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FLASH GENE
Symbol IGFBP3 contributors: mct/shn/pgu - updated : 10-03-2014
HGNC name insulin-like growth factor binding protein 3
HGNC id 5472
Location 7p12.3      Physical location : 45.951.849 - 45.960.871
Synonym name
  • IGF-binding protein 3
  • insulin-like growth factor-binding protein 3
  • acid stable subunit of the 140 K IGF complex
  • growth hormone-dependent binding protein
  • binding protein 29
  • binding protein 53
  • Synonym symbol(s) IBP3, IGBP3, BP-53, IBP-3, IGFBP-3
    DNA
    TYPE functioning gene
    STRUCTURE 9.03 kb     5 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map pter - D7S478 - D7S2427 - IGFBP3 - D7S519 - D7S2558 - cen
    Authors Eggerman (99)
    Physical map
    DDX56 7p13 DEAD (Asp-Glu-Ala-Asp) box polypeptide 56 HNLF 7p13 putative NFkB activating protein HNLF LOC392665 7 similar to myosin IG OGDH 7p14-p13 oxoglutarate (alpha-ketoglutarate) dehydrogenase (lipoamide) C7orf22 7p13 chromosome 7 open reading frame 22 LOC392666 7 similar to KIAA0363 CPR2 7p14-p13 similar to KIAA0363 DKFZp761I2123 7p13 hypothetical protein DKFZp761I2123 RAMP3 7p13-p12 receptor (calcitonin) activity modifying protein 3 PPIA 7p13-p11.2 peptidylprolyl isomerase A (cyclophilin A) H2AV 7p13 H2A histone family, member V PURB 7p13 purine-rich element binding protein B MRPS23P1 7p13 mitochondrial ribosomal protein S23 pseudogene 1 MYO1G 7p13-p11.2 myosin IG C7orf22 7p13 chromosome 7 open reading frame 22 KIAA0363 7p14-p11.2 chromosome 7 open reading frame 22 CPR2 7p14-p13 chromosome 7 open reading frame 22 RAMP3 7p13-p12 receptor (calcitonin) activity modifying protein 3 ADCY1 7p13-p12 adenylate cyclase 1 (brain) LOC392667 7 similar to cell division cycle 10 homolog LOC339494 7 hypothetical LOC339494 LOC392668 7 similar to hypothetical protein LOC349114 LOC392894 7 similar to capicua homolog IGFBP1 7p13-p12 insulin-like growth factor binding protein 1 IGFBP3 7p13-p12 insulin-like growth factor binding protein 3 ADCY1 7p13-p12 adenylate cyclase 1 (brain) LOC392895 7 similar to Tetratricopeptide repeat protein 4 (My044 protein) LOC389487 7 similar to cell division cycle 10 homolog LOC389488 7 similar to hypothetical protein LOC349114 LOC392024 7 similar to capicua homolog IGFBP1 7p13-p12 insulin-like growth factor binding protein 1 IGFBP3 7p13-p12 insulin-like growth factor binding protein 3 LOC222052 7p13 similar to Tetratricopeptide repeat protein 4 (My044 protein) CNTNAP2 7q35.1-q35.2 contactin associated protein-like 2 PRO1866 LOC392896 7 similar to Splicing factor, arginine/serine-rich, 46kD PRO1866 TENS1 7p12.3 tensin-like SH2 domain-containing 1 MRPL42P4 7p12.3 tensin-like SH2 domain-containing 1 LOC346472 7p12.3 similar to Splicing factor, arginine/serine-rich, 46kD
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    5 splicing 2638 32 297 - 1992 1373120
  • variant 1/isoform a
  • a 27 amino acids signal peptide (2.9 kDa)
  • longer transcript
  • encoding for the longer isoform A
  • 5 splicing 2620 31.6 291 - 1992 1373120
  • variant 2/isoform b
  • a 27 amino acids signal peptide (2.9 kDa)
  • shorter transcript
  • encoding for the shorter isoform B
  • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularvessel   moderately
    Digestiveintestinesmall intestine  highly
     liver   moderately
     salivary gland   predominantly
     stomach   highly
    Lymphoid/Immunespleen   highly
    Reproductivefemale systemplacenta  highly
     female systemovary  moderately
    Urinarybladder   highly
     kidney   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connective   highly
    Connectiveadipose  highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    not specificchondrocyte
    cell lineage endothelial cells of corpus luteum (
    cell lines
    fluid/secretion serum
    at STAGE
    physiological period pregnancy
    Text umbilical cord
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a 27 amino acids signal peptide (2.9 kDa)
  • invariant cysteine residues
  • twelve N terminal
  • six C terminal
  • a N terminal IGFBP motif
  • a central domain lacking cysteine residue, with a RGD motif
  • AAs in both the N- and C-terminal domains are involved in binding the retinoid receptors, and that this interaction is essential to the modulation of RAR-signaling by IGFBP3
  • isoforms Precursor a 270 amino acids mature peptide (22.3 kDa)
    HOMOLOGY
    interspecies ortholog to Igfbp3, Rattus norvegicus
    ortholog to Igfbp3, Mus musculus
    ortholog to IGFBP3, Pan troglodytes
    ortholog to igfbp3, Danio rerio
    Homologene
    FAMILY
  • sterol desaturase family
  • CATEGORY signaling cytokine growth factor
    SUBCELLULAR LOCALIZATION extracellular
        intracellular
    intracellular,nucleus
    text secreted protein, but can be internalized and translocate to the nucleus
    basic FUNCTION
  • binds to IGFs and modulates their actions
  • modulates proliferation of primitive hematopoietic cells
  • involved in perinecrotic hypoxia
  • might improve vessel repair by promoting the incorporation of bone marrow-derived endothelial progenitor cells into the retina
  • has direct proangiogenic effects on CD34+ cell migration, differentiation, and tube formation, steps required for proper vascular repair after hypoxic injury
  • mediates growth suppression signals via the TGF-beta and/or RB pathways in hepatocellular carcinoma
  • a mediator of apoptosis induced by TNF-alpha (
  • role in myoblast differentiation (
  • a modulator of vascular survival and regrowth in oxygen-induced retinopathy (
  • may mediate the inhibition of adiponectin transcription by hypoxia and TNF
  • can induce apoptosis in prostate cancer cells without binding RXRA
  • plays an important role as an invasion-metastasis suppressor in ovarian endometrioid carcinoma
  • is capable of binding BMP2/4 in a specific manner and cleavage of IGFBP3 by BMP1-like proteinases decreases the ability of IGFBP3 to bind BMP2/4
  • having a function in suppressing metastasis in prostate cancer
  • Intravitreal administration of IGFBP that does not bind IGF-1 preserves junctional integrity in the presence of VEGF or laser injury (
  • is sufficient for induction of senescence
  • functions as a secreted mediator of senescence, acting through suppression of AKT1 and requiring TP53 and RB1
  • CELLULAR PROCESS cell life, differentiation
    cell life, proliferation/growth
    cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS development
    text regulation
    PATHWAY
    metabolism
    signaling signal transduction
    a component
  • principal serum IGFBP constituent
  • complexing with IGF1, IGF2 and an acid labile subunit
  • INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • ion
  • protein
  • regulating STAT1 in chondrogenesis
  • type 1 IGF receptor, IGFR-1 (
  • Plasminogen (
  • prekallikrein (
  • insulin-like growth factor-I and -II (
  • A disintegrin and metalloprotease-12, ADAM12 (
  • retinoid X receptor-alpha (
  • fibronectin, FN (
  • lysosomal cysteine protease cathepsin L, CTSL (
  • Ialpha collagen (
  • latent transforming growth factor-beta binding protein-1, LTBP-1 (
  • Alzheimer's survival peptide humanin (
  • integrins alphav and beta1, caveolin-1, and transferrin receptor (
  • forms a ternary complex with transferrin and transferrin receptor 1 (
  • autocrine motility factor/phosphoglucose isomerase, AMF/PGI (
  • Nur77 (
  • retinoid X receptor-alpha, RXRalpha and retinoic acid receptor-alpha , RARalpha
  • TGF-beta pathway
  • nuclear retinoid X receptor, RXRA
  • RXRA
  • HCRT (
  • IGFBP3 is an important mediator of the MXI1-related proliferation mechanism
  • critical downstream target of SERPINE1-induced senescence
  • PLAT-SERPINE1 system regulates the senescence-inducing activity of IGFBP3
  • IGFBP3 proteolysis by PLAT resulted in the inactivation of senescence-inducing activity of IGFBP3
  • overexpression of IGFBP3 suppresses osteoblastic differentiation regulated by VDR in the presence of 1,25-(OH)2D3
  • CD5L binds to IGFBP2, IGFBP3 and IGFBP4, and this interaction may contribute to the mechanism of CD5L-mediated anti-apoptosis function
  • nuclear translocation of IGFBP3 by KPNB1 is a prerequisite for IGFBP3-induced apoptosis
  • MTRNR2L1 counteracts IGFBP3-induced cell death
  • IGFBP3 may trigger osteoarthritis by inducing the chondrocytes apoptotic through nucleus-mitochondria translocation of NR4A1
  • cell & other
    REGULATION
    activated by NKX3.1 (
    induced by wild-type TP53
    repressed by CDX2 (negatively regulates the well-documented growth inhibitor insulin-like growth factor binding protein-3 (IGFBP3)
    Other mainly regulated by GH
    either IGF dependent or IGF independent
    cleaved by BMP1 (cleaves IGFBP3 at a single conserved site, resulting in markedly reduced ability of cleaved IGFBP3 to bind IGF1 or to block IGF1-induced cell signaling)
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in acromegalic patients
    tumoral     --low  
    in breast cancer
    tumoral     --over  
    high expression of IGFBP-3 is associated with a low risk of cancer, whereas low expression of IGFBP3 increases the risk of cancer
    Susceptibility
  • prostate cancer with advanced stage
  • to breast cancer
  • Variant & Polymorphism
  • C allele may cumulatively increase the risk for prostate cancer metastasis and for having tumors with a biologically more aggressive phenotype
  • homozygosity for the variant allele in polymorphisms A-202C, G227C, 5606InsA, and C5827T associated with the level of blood IGFBP-3 protein and increasing the risk of breast cancer
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerdigestiveoesophagus
    may thus be useful target for improved and more individualized treatments for patients with esophageal squamous cell carcinoma
    neurosensorialvisualretina
    use of exogenous IGFBP3 in patients at risk for retinal neovascularization would have protective effects (suppresses retinopathy of prematurity through suppression of oxygen-induced vessel loss and promotion of vascular regrowth)
    cardiovascularatheroma 
    potentially a therapeutic target for treatment of ischemic conditions
    cancer  
    is a new type of cancer therapy that inhibits cancer proliferation by inducing senescence
    ANIMAL & CELL MODELS
  • GFBP3-deficient mice displa a dose-dependent increase in oxygen-induced retinal vessel loss and Igfbp3(-/-) mice had a 31% decrease in retinal vessel regrowth versus controls after returning to room air (