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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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)

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001013398 5 splicing 2638 NP_001013416 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 NM_000598 5 splicing 2620 NP_000589 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)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular vessel       moderately Digestive intestine small intestine     highly   liver       moderately   salivary gland       predominantly   stomach       highly Lymphoid/Immune spleen       highly Reproductive female system placenta     highly   female system ovary     moderately Urinary bladder       highly   kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective       highly Connective adipose     highly

cells

System Cell Pubmed Species Stage Rna symbol not specific chondrocyte

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed cancer digestive oesophagus may thus be useful target for improved and more individualized treatments for patients with esophageal squamous cell carcinoma neurosensorial visual retina 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) cardiovascular atheroma   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 (