Affinage

IGFBP4

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

Audit flag: ungrounded claim
Length
258 aa
Mass
27.9 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 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

IGFBP-4 is a secreted insulin-like growth factor binding protein that functions principally as an inhibitor of IGF signaling, sequestering IGF-I and IGF-II in the extracellular space and preventing their binding to the type I IGF receptor (PMID:7544787). This sequestration underlies its in vivo role as an antagonist of IGF-driven tissue growth: transgenic overexpression in smooth muscle causes organ hypoplasia (PMID:9564877), and paracrine overexpression in osteoblasts suppresses bone formation and produces postnatal growth retardation (PMID:12733722). The inhibitory activity is terminated by IGF-dependent proteolysis: cleavage in the non-homologous midregion (Lys120-Met121 / Met135-Lys136) generates an N-terminal fragment that no longer inhibits IGF action (PMID:7538115, PMID:10620067), and IGF promotes this cleavage by binding to IGFBP-4 itself — not to the protease — converting it into a better substrate (PMID:10898936, PMID:11522292). PAPP-A is the predominant IGF-dependent IGFBP-4 protease across pregnancy serum, osteoblasts, trophoblasts, and decidual stroma (PMID:11158056, PMID:15341545, PMID:11994388), and protease-resistant IGFBP-4 mutants are correspondingly more potent and longer-acting IGF inhibitors in vivo (PMID:11923290), whereas wild-type IGFBP-4 proteolysis releases IGF and raises IGF bioavailability (PMID:11356715). Independent of IGF binding, IGFBP-4 inhibits canonical Wnt/β-catenin signaling by physically interacting with the Wnt co-receptors Frizzled-8 and LRP6 and blocking Wnt3A binding, an activity required for cardiomyocyte differentiation and cardioprotection that, unlike Dkk1, does not deplete LRP5/6 (PMID:18528331, PMID:27803037). A C-terminal thyroglobulin type-1 fragment carries additional IGF-independent anti-angiogenic and anti-tumorigenic activity linked to cathepsin B inhibition (PMID:23633927). IGFBP-4 is also required for adipogenesis (PMID:28938423) and contributes to skeletal homeostasis with sex-specific effects (PMID:28184001). Its expression is controlled transcriptionally by SOX9, GATA-4, cAMP and 1,25(OH)2D3 (PMID:23660500, PMID:21846294, PMID:9615225, PMID:7521341), and post-transcriptionally by MEX3A-mediated mRNA decay and METTL3/YTHDF1-dependent m6A regulation of translation (PMID:37433992, PMID:35971034).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1995 High

    Established the core molecular mechanism of IGFBP-4 as an IGF antagonist, answering how it blocks growth-factor action.

    Evidence Radioligand binding to purified type I IGF receptor and competition with reduced-affinity IGF analogs in bone cells

    PMID:7544787

    Open questions at the time
    • Does not address proteolytic turnover
    • No structure of the IGF-IGFBP-4 complex
  2. 1995 High

    Identified the midregion proteolytic cleavage site and showed cleavage abolishes inhibitory activity, explaining how IGFBP-4 inhibition is switched off.

    Evidence Mass spectrometry, N-terminal sequencing, K120A mutagenesis and thymidine incorporation bioassay

    PMID:7538115

    Open questions at the time
    • Protease identity not yet determined
    • IGF dependence of cleavage not yet dissected
  3. 2000 High

    Defined the precise IGF-dependent cleavage site (Met135-Lys136) and showed a distal conformational region (94-119) is required for protease susceptibility.

    Evidence MS/sequencing of His-tagged IGFBP-4 fragments, deletion mutants and osteoblast proliferation assays

    PMID:10620067

    Open questions at the time
    • Enzyme not identified in this study
    • Conformational basis of region 94-119 requirement unresolved
  4. 2000 High

    Characterized circulating IGFBP-4 fragments, showing the N-terminal fragment retains IGF binding while the C-terminal fragment does not, refining the functional consequence of cleavage.

    Evidence Purification from human hemofiltrate, mass spectrometry, surface plasmon resonance, disulfide mapping

    PMID:10819974

    Open questions at the time
    • Physiological role of retained N-terminal IGF binding unclear
    • Does not address Wnt or anti-angiogenic functions
  5. 2001 High

    Resolved the directionality of IGF-enhanced proteolysis by showing IGF binds IGFBP-4 (not the protease) to render it a better substrate.

    Evidence Cell-free PAPP-A protease assays with pre-incubation/removal and IGF-binding-deficient deletion mutants

    PMID:10898936 PMID:11522292

    Open questions at the time
    • Slow IGF-independent cleavage rate not mechanistically explained
    • Substrate conformational change not directly visualized
  6. 2002 High

    Identified PAPP-A as the predominant physiological IGFBP-4 protease across multiple tissues, unifying the proteolytic mechanism.

    Evidence Immunodepletion/immunoinhibition and neutralizing antibodies in pregnancy serum, osteoblasts, trophoblasts and decidual stroma; protease-resistant mutant rescue

    PMID:11158056 PMID:11994388 PMID:15341545

    Open questions at the time
    • Other proteases (plasmin, kallikrein) contribute in specific contexts
    • Regulation of PAPP-A activity by proMBP only partly addressed
  7. 2002 High

    Demonstrated in vivo that proteolysis tunes IGFBP-4 activity, by showing protease-resistant IGFBP-4 is stabilized and more inhibitory while wild-type proteolysis releases IGF.

    Evidence Transgenic mice expressing native vs. protease-resistant IGFBP-4 in smooth muscle; systemic administration with free IGF-I measurement

    PMID:11356715 PMID:11923290

    Open questions at the time
    • Tissue-specific protease availability not mapped
    • Does not address IGF-independent functions
  8. 2008 High

    Uncovered an IGF-independent function of IGFBP-4 as a Wnt/β-catenin inhibitor essential for cardiomyocyte differentiation, expanding its mechanistic repertoire.

    Evidence Reciprocal Co-IP with Frizzled-8 and LRP6, Wnt3A competitive binding, in vitro/in vivo Igfbp4 knockdown

    PMID:18528331

    Open questions at the time
    • Structural basis of receptor interaction unknown
    • Relationship between Wnt-inhibitory and IGF-sequestering surfaces unresolved
  9. 2016 High

    Distinguished IGFBP-4 mechanistically from Dkk1 by showing it inhibits β-catenin without inducing LRP5/6 degradation, defining a distinct Wnt-inhibition mode with cardioprotective consequences.

    Evidence Cardiomyocyte-specific LRP5/6 and β-catenin knockout mice, recombinant protein injection in MI model, β-catenin Western blot

    PMID:27803037

    Open questions at the time
    • Molecular reason for differential LRP turnover unclear
    • Therapeutic window not defined
  10. 2013 Medium

    Mapped the IGF-independent anti-angiogenic activity to the C-terminal thyroglobulin type-1 fragment acting via cathepsin B inhibition.

    Evidence In vitro cathepsin B assay, lysosomal co-localization, endothelial tubulogenesis, glioblastoma xenograft

    PMID:23633927

    Open questions at the time
    • Limited mutagenesis confirmation of the cathepsin B mechanism
    • Single lab; in vivo target engagement not directly shown
  11. 2017 High

    Established IGFBP-4 as required for adipogenesis and as a sex-specific regulator of skeletal homeostasis through genetic loss-of-function.

    Evidence Igfbp4 knockout mice with primary cell differentiation assays, p-Akt analysis, μCT and histomorphometry

    PMID:28184001 PMID:28938423

    Open questions at the time
    • Mechanistic basis of sex-specific bone effects unresolved
    • Relative contribution of IGF vs. Wnt functions in fat/bone not separated
  12. 2022 Medium

    Defined transcriptional and post-transcriptional regulators of IGFBP-4, connecting its expression level to IGF-pathway output in normal and cancer contexts.

    Evidence SOX9 ChIP/rescue, GATA-4 epistasis, cAMP and 1,25(OH)2D3 promoter/expression studies, MEX3A RIP, METTL3/YTHDF1 MeRIP and polysome profiling

    PMID:21846294 PMID:23660500 PMID:35971034 PMID:37433992 PMID:7521341 PMID:9615225

    Open questions at the time
    • WT1 regulation rests on a single array screen without promoter confirmation
    • Integration of multiple regulatory inputs in a single tissue not modeled
  13. 2020 Medium

    Implicated IGFBP-4 as a pro-aging SASP factor, linking its secretion to systemic senescence.

    Evidence Mouse irradiation gain/loss model and systemic IGFBP-4 injection with senescent cell quantification, plus human data

    PMID:32223893

    Open questions at the time
    • Receptor/pathway mediating pro-senescence effect not identified
    • Whether effect is IGF- or Wnt-dependent unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct IGF-sequestering, PAPP-A-substrate, and Wnt co-receptor-binding surfaces of a single IGFBP-4 molecule are structurally and contextually coordinated remains unresolved.
  • No structure of IGFBP-4 bound to Frizzled-8/LRP6
  • Determinants selecting IGF-dependent vs. IGF-independent activity in a given tissue unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0140313 molecular sequestering activity 2 GO:0008289 lipid binding 1
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 2
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2
Partners
FZD8IGF1IGF2LRP6PAPPA

Evidence

Reading pass · 33 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; IGFBP-4 decreased binding of both 125I-IGF-I and 125I-IGF-II to bone cells and decreased binding of IGF-I tracer to purified type I IGF receptor. IGF analogs with >100-fold reduced affinity for IGFBP-4 were not inhibited, confirming the mechanism requires ligand sequestration. Radioligand binding assay with purified type I IGF receptor; cell proliferation assays with IGF analogs having reduced IGFBP-4 affinity The Journal of biological chemistry High 7544787
1995 Proteolytic cleavage of IGFBP-4 occurs between residues Lys-120 and Met-121 (the non-homologous midregion); the resulting ~16 kDa N-terminal fragment no longer inhibits IGF-1-stimulated thymidine uptake. Mutagenesis of Lys-120 to Ala (K120A) produced a protease-resistant IGFBP-4, confirming this as the cleavage site. Electrospray mass spectrometry, N-terminal amino acid sequencing, site-directed mutagenesis (K120A), thymidine incorporation bioassay The Journal of biological chemistry High 7538115
2001 IGF-II enhances IGFBP-4 proteolysis by PAPP-A by binding to IGFBP-4 (not to PAPP-A); pre-incubation of IGFBP-4 with IGF-II followed by removal of free IGF-II was sufficient for proteolysis, whereas pre-incubation of PAPP-A with IGF-II was not. IGFBP-4 mutants lacking IGF-binding activity (deletions of Leu72-His74 or Cys183-Glu237) were resistant to cleavage even in the presence of IGF-II. Cell-free protease assay with purified PAPP-A; pre-incubation/removal experiments; IGFBP-4 deletion mutants lacking IGF-binding activity Archives of biochemistry and biophysics High 10898936
2001 PAPP-A is the predominant IGFBP-4 protease in human pregnancy serum; immunoprecipitation of PAPP-A completely abolished both IGF-II-dependent and IGF-II-independent IGFBP-4 proteolytic activity in pregnancy serum. PAPP-A also enhances IGF bioactivity in vitro by degrading IGFBP-4, as shown using protease-resistant IGFBP-4. 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
2001 PAPP-A cleaves IGFBP-5 independent of IGF, but cleavage of IGFBP-4 by PAPP-A can also occur in the absence of IGF at a very slow rate; IGF binds to IGFBP-4 to make it a better substrate for PAPP-A rather than binding directly to PAPP-A. In vitro cleavage assay using highly purified recombinant proteins; rate comparisons with and without IGF; IGF binding competition with PAPP-A FEBS letters High 11522292
1999 The IGF-II-dependent IGFBP-4 protease in human osteoblasts cleaves IGFBP-4 at Met135-Lys136 as the sole cleavage site; residues 94-119 (containing no cleavage site) are required for protease susceptibility, suggesting they maintain the IGFBP-4 conformation needed to expose the cleavage site. Protease-resistant IGFBP-4 analogs were more potent inhibitors of IGF-II-induced cell proliferation in protease-producing osteoblasts than wild-type. N-terminal amino acid sequencing and mass spectrometry of proteolytic fragments of His-tagged IGFBP-4; deletion mutants; cell proliferation assay comparing wild-type vs. protease-resistant analogs Journal of bone and mineral research High 10620067
2008 IGFBP-4 functions as a Wnt signaling inhibitor independent of IGF binding: IGFBP-4 physically interacts with Frizzled 8 (Frz8) and LRP6, blocking Wnt3A binding to these receptors and inhibiting canonical Wnt/β-catenin signaling. This cardiogenic activity was IGF-independent but was attenuated by IGFs through IGFBP-4 sequestration. Co-immunoprecipitation (IGFBP-4 with Frz8 and LRP6); competitive binding assay (Wnt3A displacement); in vitro cardiomyocyte differentiation; Igfbp4 knockdown in vitro and in vivo Nature High 18528331
2016 IGFBP-4 protects the ischemic heart by inhibiting β-catenin signaling, without inducing LRP5/6 endocytosis/degradation (unlike Dkk1). Direct intracardiac injection of recombinant IGFBP-4 post-MI inhibited β-catenin while preserving LRP5/6 protein levels, defining a mechanistic distinction between IGFBP-4 and Dkk1 as Wnt inhibitors. Conditional cardiomyocyte-specific LRP5/6 and β-catenin knockout mice; direct intracardiac injection of recombinant IGFBP-4 and Dkk1; surgical MI model; Western blot for β-catenin Circulation High 27803037
2002 A protease-resistant IGFBP-4 mutant (IGFBP-4.7A, with 7 basic residues in the cleavage domain substituted to alanines) is stabilized in vivo in smooth muscle tissue of transgenic mice and produces greater smooth muscle hypotrophy than equivalent expression of native IGFBP-4, demonstrating that proteolytic processing of IGFBP-4 reduces its inhibitory activity in vivo. Targeted expression of protease-resistant vs. native IGFBP-4 in transgenic mice (smooth muscle alpha-actin promoter); tissue weight measurements; Western blot quantification of protein levels The Journal of biological chemistry High 11923290
2001 Systemic administration of wild-type IGFBP-4 (but not protease-resistant IGFBP-4) increases bone formation parameters and free IGF-I in serum, indicating that proteolytic degradation of systemically administered IGFBP-4 releases IGF and increases IGF bioavailability in vivo. In vivo biochemical markers (osteocalcin, ALP) in mice; free IGF-I measurement; comparison of wild-type vs. protease-resistant IGFBP-4; IGF-I-deficient mouse model Endocrinology High 11356715
1998 Overexpression of IGFBP-4 in smooth muscle cells of transgenic mice (via smooth muscle alpha-actin promoter) causes smooth muscle hypoplasia in bladder, aorta, intestine, uterus, and stomach, demonstrating IGFBP-4 functions as a functional in vivo antagonist of IGF-I action on smooth muscle cell growth. Transgenic mouse overexpression (SMC-specific); organ weight measurements; in situ hybridization for transgene localization; Western ligand blot for IGFBP-4 protein levels Endocrinology High 9564877
2003 Paracrine overexpression of IGFBP-4 in osteoblasts (via osteocalcin promoter transgene) causes a 25-fold increase in bone IGFBP-4, reduces IGFBP-5, decreases osteoblast number and bone formation rate by ~50%, and induces global postnatal growth retardation with disproportionate reduction in bone size, attributed to sequestration of IGF-1. Transgenic mouse overexpression (osteocalcin promoter); histomorphometry; Western ligand blot; organ allometry Journal of bone and mineral research High 12733722
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; mutation of basic residues near the PAPP-A cleavage site in IGFBP-4 inhibited degradation; PAPP-A mRNA is expressed throughout osteoblast differentiation. Immunodepletion of PAPP-A from conditioned medium; IGFBP-4 mutants with basic residue substitutions near cleavage site; RT-PCR for PAPP-A mRNA Biochemical and biophysical research communications High 15341545
1997 IGFBP-3, -5, and -6 inhibit IGFBP-4 proteolysis through highly basic, heparin-binding C-terminal domains (thyroglobulin type-1 motifs); synthetic peptides from these regions inhibit IGFBP-4 degradation with different potencies; IGFs reverse the inhibitory effect of these IGFBPs; heparin also reverses inhibition, suggesting the basic domain competitively sequesters the protease. In vitro protease assay with 125I-IGFBP-4 substrate in MC3T3-E1 conditioned medium; synthetic peptides; heparin competition assay Endocrinology High 9165012
1995 IGFBP-3 functions as an IGF-reversible inhibitor of IGFBP-4-degrading proteinase activity in MC3T3-E1 osteoblast conditioned medium; the inhibitory activity resides in mid-region and C-terminal basic/heparin-binding peptides of IGFBP-3, not the N-terminal IGF-binding domain; heparin partially reverses inhibition. In vitro protease assay with 125I-rhIGFBP-4; recombinant IGFBP-3 fragments; synthetic IGFBP-3 peptides; heparin competition The Journal of biological chemistry High 7499205
1994 TGF-β augments IGF-II-dependent IGFBP-4 proteolysis in human osteoblast-like cells and independently decreases IGFBP-4 mRNA expression; other bone-relevant hormones (PTH, GH, insulin, calcitonin, glucocorticoids, sex steroids, 1,25(OH)2D3, EGF) had no significant effect on IGFBP-4 protease activity. Cell-free IGFBP-4 protease assay using conditioned medium from treated hOB cells; Western ligand blot; Northern blot for IGFBP-4 mRNA The Journal of clinical endocrinology and metabolism High 7527411
2000 The IGF-dependent IGFBP-4 protease from human fibroblasts also cleaves recombinant rat IGFBP-4 at a KMKV site (carboxyl side of Met-131); this site is not present in other IGFBPs, explaining substrate specificity. Kallikrein can also cleave at this site but non-specifically. In vitro cleavage assay; mass spectrometric characterization of cleavage site; kallikrein comparison Growth hormone & IGF research Medium 11161967
1992 IGFBP-4 (both glycosylated and non-glycosylated forms) crosses the capillary boundary of the isolated perfused rat heart and distributes preferentially in subendothelial connective tissue (connective tissue/cardiac muscle ratio ~20-27:1), whereas IGFBP-1, -2, -3 and IGF-I preferentially localize in cardiac muscle. The connective tissue distribution of endothelial cell IGFBPs is accounted for specifically by IGFBP-4. Perfusion of isolated beating rat hearts with purified glycosylated and non-glycosylated IGFBP-4; autoradiographic distribution analysis; comparison with other IGFBPs Endocrinology Medium 1377125
2001 The C-terminal basic domain of IGFBP-3 (20-amino-acid stretch) determines cardiac tissue distribution; chimeric IGFBP-3(4) (IGFBP-3 with IGFBP-4's C-terminal region) localizes in connective tissue like IGFBP-4, while IGFBP-4(3) (IGFBP-4 with IGFBP-3's C-terminal region) localizes in cardiac muscle like IGFBP-3. IGFBP-4(3) also binds microvascular endothelial cells with higher affinity than IGFBP-3. Chimeric IGFBP construction; perfused rat heart distribution studies; 125I-IGFBP binding to microvascular endothelial cells Endocrinology High 11517150
2000 Circulating N-terminal (Asp1-Phe122, Mr 13,233 Da) and C-terminal (Lys136-Glu237, Mr 11,344 Da) fragments of IGFBP-4 are present in human plasma; the N-terminal fragment retains significant IGF binding (IGF-II Kd ~17 nM, IGF-I Kd ~5 nM), whereas the C-terminal fragment has very low IGF affinity (IGF-II Kd ~690 nM, IGF-I Kd >60 nM). Disulfide bonding pattern of C-terminal fragment: Cys153-183, Cys194-205, Cys207-228. Purification from human hemofiltrate by chromatography; mass spectrometry and N-terminal sequencing; plasmon resonance spectroscopy; ligand blot; saturation/displacement binding studies; proteolytic digestion for disulfide mapping Biochemistry High 10819974
1997 Surface-bound plasmin (generated by u-PA/plasminogen at the HT29-D4 cell surface) selectively cleaves IGFBP-4 (>95%) without affecting IGFBP-2 or IGFBP-6 (though soluble plasmin cleaves all three), yielding 18- and 14-kDa fragments with poor IGF-II affinity, thereby releasing ~20% of cell surface-associated IGF-II for binding to IGF-I receptors. Cell-surface plasmin generation assay; Western ligand blot; 125I-IGF-II receptor binding after IGFBP-4 proteolysis; comparison of cell-bound vs. soluble plasmin International journal of cancer Medium 9311602
1993 1,25-dihydroxyvitamin D3 increases IGFBP-4 mRNA up to 11-fold and protein secretion 2-3 fold in human osteoblast-like cells in vitro; consistent in vivo elevation of serum IGFBP-4 was observed in human subjects treated with high-dose oral 1,25(OH)2D3. Northern blot; Western ligand blot; human subject treatment with oral 1,25(OH)2D3 for psoriasis The Journal of clinical endocrinology and metabolism Medium 7521341
2013 SOX9 directly regulates IGFBP-4 transcription in intestinal epithelial cells; SOX9 binds the IGFBP-4 promoter as shown by ChIP; overexpression of SOX9 reduces cell proliferation which is restored by IGFBP-4 neutralizing antibody, placing IGFBP-4 downstream of SOX9 in a proliferation-suppressing pathway. Chromatin immunoprecipitation (ChIP) of SOX9 at IGFBP-4 promoter; reporter assay; SOX9 overexpression with IGFBP-4 neutralizing antibody rescue; Sox9-deficient mouse intestinal epithelial cells American journal of physiology. Gastrointestinal and liver physiology High 23660500
2013 The anti-angiogenic and anti-tumorigenic activities of IGFBP-4 reside in the C-terminal fragment (CIBP-4) containing a thyroglobulin type-1 domain; CIBP-4 inhibits cathepsin B (CatB) activity, internalizes into lysosomal-like structures in endothelial and tumor cells, inhibits EC tubulogenesis and IGF-independent angiogenesis, and reduces glioblastoma tumor growth by 60% in a xenograft model. In vitro CatB activity assay; intracellular co-localization (lysosomal markers); EC tubulogenesis in Matrigel; biodistribution with Cy5.5-labeled CIBP-4; glioblastoma xenograft model Neoplasia Medium 23633927
2017 IGFBP-4 is required for adipogenesis; Igfbp4-null mice have reduced inguinal and gonadal white adipose tissue weights and Pparγ expression; primary bone marrow stromal cells and ear mesenchymal stem cells from Igfbp4-/- mice show reduced adipogenesis in culture; Igfbp4 is strongly induced during adipogenesis; phospho-Akt (downstream of IGF-I) increase is blunted in mutant eMSCs. Igfbp4 knockout mouse; primary cell culture adipogenesis assay; Western blot for p-Akt; adipose tissue weight and gene expression Endocrinology High 28938423
2017 Igfbp4 null mice show sex-specific skeletal phenotypes: females have reduced bone mineral density, trabecular bone volume and thickness, lower bone formation, and increased osteoclastogenesis; males have more trabeculae with higher connectivity, lower mineralized surface, decreased osteoclastogenesis and reduced circulating sclerostin. Bone marrow stromal cultures show increased osteogenesis in both sexes. Igfbp4 knockout mouse; μCT; bone histomorphometry; osteoclastogenesis and osteogenesis in primary BMSCs; sclerostin ELISA The Journal of endocrinology High 28184001
2011 GATA-4 overexpression in mesenchymal stromal cells upregulates IGFBP-4 expression, and IGFBP-4 knockdown reduces the GATA-4-induced myocardial transdifferentiation, placing IGFBP-4 downstream of GATA-4 in cardiac lineage specification of MSCs. Retroviral GATA-4 overexpression in MSCs; IGFBP-4 knockdown (siRNA); immunostaining for cardiac markers; electrophysiologic recording; flow cytometry for transdifferentiation rate Cytotherapy Medium 21846294
1998 The IGFBP4 gene core promoter activity is located downstream of position -289; cAMP stimulation produces a ~2-fold increase in promoter activity through elements residing between positions -869 and -6. The transcription initiation site is 28 bp downstream of a TATA box, 286 bp upstream of the translation start codon. Deletion mutagenesis of IGFBP4 promoter with reporter assay; dibutyryl-cAMP stimulation; 5'-RACE for transcription start site Genomics Medium 9615225
2022 m6A methylation (via METTL3/YTHDF1) directly modulates IGFBP4 mRNA translation; reduced m6A methylation in endometrial cancer decreases YTHDF1-mediated IGFBP4 translation, leading to reduced IGFBP-4 protein, which activates IGF1-induced ERK, AKT, and NF-κB pathways. Overexpression of IGFBP4 partially rescued disease progression caused by reduced m6A methylation. MeRIP-qPCR; m6A-seq; polysome profiling; Western blot; overexpression/knockdown rescue experiments; in vivo tumor formation Cell biology and toxicology Medium 35971034
2023 The RNA-binding protein MEX3A binds IGFBP4 mRNA and decreases IGFBP4 mRNA levels, thereby activating PI3K/AKT and downstream cell cycle/migration pathways in breast cancer cells. MEX3A knockdown increases IGFBP4 expression and reduces tumor growth in vivo. RNA pulldown and RNA immunoprecipitation (RIP) confirming MEX3A-IGFBP4 mRNA interaction; Western blot; CCK-8/EdU/colony formation; xenograft mouse model Breast cancer research and treatment Medium 37433992
2002 PAPP-A is the IGFBP-4 protease in human trophoblasts and decidualized endometrial stromal cells; specific immunoinhibition and immunodepletion of PAPP-A completely abolished IGFBP-4 proteolytic activity in conditioned media; activity was IGF-II-dependent; proMBP functions as a physiological inhibitor of PAPP-A in this tissue. Immunoinhibition and immunodepletion of PAPP-A from trophoblast and decidual conditioned media; 125I-IGFBP-4 substrate assay; PAPP-A and proMBP ELISA The Journal of clinical endocrinology and metabolism High 11994388
2001 WT1 (Wilms tumor gene) acts as a transcriptional regulator of IGFBP4; truncation of WT1 that disrupts the DNA-binding zinc finger region results in downregulation of IGFBP4 expression, identified by cDNA macroarray analysis of gene-targeted cells. Gene targeting to generate WT1 truncation; cDNA macroarray gene expression analysis Biochemical and biophysical research communications Low 11573961
2020 IGFBP-4 is a component of the senescence-associated secretory phenotype (SASP); genotoxic injury (irradiation) promotes IGFBP-4 release in bloodstream in mice and humans; systemic injection of IGFBP-4 in mice increases senescent cells in lungs, heart, and kidneys, demonstrating IGFBP-4 as a pro-aging paracrine mediator. Mouse irradiation model (100 mGy X-ray) and human CT scan; IGFBP-4 intraperitoneal injection in mice for 2 months; quantification of senescent cells in organs eLife Medium 32223893

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 255 11522292
2008 IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis. Nature 198 18528331
2017 Overexpression of lncRNA IGFBP4-1 reprograms energy metabolism to promote lung cancer progression. Molecular cancer 119 28946875
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
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
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 92 8772582
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
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
2016 Opposing Roles of Wnt Inhibitors IGFBP-4 and Dkk1 in Cardiac Ischemia by Differential Targeting of LRP5/6 and β-catenin. Circulation 87 27803037
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
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 79 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
2011 IGFBP-4 activates the Wnt/beta-catenin signaling pathway and induces M-CAM expression in human renal cell carcinoma. International journal of cancer 55 21207373
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
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 55 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 54 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 52 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
2020 Increase of circulating IGFBP-4 following genotoxic stress and its implication for senescence. eLife 40 32223893
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
2017 IGFBP-4 regulates adult skeletal growth in a sex-specific manner. The Journal of endocrinology 37 28184001
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 37 22306170
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
2001 Plasma levels of insulin-like growth factor binding protein-4 (IGFBP-4) under normal and pathological conditions. Clinical endocrinology 36 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
2016 PAPP-A, IGFBP-4 and IGF-II are secreted by human adipose tissue cultures in a depot-specific manner. European journal of endocrinology 29 27585595
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
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
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 18 35971034
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
1998 Structure and transcription regulation of the human insulin-like growth factor binding protein 4 gene (IGFBP4). Genomics 18 9615225
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
2021 Metabolic improvement after gastric bypass correlates with changes in IGF-regulatory proteins stanniocalcin-2 and IGFBP-4. Metabolism: clinical and experimental 16 34506805
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
2015 Serum IGFBP4 concentration decreased in dairy heifers towards day 18 of pregnancy. Journal of veterinary science 15 26243597
2013 Rescue of silenced UCHL1 and IGFBP4 expression suppresses clonogenicity of giant cell tumor-derived stromal cells. Cancer letters 15 23603559
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
2020 IGFBP-4 enhances VEGF-induced angiogenesis in a mouse model of myocardial infarction. Journal of cellular and molecular medicine 13 32597006
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
2023 Increased Levels of Circulating IGFBP4 and ANGPTL8 with a Prospective Role in Diabetic Nephropathy. International journal of molecular sciences 12 37762544
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
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 12 29946296
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
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) 11 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 11 33061500
2001 Truncation of WT1 results in downregulation of cyclin G1 and IGFBP-4 expression. Biochemical and biophysical research communications 11 11573961
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
2004 IGFBP-4 degradation by pregnancy-associated plasma protein-A in MC3T3 osteoblasts. Biochemical and biophysical research communications 9 15541345
2000 Characterization of the enzymatic specificity of the IGF-dependent insulin-like growth factor binding protein-4 (IGFBP-4) protease. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 9 11161967

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