependent release model in vivo.

    Evidence Transgenic and double-transgenic mice with SMC-specific IGFBP-4 and IGF-I expression; protease-resistant mutant transgene comparison

    PMID:11923290 PMID:9564877

    Open questions at the time
    • Whether Wnt-inhibitory functions of IGFBP-4 contribute to the smooth muscle phenotype was not tested
    • Effects on smooth muscle function (contractility) beyond mass not assessed
  7. 2008 High

    A paradigm shift: IGFBP-4 was found to possess IGF-independent activity as a direct inhibitor of canonical Wnt signaling, physically binding LRP6 and Frizzled-8 to block Wnt3A engagement—this explained its cardiogenic activity and opened a new functional axis distinct from IGF sequestration.

    Evidence Co-immunoprecipitation of IGFBP-4 with LRP6 and Frz8, IGF-binding-deficient mutant retaining Wnt inhibition, Igfbp4 knockdown blocking cardiomyocyte differentiation in vitro and in Xenopus

    PMID:18528331

    Open questions at the time
    • Binding interface between IGFBP-4 and LRP6/Frz8 not structurally resolved
    • Whether Wnt inhibition is relevant outside cardiac differentiation contexts not established
  8. 2013 High

    The C-terminal thyroglobulin type-1 domain was identified as an autonomous anti-angiogenic module that inhibits cathepsin B after cell internalization and reduces glioblastoma growth, revealing an IGF- and Wnt-independent effector function of IGFBP-4 proteolytic fragments.

    Evidence Recombinant C-terminal IGFBP-4 fragment tested in cathepsin B activity assay, EC tubulogenesis assay, and xenograft tumor model

    PMID:23633927

    Open questions at the time
    • Whether PAPP-A-generated C-terminal fragments achieve sufficient local concentration for cathepsin B inhibition in vivo is unknown
    • Specificity for cathepsin B versus other cathepsins not fully tested
  9. 2016 High

    The Wnt-inhibitory mechanism was refined in the ischemic heart: IGFBP-4 targets β-catenin rather than LRP5/6 (unlike Dkk1), and direct intracardiac injection of recombinant IGFBP-4 was cardioprotective, establishing the molecular specificity and therapeutic relevance of IGFBP-4-mediated Wnt inhibition.

    Evidence Conditional cardiomyocyte-specific LRP5/6 and β-catenin knockout mice subjected to myocardial infarction, recombinant protein injection, Tcf reporter assay

    PMID:27803037

    Open questions at the time
    • Reconciliation with the 2008 finding of LRP6/Frz8 binding is needed—different targets in different cell types possible but not tested
    • Long-term cardiac functional outcomes not reported
  10. 2017 High

    Global Igfbp4 knockout revealed in vivo requirements for adipogenesis and sex-specific skeletal homeostasis, establishing that IGFBP-4 is not simply redundant with other IGFBPs but has non-redundant roles in mesenchymal cell fate decisions including adipocyte differentiation (via Akt signaling) and osteoclastogenesis.

    Evidence Igfbp4 knockout mice analyzed by micro-CT, histomorphometry, primary BMSC/eMSC adipogenesis assays, high-fat diet and ovariectomy challenges

    PMID:28184001 PMID:28938423

    Open questions at the time
    • Relative contributions of IGF-dependent vs. Wnt-dependent mechanisms to the knockout phenotypes not dissected
    • Compensatory changes in other IGFBPs in knockout mice not fully characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of IGF-II-induced conformational change enabling PAPP-A cleavage, the relative in vivo contributions of IGF-sequestration versus Wnt-inhibition versus cathepsin B inhibition across tissues, and whether the apparently discrepant Wnt-pathway targets (LRP6/Frz8 vs. β-catenin) reflect context-dependent mechanisms.
  • No high-resolution structure of IGFBP-4 in complex with PAPP-A or Wnt pathway components
  • Tissue-specific dissection of IGF-dependent vs. IGF-independent functions lacking
  • No human genetic disease directly linked to IGFBP4 loss-of-function mutations

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0048018 receptor ligand activity 2 GO:0140313 molecular sequestering activity 2
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 2
Partners
CTNNB1FZD8IGF1IGF2LRP6PAPP-A

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 IGFBP-4 inhibits IGF action by preventing binding of IGF-I and IGF-II to the type I IGF receptor; coincubation with IGFBP-4 decreased binding of both 125I-IGF-I and 125I-IGF-II to bone cells and to purified type I IGF receptor in a dose-dependent manner, and IGFBP-4 had no effect on proliferation induced by IGF analogs with >100-fold reduced affinity for IGFBP-4. Radioligand binding assays, cell proliferation assays with IGF analogs of reduced IGFBP affinity The Journal of biological chemistry High 7544787
1995 The protease that cleaves IGFBP-4 cuts at the peptide bond between residues 120-121 (Lys-120/Met-121) within the non-homologous mid-region of IGFBP-4; site-directed mutagenesis of K120A rendered IGFBP-4 relatively resistant to cleavage, and the resulting 16-kDa N-terminal fragment lost the ability to inhibit IGF-1-stimulated thymidine uptake. Electrospray mass spectrometry, amino acid sequencing, site-directed mutagenesis (K120A), thymidine incorporation assay The Journal of biological chemistry High 7538115
1999 The human osteoblast IGF-II-dependent IGFBP-4 protease cleaves at Met135-Lys136 as the sole cleavage site; deletion of residues 94-119 (which contain no cleavage site) blocked proteolysis, suggesting these residues maintain the IGFBP-4 conformation required to expose the cleavage site; protease-resistant analogs were more potent inhibitors of IGF-II-induced proliferation in osteoblasts (which produce the protease) than wild-type IGFBP-4. N-terminal amino acid sequencing, mass spectrometry of proteolytic fragments, deletion mutagenesis, cell proliferation assay Journal of bone and mineral research High 10620067
2000 The interaction between IGF-II and IGFBP-4 (not between IGF-II and PAPP-A) is essential for efficient IGFBP-4 proteolysis by PAPP-A; pre-incubation of IGFBP-4 with IGF-II followed by removal of free IGF-II allowed proteolysis, while pre-incubation of PAPP-A with IGF-II did not; IGFBP-4 mutants lacking IGF-binding activity but retaining the cleavage site were resistant to proteolysis regardless of IGF-II presence. Cell-free protease assay, PAPP-A antibody immunoprecipitation, IGF-binding domain deletion mutants, pre-incubation experiments Archives of biochemistry and biophysics High 10898936
2001 PAPP-A is identified as the protease responsible for IGF-II-dependent IGFBP-4 cleavage in human pregnancy serum; cleavage of IGFBP-4 by PAPP-A can occur without IGF in the absence of IGF but at a very slow rate; IGF-II enhances proteolysis by binding to IGFBP-4 (making IGFBP-4 the substrate), not by directly interacting with PAPP-A. Specific PAPP-A antibody immunoprecipitation/immunodepletion of protease activity, cell-free proteolysis assay, IGF binding studies with purified recombinant proteins FEBS letters High 11522292
2001 PAPP-A accounts for the predominant IGFBP-4 proteolytic activity in human pregnancy serum; immunoprecipitation with PAPP-A antibody completely abolished both IGF-II-dependent and IGF-II-independent IGFBP-4 proteolytic activity; serum PAPP-A enhanced IGF bioactivity in vitro by degrading IGFBP-4, an effect blocked by PAPP-A neutralizing antibody. Immunoprecipitation/immunodepletion of PAPP-A from pregnancy serum, cell proliferation assay with wild-type vs. protease-resistant IGFBP-4, PAPP-A neutralizing antibody The Journal of clinical endocrinology and metabolism High 11158056
2002 PAPP-A is the IGFBP-4 protease in human trophoblasts and decidualized endometrial stromal cells; IGFBP-4 protease activity was confirmed by specific immunoinhibition and immunodepletion with PAPP-A antibodies; proteolysis was IGF-II-dependent, and its physiological inhibitor proMBP was identified in trophoblast conditioned medium. Immunoinhibition, immunodepletion with specific PAPP-A antibodies, conditioned medium protease assay, ELISA for PAPP-A and proMBP The Journal of clinical endocrinology and metabolism High 11994388
2008 IGFBP-4 functions as an inhibitor of canonical Wnt signaling independent of its IGF-binding activity; IGFBP-4 physically interacts with Wnt co-receptor LRP6 and Frizzled-8 (Frz8), inhibiting Wnt3A binding to these receptors; this cardiogenic effect was attenuated by IGFs through IGFBP-4 sequestration. Co-immunoprecipitation of IGFBP-4 with LRP6 and Frz8, in vitro cardiomyocyte differentiation, Igfbp4 knockdown in vitro and in vivo, IGF-binding-deficient IGFBP-4 mutant, Wnt3A binding competition assay Nature High 18528331
1995 IGFBP-3 functions as an IGF-reversible inhibitor of IGFBP-4 proteolysis; recombinant IGFBP-3 added to osteoblast conditioned medium inhibited 125I-IGFBP-4 proteolysis by 90%, and this inhibition was reversed by IGF-I or IGF-II; synthetic peptides spanning the highly basic, putative heparin-binding C-terminal region of IGFBP-3 mediated this inhibition, and heparin reversed the inhibitory effect. Cell-free protease assay with 125I-IGFBP-4, synthetic peptide competition, heparin reversal experiment The Journal of biological chemistry High 7499205
1997 IGFBP-3, -5, and -6 all inhibit IGFBP-4 proteolysis through homologous highly basic, heparin-binding domains within the conserved thyroglobulin type-1 motif at their C-termini; synthetic peptides from these regions inhibited 125I-IGFBP-4 proteolysis by MC3T3-E1 osteoblast conditioned medium, and heparin reversed their inhibitory effects. Cell-free protease assay with 125I-IGFBP-4, synthetic peptide competition assay, heparin binding studies, IC50 determination Endocrinology High 9165012
2001 Systemic administration of wild-type IGFBP-4 increased bone formation parameters in mice by increasing IGF bioavailability through proteolysis of IGFBP-4; protease-resistant IGFBP-4 administered systemically did not increase bone formation or serum free IGF-I, whereas wild-type IGFBP-4 did, confirming that the stimulatory effect requires IGFBP-4 protease-mediated release of IGF. In vivo systemic administration of wild-type vs. protease-resistant IGFBP-4, biochemical bone formation markers (serum osteocalcin, ALP), serum free IGF-I measurement, local administration assay Endocrinology High 11356715
1998 Overexpression of IGFBP-4 in smooth muscle cells (SMC) of transgenic mice caused smooth muscle hypoplasia in multiple SMC-rich organs, a reciprocal phenotype to IGF-I-overexpressing transgenic mice; IGFBP-4 overexpression was confirmed to be the functional antagonist of IGF-I in SMC in vivo. Transgenic mouse generation with SMC-specific promoter (SMP8-BP-4), tissue weight measurements, in situ hybridization, Western ligand blotting, double transgenic cross with SMP8-IGF-I mice Endocrinology High 9564877
2002 Protease-resistant IGFBP-4 (with substitutions 119-AAMAAVADASAMA-133 in the cleavage domain) is stabilized in vivo and causes greater growth inhibition of SMC-rich tissues than equivalent levels of native IGFBP-4, demonstrating that IGFBP-4 proteolysis is required for local IGF-I action in smooth muscle. Site-directed mutagenesis of IGFBP-4 cleavage domain, transgenic mice with SMC-specific expression, tissue weight measurements, Western blot quantification of IGFBP-4/transgene mRNA ratio The Journal of biological chemistry High 11923290
2004 PAPP-A is the IGFBP-4 protease in MC3T3-E1 osteoblasts; immunodepletion of PAPP-A from MC3T3-E1 conditioned medium abolished IGFBP-4 degradation; IGFBP-4 degradation was enhanced by IGF-II and inhibited by mutation of basic residues at/near the PAPP-A cleavage site. Immunodepletion of PAPP-A from conditioned medium, IGFBP-4 degradation assay, site-directed mutagenesis of IGFBP-4 cleavage site, RT-PCR for PAPP-A mRNA Biochemical and biophysical research communications High 15541345
2003 Paracrine overexpression of IGFBP-4 in osteoblasts via an osteocalcin promoter transgene caused 25-fold increased calvaria IGFBP-4, reduced bone turnover (osteoblast number and bone formation rate ~50% of controls), global growth retardation, and disproportionate reduction of skeletal weight, attributed to IGF-1 sequestration. Transgenic mice (OC-BP4), Western ligand blot, quantitative bone histomorphometry, organ allometry Journal of bone and mineral research High 12733722
2013 SOX9 directly binds the IGFBP-4 promoter and transcriptionally activates IGFBP-4 expression in intestinal epithelial cells; IGFBP-4 was significantly downregulated in Sox9-deficient crypts and adenoma cells; SOX9-induced inhibition of cell proliferation was restored by a neutralizing IGFBP-4 antibody. Chromatin immunoprecipitation (ChIP) of SOX9 at IGFBP-4 promoter, reporter assay, Sox9 knockout mouse model, neutralizing antibody rescue experiment, immunolocalization American journal of physiology. Gastrointestinal and liver physiology High 23660500
2013 The anti-angiogenic and anti-tumorigenic activities of IGFBP-4 are located in its C-terminal fragment (CIBP-4) containing a thyroglobulin type-1 (Tg1) domain; CIBP-4 internalized into endothelial cells and glioblastoma cells, co-localizing with lysosomal structures, inhibited cathepsin B (CatB) activity, blocked EC tubulogenesis, and reduced glioblastoma tumor growth by 60% in vivo. C-terminal IGFBP-4 fragment production, in vitro cathepsin B activity assay, Matrigel EC tubulogenesis assay, in vivo biodistribution with Cy5.5 labeling, xenograft tumor model Neoplasia (New York, N.Y.) High 23633927
2016 IGFBP-4 inhibits β-catenin signaling in the ischemic heart by targeting β-catenin (not LRP5/6), whereas Dkk1 exerts injury mainly by inducing LRP5/6 endocytosis and degradation; direct injection of recombinant IGFBP-4 into infarcted hearts protected against ischemic injury through β-catenin inhibition. Conditional cardiomyocyte-specific LRP5/6 and β-catenin knockout mice, surgical myocardial infarction model, recombinant protein injection, Tcf reporter assay Circulation High 27803037
2017 IGFBP-4 is required for adipogenesis; Igfbp4-null mice had decreased inguinal and gonadal white adipose tissue weight, reduced Pparγ expression, and impaired adipogenic differentiation of primary bone marrow stromal cells (BMSCs) and ear mesenchymal stem cells (eMSCs); loss of Igfbp4 blunted phosphorylated Akt increases during adipogenesis. Igfbp4 knockout mice, primary BMSC and eMSC culture adipogenesis assay, high-fat diet challenge, ovariectomy, Western blot for p-Akt Endocrinology High 28938423
2017 Igfbp4-null mice exhibit marked sex-specific skeletal phenotypes; female knockouts had reduced aBMD/aBMC, lower trabecular BV/TV, higher osteoclastogenesis, and lower bone formation, while males had increased trabeculae with higher connectivity density and reduced mineralized surface; loss of Igfbp4 modulates mesenchymal stromal cell differentiation and osteoclastogenesis in a gender-specific manner. Igfbp4 knockout mice, micro-CT, histomorphometry, osteoblast/osteoclast culture assays, sclerostin ELISA The Journal of endocrinology High 28184001
1992 IGFBP-4 purified from bovine pulmonary artery endothelial cells crossed the capillary boundary of the isolated perfused rat heart and distributed preferentially in subendothelial connective tissue (connective tissue/muscle ratio ~20-27:1), unlike IGFBP-1, -2, -3 and IGF-I which preferentially localized in cardiac muscle. Perfused isolated beating rat heart, purified glycosylated and nonglycosylated IGFBP-4, tissue distribution quantification Endocrinology Medium 1377125
2001 The C-terminal basic region of IGFBP-4 determines its connective tissue distribution in the rat heart; chimeric IGFBP-4(3) (IGFBP-4 carrying the IGFBP-3 C-terminal basic region) redistributed to cardiac muscle like IGFBP-3, and IGFBP-3(4) localized in connective tissue like IGFBP-4. Chimeric IGFBP-3/4 protein construction, perfused rat heart distribution assay, microvascular endothelial cell binding assay Endocrinology Medium 11517150
1994 IGFBP-4 in the IGFBP-4 protease system of human osteoblast-like cells is regulated by TGF-β, which augmented IGF-II-dependent IGFBP-4 proteolysis and decreased IGFBP-4 mRNA expression; other factors (PTH, GH, insulin, calcitonin, glucocorticoids, sex steroids, 1,25-dihydroxyvitamin D3, EGF) had no significant effect on IGFBP-4 protease activity. Cell-free IGFBP-4 protease activity assay, Western ligand blotting with densitometry, Northern analysis for mRNA The Journal of clinical endocrinology and metabolism Medium 7527411
2000 Circulating N-terminal (Asp1-Phe122) and C-terminal (Lys136-Glu237) fragments of IGFBP-4 generated by in vivo proteolysis were isolated from human hemofiltrate; the N-terminal fragment retained significant IGF binding (Kd IGF-II=17 nM, IGF-I=5 nM), while the C-terminal fragment had very low IGF affinity (Kd IGF-II=690 nM, IGF-I>60 nM); disulfide bonding pattern of C-terminal fragment: 153-183, 194-205, 207-228. Affinity purification from human hemofiltrate, mass spectrometry, Edman sequencing, plasmon resonance spectroscopy, ligand blot, saturation and displacement binding studies, proteolytic digestion for disulfide mapping Biochemistry High 10819974
1998 The IGFBP4 gene core promoter activity resides downstream of position -289 and upstream of -6; cAMP response elements between positions -869 and -6 mediate a ~2-fold increase in promoter activity upon dibutyryl-cAMP stimulation, consistent with PTH- and cAMP-dependent regulation of IGFBP-4 expression in osteoblasts. Deletion mutagenesis of IGFBP4 promoter constructs, reporter assay, TATA box and transcription start site mapping Genomics Medium 9615225
1997 Surface-bound plasmin (generated by exogenous u-PA/plasminogen at HT29-D4 colon carcinoma cell surface) selectively cleaved IGFBP-4 (>95%) among IGFBP-2, -4, and -6 present, generating 18- and 14-kDa fragments with poor IGF-II affinity; approximately 20% of 125I-IGF-II released from IGFBP complexes was transferred to cell-surface IGF-I receptors. Cell surface plasmin activation assay, Western ligand blot, 125I-IGF-II transfer to IGF-I receptor measurement International journal of cancer Medium 9311602
2011 GATA-4 overexpression in mesenchymal stromal cells significantly upregulated IGFBP-4 expression; knockdown of IGFBP-4 reduced the cardiomyogenic transdifferentiation rate of GATA-4-overexpressing MSCs, demonstrating that IGFBP-4 acts downstream of GATA-4 to promote myocardial differentiation. Retroviral GATA-4 overexpression, IGFBP-4 siRNA knockdown, flow cytometry for α-sarcomeric actinin, electrophysiologic recording Cytotherapy Medium 21846294
2023 MEX3A, an RNA-binding protein, binds IGFBP4 mRNA in breast cancer cells and decreases IGFBP4 mRNA levels, thereby reducing IGFBP-4 protein and activating PI3K/AKT and downstream signaling pathways promoting cell cycle progression and migration. RNA pull-down, RNA immunoprecipitation (RIP), MEX3A knockdown/overexpression, xenograft tumor model, Western blot for PI3K/AKT pathway Breast cancer research and treatment Medium 37433992
2022 m6A methylation of IGFBP4 mRNA by METTL3 promotes YTHDF1-mediated IGFBP4 translation; reduced m6A methylation in endometrial cancer cells decreased IGFBP4 protein, and overexpression of IGFBP4 partially reversed cancer cell malignancy caused by reduced m6A methylation through suppression of NF-κB, ERK, and AKT pathways. MeRIP-qPCR, m6A-seq, polysome profiling, Western blot, METTL3 knockdown, IGFBP4 overexpression rescue, in vivo tumor formation Cell biology and toxicology Medium 35971034
2014 Inhibition of tumor-associated αvβ3 integrin in melanoma cells enhanced IGFBP-4 expression through a p38 MAPK and matrix metalloproteinase-dependent mechanism, leading to reduced melanoma growth and angiogenesis in vivo. αvβ3 integrin inhibition in melanoma cells, IGFBP-4 expression measurement, p38 MAPK inhibitor studies, in vivo tumor angiogenesis model Angiogenesis Low 25249331
2001 Truncation of WT1 (disrupting its DNA-binding zinc finger domain) results in downregulation of IGFBP4 expression, identified by cDNA macroarray analysis, suggesting IGFBP4 as a transcriptional target of WT1. Gene targeting to generate WT1 truncation, cDNA macroarray gene expression analysis Biochemical and biophysical research communications Low 11573961

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Studies on the mechanisms by which insulin-like growth factor (IGF) binding protein-4 (IGFBP-4) and IGFBP-5 modulate IGF actions in bone cells. The Journal of biological chemistry 263 7544787
2001 Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A. FEBS letters 254 11522292
2008 IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis. Nature 195 18528331
1991 Characterization of an insulin-like growth factor binding protein (IGFBP-4) produced by the B104 rat neuronal cell line: chemical and biological properties and differential synthesis by sublines. Endocrinology 118 1713156
2017 Overexpression of lncRNA IGFBP4-1 reprograms energy metabolism to promote lung cancer progression. Molecular cancer 117 28946875
2002 Identification and regulation of the IGFBP-4 protease and its physiological inhibitor in human trophoblasts and endometrial stroma: evidence for paracrine regulation of IGF-II bioavailability in the placental bed during human implantation. The Journal of clinical endocrinology and metabolism 98 11994388
1998 Modulation of insulin-like growth factor actions in L6A1 myoblasts by insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5: a dual role for IGFBP-5. Journal of cellular physiology 97 9731744
1991 Differential effects of insulin-like growth factor (IGF)-I and IGF-II on the expression of IGF binding proteins (IGFBPs) in a rat neuroblastoma cell line: isolation and characterization of two forms of IGFBP-4. Endocrinology 96 1709857
2001 Pregnancy-associated plasma protein-A accounts for the insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) proteolytic activity in human pregnancy serum and enhances the mitogenic activity of IGF by degrading IGFBP-4 in vitro. The Journal of clinical endocrinology and metabolism 91 11158056
1996 Chondrocytes from osteoarthritic cartilage have increased expression of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) and -5, but not IGF-II or IGFBP-4. The Journal of clinical endocrinology and metabolism 91 8772582
1998 Overexpression of insulin-like growth factor-binding protein-4 (IGFBP-4) in smooth muscle cells of transgenic mice through a smooth muscle alpha-actin-IGFBP-4 fusion gene induces smooth muscle hypoplasia. Endocrinology 89 9564877
1992 Insulin-like growth factors (IGFs) reduce IGF-binding protein-4 (IGFBP-4) concentration and stimulate IGFBP-3 independently of IGF receptors in human fibroblasts and epidermal cells. Endocrinology 85 1370799
2016 Opposing Roles of Wnt Inhibitors IGFBP-4 and Dkk1 in Cardiac Ischemia by Differential Targeting of LRP5/6 and β-catenin. Circulation 84 27803037
1998 Overexpression of an inhibitory insulin-like growth factor binding protein (IGFBP), IGFBP-4, delays onset of prostate tumor formation. Endocrinology 82 9681496
2006 Insulin-like growth factor-II (IGF-II), IGF-binding protein-3 (IGFBP-3), and IGFBP-4 in follicular fluid are associated with oocyte maturation and embryo development. Fertility and sterility 81 17070193
2001 Systemic administration of insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) increases bone formation parameters in mice by increasing IGF bioavailability via an IGFBP-4 protease-dependent mechanism. Endocrinology 81 11356715
2003 Paracrine overexpression of IGFBP-4 in osteoblasts of transgenic mice decreases bone turnover and causes global growth retardation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 77 12733722
1996 Recombinant synthesis of insulin-like growth factor-binding protein-4 (IGFBP-4): Development, validation, and application of a radioimmunoassay for IGFBP-4 in human serum and other biological fluids. The Journal of clinical endocrinology and metabolism 74 8636339
1997 Heparin-binding, highly basic regions within the thyroglobulin type-1 repeat of insulin-like growth factor (IGF)-binding proteins (IGFBPs) -3, -5, and -6 inhibit IGFBP-4 degradation. Endocrinology 73 9165012
1995 Proteolytic cleavage of insulin-like growth factor binding protein 4 (IGFBP-4). Localization of cleavage site to non-homologous region of native IGFBP-4. The Journal of biological chemistry 72 7538115
2000 Evidence that the interaction between insulin-like growth factor (IGF)-II and IGF binding protein (IGFBP)-4 is essential for the action of the IGF-II-dependent IGFBP-4 protease. Archives of biochemistry and biophysics 70 10898936
2004 Up date on IGFBP-4: regulation of IGFBP-4 levels and functions, in vitro and in vivo. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 69 15123166
1995 Age-related changes in IGFBP-4 and IGFBP-5 levels in human serum and bone: implications for bone loss with aging. Progress in growth factor research 60 8817691
1993 Differential expression of insulin-like growth factor binding proteins (IGFBP) 4 and 5 mRNA in the rat brain after transient hypoxic-ischemic injury. Brain research. Molecular brain research 60 7684482
2007 Insulin-like growth factor binding proteins IGFBP3, IGFBP4, and IGFBP5 predict endocrine responsiveness in patients with ovarian cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 59 17332286
1992 Studies on regulation of insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-4 production in human bone cells. Acta endocrinologica 56 1283479
1996 Insulin-like growth factor-binding proteins (IGFBP)-4, -5, and -6 in the benign and malignant human prostate: IGFBP-5 messenger ribonucleic acid localization differs from IGFBP-5 protein localization. The Journal of clinical endocrinology and metabolism 55 8855838
2011 IGFBP-4 activates the Wnt/beta-catenin signaling pathway and induces M-CAM expression in human renal cell carcinoma. International journal of cancer 54 21207373
1993 1,25-Dihydroxyvitamin D3 increases secretion of insulin-like growth factor binding protein-4 (IGFBP-4) by human osteoblast-like cells in vitro and elevates IGFBP-4 serum levels in vivo. The Journal of clinical endocrinology and metabolism 54 7521341
2018 IGFBP-4 and PAPP-A in normal physiology and disease. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 53 29864720
1995 Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) functions as an IGF-reversible inhibitor of IGFBP-4 proteolysis. The Journal of biological chemistry 53 7499205
1994 Signaling by insulin-like growth factors in paralyzed skeletal muscle: rapid induction of IGF1 expression in muscle fibers and prevention of interstitial cell proliferation by IGF-BP5 and IGF-BP4. The Journal of neuroscience : the official journal of the Society for Neuroscience 53 7514217
1994 The insulin-like growth factor-binding protein-4 (IGFBP-4)-IGFBP-4 protease system in normal human osteoblast-like cells: regulation by transforming growth factor-beta. The Journal of clinical endocrinology and metabolism 51 7527411
2002 Targeted expression of a protease-resistant IGFBP-4 mutant in smooth muscle of transgenic mice results in IGFBP-4 stabilization and smooth muscle hypotrophy. The Journal of biological chemistry 47 11923290
1998 Potent inhibition of human ovarian steroidogenesis by insulin-like growth factor binding protein-4 (IGFBP-4). The Journal of clinical endocrinology and metabolism 45 9435457
2017 IGFBP4 Is Required for Adipogenesis and Influences the Distribution of Adipose Depots. Endocrinology 43 28938423
1999 Studies on the role of human insulin-like growth factor-II (IGF-II)-dependent IGF binding protein (hIGFBP)-4 protease in human osteoblasts using protease-resistant IGFBP-4 analogs. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 43 10620067
1992 Insulin-like growth factor binding protein (IGFBP)4 accounts for the connective tissue distribution of endothelial cell IGFBPs perfused through the isolated heart. Endocrinology 43 1377125
2006 Insulin-like growth factor binding protein-4 (IGFBP-4) is a novel anti-angiogenic and anti-tumorigenic mediator secreted by dibutyryl cyclic AMP (dB-cAMP)-differentiated glioblastoma cells. Glia 40 16586492
2000 Serum insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 in children with chronic renal failure: relationship to growth and glomerular filtration rate. The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood. German Study Group for Growth Hormone Treatment in Chronic Renal Failure. Pediatric nephrology (Berlin, Germany) 40 10912524
1996 Insulin-like growth factors stimulate the release of insulin-like growth factor-binding protein-3 (IGFBP-3) and degradation of IGFBP-4 in nonsmall cell lung cancer cell lines. The Journal of clinical endocrinology and metabolism 40 8675593
2020 Increase of circulating IGFBP-4 following genotoxic stress and its implication for senescence. eLife 38 32223893
2000 Partial IGF affinity of circulating N- and C-terminal fragments of human insulin-like growth factor binding protein-4 (IGFBP-4) and the disulfide bonding pattern of the C-terminal IGFBP-4 domain. Biochemistry 37 10819974
2015 IGFBP-4 Fragments as Markers of Cardiovascular Mortality in Type 1 Diabetes Patients With and Without Nephropathy. The Journal of clinical endocrinology and metabolism 36 26046968
2012 N-terminal and C-terminal fragments of IGFBP-4 as novel biomarkers for short-term risk assessment of major adverse cardiac events in patients presenting with ischemia. Clinical biochemistry 36 22306170
2017 IGFBP-4 regulates adult skeletal growth in a sex-specific manner. The Journal of endocrinology 35 28184001
2001 Plasma levels of insulin-like growth factor binding protein-4 (IGFBP-4) under normal and pathological conditions. Clinical endocrinology 35 11380497
1999 Effects of chronic renal failure and growth hormone on serum levels of insulin-like growth factor-binding protein-4 (IGFBP-4) and IGFBP-5 in children: a report of the Southwest Pediatric Nephrology Study Group. The Journal of clinical endocrinology and metabolism 35 10022422
2011 GATA-4 promotes myocardial transdifferentiation of mesenchymal stromal cells via up-regulating IGFBP-4. Cytotherapy 33 21846294
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
2006 Comparison of follicular fluid IGF-I, IGF-II, IGFBP-3, IGFBP-4 and PAPP-A concentrations and their ratios between GnRH agonist and GnRH antagonist protocols for controlled ovarian stimulation in IVF-embryo transfer patients. Human reproduction (Oxford, England) 32 16601008
2013 IGFBP-4 anti-angiogenic and anti-tumorigenic effects are associated with anti-cathepsin B activity. Neoplasia (New York, N.Y.) 31 23633927
2013 SOX9 directly regulates IGFBP-4 in the intestinal epithelium. American journal of physiology. Gastrointestinal and liver physiology 29 23660500
2005 Sepsis and inflammatory insults downregulate IGFBP-5, but not IGFBP-4, in skeletal muscle via a TNF-dependent mechanism. American journal of physiology. Regulatory, integrative and comparative physiology 29 16339387
2016 PAPP-A, IGFBP-4 and IGF-II are secreted by human adipose tissue cultures in a depot-specific manner. European journal of endocrinology 28 27585595
2014 PAPP-A and IGFBP-4 fragment levels in patients with ST-elevation myocardial infarction treated with heparin and PCI. Clinical biochemistry 28 25489725
2012 Significance of IGFBP-4 in the development of fetal growth restriction. The Journal of clinical endocrinology and metabolism 28 22689691
2005 Effects of hormone replacement therapy on insulin-like growth factor (IGF)-I, IGF-II and IGF binding protein (IGFBP)-1 to IGFBP-4: implications for cardiovascular risk. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 28 16019358
2001 Inhibition of growth and increased expression of insulin-like growth factor-binding protein-3 (IGFBP-3) and -6 in prostate cancer cells stably transfected with antisense IGFBP-4 complementary deoxyribonucleic acid. Endocrinology 28 11316765
1998 Elevated insulin-like growth factor (IGF) binding protein (IGFBP)-2 and IGFBP-4 expression of leukemic T-cells is affected by autocrine/paracrine IGF-II action but not by IGF type I receptor expression. European journal of endocrinology 27 9539310
2014 Inhibition of tumor-associated αvβ3 integrin regulates the angiogenic switch by enhancing expression of IGFBP-4 leading to reduced melanoma growth and angiogenesis in vivo. Angiogenesis 26 25249331
1994 Isolation and characterization of ovine IGFBP-4: protein purification and cDNA sequence. Journal of molecular endocrinology 26 7531449
1997 Serum insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 levels in aging and age-associated diseases. Endocrine 25 9449039
2014 IGFBP-4 and -5 are expressed in first-trimester villi and differentially regulate the migration of HTR-8/SVneo cells. Reproductive biology and endocrinology : RB&E 24 25475528
2012 IGFBP-4 tumor and serum levels are increased across all stages of epithelial ovarian cancer. Journal of ovarian research 24 22264331
1996 The role of IGFBP-3 in the regulation of IGFBP-4 proteolysis. The Journal of endocrinology 24 8691093
1995 Characterization of insulin-like growth factor binding proteins (IGFBP) and regulation of IGFBP-4 in bone marrow stromal cells. British journal of haematology 24 7540852
2019 Glia-Like Cells from Late-Passage Human MSCs Protect Against Ischemic Stroke Through IGFBP-4. Molecular neurobiology 23 31081524
1997 Surface-bound plasmin induces selective proteolysis of insulin-like-growth-factor (IGF)-binding protein-4 (IGFBP-4) and promotes autocrine IGF-II bio-availability in human colon-carcinoma cells. International journal of cancer 22 9311602
1995 Insulin-like growth factor-I (IGF-I) regulates IGFBP-3 and IGFBP-4 by multiple mechanisms in A549 human adenocarcinoma cells. American journal of respiratory cell and molecular biology 22 7546777
1993 Expression of insulin-like growth factor binding protein-4 (IGFBP-4) by rat neural cells--comparison to other IGFBPs. Regulatory peptides 22 7505459
1993 Molecular cloning of IGFBP-5 from SCLC cell lines and expression of IGFBP-4, IGFBP-5 and IGFBP-6 in lung cancer cell lines and primary tumours. European journal of cancer (Oxford, England : 1990) 22 7692907
2010 Circulating insulin-like growth factor binding protein-4 (IGFBP-4) is not regulated by parathyroid hormone and vitamin D in vivo: evidence from children with rickets. Journal of clinical research in pediatric endocrinology 21 21274331
2013 Human annulus cells regulate PAPP-A and IGFBP-4 expression, and thereby insulin-like growth factor bioavailability, in response to proinflammatory cytokine exposure in vitro. Connective tissue research 18 24060054
2022 m6A mRNA methylation regulates the ERK/NF-κB/AKT signaling pathway through the PAPPA/IGFBP4 axis to promote proliferation and tumor formation in endometrial cancer. Cell biology and toxicology 17 35971034
2021 IGFBP-4: A promising biomarker for lung cancer. Journal of medical biochemistry 17 34177367
2015 Characterization of endogenously circulating IGFBP-4 fragments-Novel biomarkers for cardiac risk assessment. Clinical biochemistry 17 26025773
1998 Structure and transcription regulation of the human insulin-like growth factor binding protein 4 gene (IGFBP4). Genomics 17 9615225
2019 The IGF system in patients with inflammatory bowel disease treated with prednisolone or infliximab: potential role of the stanniocalcin-2 / PAPP-A / IGFBP-4 axis. BMC gastroenterology 16 31159802
2001 Distribution of chimeric IGF binding protein (IGFBP)-3 and IGFBP-4 in the rat heart: importance of C-terminal basic region. Endocrinology 16 11517150
1997 MK-801 inhibits the cortical increase in IGF-1, IGFBP-2 and IGFBP-4 expression following trauma. Neuroreport 16 9080428
2013 Rescue of silenced UCHL1 and IGFBP4 expression suppresses clonogenicity of giant cell tumor-derived stromal cells. Cancer letters 15 23603559
2021 Metabolic improvement after gastric bypass correlates with changes in IGF-regulatory proteins stanniocalcin-2 and IGFBP-4. Metabolism: clinical and experimental 14 34506805
2020 LncRNA IGFBP4-1 promotes tumor development by activating Janus kinase-signal transducer and activator of transcription pathway in bladder urothelial carcinoma. International journal of biological sciences 14 32760196
2017 Physiological parameters regulating circulating levels of the IGFBP-4/Stanniocalcin-2/PAPP-A axis. Metabolism: clinical and experimental 14 28964325
2015 Serum IGFBP4 concentration decreased in dairy heifers towards day 18 of pregnancy. Journal of veterinary science 14 26243597
2000 Regulation of IGFBP-4 levels in human intestinal muscle by an IGF-I-activated, confluence-dependent protease. American journal of physiology. Gastrointestinal and liver physiology 13 11052994
2020 Significant polyomic and functional upregulation of the PAPP-A/IGFBP-4/5/IGF-1 axis in chronic rhinosinusitis with nasal polyps. International forum of allergy & rhinology 12 31930684
2020 IGFBP-4 enhances VEGF-induced angiogenesis in a mouse model of myocardial infarction. Journal of cellular and molecular medicine 12 32597006
2015 Comparative RNA-seq analysis of the Tritrichomonas foetus PIG30/1 isolate from pigs reveals close association with Tritrichomonas foetus BP-4 isolate 'bovine genotype'. Veterinary parasitology 12 26315127
2004 Expression of insulin-like growth factor I (IGF-I) gene and of genes for IGF-binding proteins 1, 2, 3, 4 (IGFBP-1-IGFBP-4) in non-neoplastic human thyroid cells and in certain human thyroid cancers. Effect of exogenous IGF-I on this expression. Endocrine research 12 15098919
2023 Increased Levels of Circulating IGFBP4 and ANGPTL8 with a Prospective Role in Diabetic Nephropathy. International journal of molecular sciences 11 37762544
2018 Increased Concentrations of Insulin-Like Growth Factor Binding Protein (IGFBP)-2, IGFBP-3, and IGFBP-4 Are Associated With Fetal Mortality in Pregnant Cows. Frontiers in endocrinology 11 29946296
2001 Truncation of WT1 results in downregulation of cyclin G1 and IGFBP-4 expression. Biochemical and biophysical research communications 11 11573961
2022 Cytotoxicity of BP-3 and BP-4: Blockage of extrusion pumps, oxidative damage and programmed cell death on Chlamydomonas reinhardtii. Aquatic toxicology (Amsterdam, Netherlands) 10 36087491
2020 Effect of Anthocyanins Supplementation on Serum IGFBP-4 Fragments and Glycemic Control in Patients with Fasting Hyperglycemia: A Randomized Controlled Trial. Diabetes, metabolic syndrome and obesity : targets and therapy 10 33061500
1997 Transforming growth factor-alpha stimulates insulin-like growth factor binding protein-4 (IGFBP-4) expression and blocks follicle-stimulating hormone regulation of IGFBP-4 production in rat granulosa cells. Molecular and cellular endocrinology 10 9359468
2023 The RNA binding protein MEX3A promotes tumor progression of breast cancer by post-transcriptional regulation of IGFBP4. Breast cancer research and treatment 9 37433992
2007 Insulin-like growth factor binding protein (IGFBP)-mediated hair cell survival on the mouse utricle exposed to neomycin: the roles of IGFBP-4 and IGFBP-5. Acta oto-laryngologica. Supplementum 9 17882566
2004 IGFBP-4 degradation by pregnancy-associated plasma protein-A in MC3T3 osteoblasts. Biochemical and biophysical research communications 9 15541345