Alternative titles; symbols
HGNC Approved Gene Symbol: IGFBP3
Cytogenetic location: 7p12.3 Genomic coordinates (GRCh38): 7:45,912,245-45,921,272 (from NCBI)
The insulin-like growth factors (IGF), their receptors, and their binding proteins play key roles in regulating cell proliferation and apoptosis. Among the several roles of IGFBP3 are its function as the major carrying protein for IGF1 (147440) and IGF2 (147470) in the circulation, and its action as a modulator of IGF bioactivity and as a direct growth inhibitor in the extravascular tissue compartment, where it is expressed in a highly regulated manner (Ferry et al., 1999).
See also 601489, the entry describing the acid-labile subunit of the IGF binding complex, which is found in a ternary complex of 150 kD containing also IGF and IGFBP3.
Based on sequence data derived from GH-dependent IGF-binding protein, referred to as BP-53, purified from human plasma, Wood et al. (1988) isolated full-length BP-53 cDNA clones.
By somatic cell hybrid analysis, Ehrenborg et al. (1992) demonstrated that, like IGFBP1 (146730), IGFBP3 is located on chromosome 7. Pulsed field gel electrophoresis was used to demonstrate the close physical linkage between the 2 genes. Restriction endonuclease mapping showed that the genes are arranged in a tail-to-tail fashion separated by 20 kb of DNA.
Gross (2023) mapped the IGFBP3 gene to chromosome 7p12.3 based on an alignment of the IGFBP3 sequence (GenBank BC000013) with the genomic sequence (GRCh38).
Fraser et al. (2000) found that IGFBP3 mRNA is expressed in the endothelium of the human corpus luteum and that the levels of message change during luteal development and rescue by human chorionic gonadotropin (CG; see 118860). The signal was strong during the early luteal phase, but showed significant reduction during the mid- and late luteal phases. Administration of human CG caused a marked increase in the levels of IGFBP3 mRNA in luteal endothelial cells that was comparable to that observed during the early luteal phase. The authors concluded that endothelial cell IGFBP3 expression is a physiologic property of the corpus luteum of menstruation and pregnancy, and they speculated that the regulated expression of endothelial IGFBP3 may play a role in controlling angiogenesis and cell responses in the human corpus luteum by autocrine/paracrine mechanisms.
Popovici et al. (2001) established highly pure primary cultures of human fetal hepatocytes in vitro and investigated the expression of IGFBP1 and the effects of hypoxia on expression of IGFBP1 mRNA and protein. Western blot analysis of conditioned medium revealed the presence of IGFBP1, IGFBP2 (146731), IGFBP3, and IGFBP4 (146733). A 3-fold increase in IGFBP3 mRNA, but not other IGFBPs, was noted under hypoxic, compared with normoxic, conditions. The authors concluded that hypoxia upregulates fetal hepatocyte IGFBP1 mRNA steady-state levels and protein, with this being the major IGFBP derived from the fetal hepatocyte.
IGFBP3 possesses both growth-inhibitory and -potentiating effects on cells that are independent of IGF action and are mediated through specific IGFBP3-binding proteins/receptors located at the cell membrane, cytosol, or nuclear compartments and in the extracellular matrix. Weinzimer et al. (2001) characterized transferrin (190000) as one of these IGFBP3-binding proteins. Biosensor interaction analysis confirmed that this interaction is specific and sensitive, with a high association rate similar to that of IGF1, and suggested that binding occurs in the vicinity of the IGFBP3 nuclear localization site. Transferrin treatment blocked IGFBP3-induced cell proliferation in bladder smooth muscle cells and IGFBP3-induced apoptosis in prostate cancer cells.
To examine more critically the amino acids important for IGF binding within the full-length IGFBP3 protein while minimizing changes in the tertiary structure, Buckway et al. (2001) targeted residues I56, L80, and L81 within the proposed hydrophobic pocket for mutation. With a single change at these sites to the nonconserved glycine there was a notable decrease in binding. A greater reduction was seen when both L80 and L81 were substituted with glycine, and complete loss of affinity for IGF1 (147440) and IGF2 (147470) occurred when all 3 targeted amino acids were changed to glycine. The authors concluded that their data supported the hypothesis that an N-terminal hydrophobic pocket is the primary site of high affinity binding of IGF to IGFBP3.
Spagnoli et al. (2002) found that Igf-independent apoptotic effects of Igfbp3 were mediated by Stat1 (600555) in rat chondrocytes. Igfbp3 upregulated Stat1 mRNA and protein expression and induced Stat1 phosphorylation and nuclear localization.
Spoerri et al. (2003) found that cultured human retinal endothelial cells expressed endogenous IGFBP3. Exogenous administration of IGFBP3 induced growth inhibition and apoptosis, supporting a regulatory role for IGFBP3 in endothelial cells. Somatostatin receptor (SSTR) agonists mediated their growth-inhibitory effect, in part, by increasing expression of IGFBP3.
In rodents and humans there is a sexually dimorphic pattern of GH (139250) secretion that influences the serum concentration of IGF1. Geary et al. (2003) studied the plasma concentrations of IGF1, IGF2, IGFBP3, and GH in cord blood taken from the offspring of 987 singleton Caucasian pregnancies born at term and related these values to birth weight, length, and head circumference. Cord plasma concentrations of IGF1, IGF2, and IGFBP3 were influenced by factors related to birth size: gestational age at delivery, mode of delivery, maternal height, and parity of the mother. Plasma GH concentrations were inversely related to the plasma concentrations of IGF1 and IGFBP3; 10.2% of the variability in cord plasma IGF1 concentration and 2.7% for IGFBP3 was explained by sex of the offspring and parity. Birth weight, length, and head circumference measurements were greater in males than females (P less than 0.001). Mean cord plasma concentrations of IGF1 and IGFBP3 were significantly lower in males than females. Cord plasma GH concentrations were higher in males than females, but no difference was noted between the sexes for IGF2. After adjustment for gestational age, parity, and maternal height, cord plasma concentrations of IGF1 and IGFBP3 along with sex explained 38.0% of the variability in birth weight, 25.0% in birth length, and 22.7% in head circumference.
In a prospective clinical study, Lofqvist et al. (2007) measured plasma IGFBP3 and examined retinas in 79 premature infants born at less than 32 weeks gestational age, and found that the mean level of IGFBP3 for infants with proliferative retinopathy of prematurity (ROP) was significantly lower than that for infants with no ROP (p less than 0.03).
Baxter (2013) reviewed non-IGF ligands of IGFBP3 and their roles in IGFBP3 growth-inhibitory and -stimulatory functions.
By RT-PCR analysis, D'Addio et al. (2022) showed that the the IGFBP3 receptor TMEM219 (620290) was expressed in human islets and that expression was higher in islet-derived insulin-positive cells than in islet-derived insulin-negative cells. TMEM219 was the sole IGFBP3 receptor expressed in islet beta cells in human, and a dysfunctional IGFBP3/TMEM219 pathway was associated with disrupted beta-cell homeostasis in diabetic patients and triggered beta-cell apoptosis in human islets via caspase-8 (CASP8; 601763) activation/AKT (see 164730) inhibition. Likewise, Tmem219 was the sole Igfbp3 receptor in mouse pancreatic islets, and the Igfbp3/Tmem219 pathway was associated with increased apoptosis, upregulated caspase-8, and decreased insulin expression. Blockade of the Igfbp3/Tmem219 pathway with purified recombinant TMEM219 abrogated Igfbp3-induced detrimental effects in mouse pancreatic islets in vitro. Targeting Igfbp3/Tmem219 signaling protected beta cells in preclinical mouse models of diabetes, as well as in nonobese diabetic mice.
Deal et al. (2001) pointed to evidence that the circulating level of IGFBP3 is inversely related to the risk of several common cancers, and that antiproliferative agents such as antiestrogens and retinoids act in part by upregulating IGFBP3 expression. Using direct sequencing of genomic DNA specimens from a multiethnic population, Deal et al. (2001) identified several single-nucleotide polymorphisms (SNPs) in the promoter region of IGFBP3. For the most common SNP found to be in Hardy-Weinberg equilibrium (A-C at nucleotide -202), genotype was highly correlated to circulating level of IGFBP3 in 478 men. The authors documented in vitro significantly higher promoter activity of the A allele at the -202 locus compared with the C allele, consistent with the relationship observed between genotype and circulating IGFBP3. A positive correlation was observed between circulating retinol levels and circulating IGFBP3 levels; subset analysis by genotype showed that this relationship was only present among individuals carrying an A allele at -202. Tall individuals or individuals with a body mass index of 27 or greater had levels of circulating IGFBP3 that were significantly higher when they possessed at least one A allele.
Cheng et al. (2007) conducted a cross-sectional study of African American, Native Hawaiian, Japanese American, Latino, and white men and women in the Multiethnic Cohort to determine if common genetic variations in IGF1, IGFBP1, or IGFBP3 influence circulating levels of the corresponding proteins. Five highly correlated IGFBP3 SNPs (rs3110697, rs2854747, rs2854746, rs2854744, and rs2132570) demonstrated strongly significant associations with IGFBP3 levels when conservatively adjusted for multiple hypothesis testing (Bonferroni adjusted P trends = 7.75 x 10(-8) to 1.44 x 10(-5)). Patterns of associations were consistent across the 5 racial/ethnic groups.
Chang et al. (2007) exposed CD34+ endothelial precursor cells to IGFBP3 and observed rapid differentiation into endothelial cells and dose-dependent increases in cell migration and capillary tube formation. In neonatal mice undergoing oxygen-induced retinopathy (OIR), administration of either Igfbp3 plasmid alone or hematopoietic stem cells transfected with the plasmid resulted in a similar reduction in areas of vasoobliteration, protection of the developing vasculature from hyperoxia-induced regression, and reduction in preretinal neovascularization compared to controls. Chang et al. (2007) concluded that IGFBP3 mediates endothelial precursor cell migration, differentiation, and capillary formation in vitro, and that targeted expression of IGFBP3 protects the vasculature from damage and promotes vascular repair after hyperoxic insult in the OIR model.
Lofqvist et al. (2007) generated Igfbp3 -/- mice and observed a dose-dependent increase in oxygen-induced retinal vessel loss and a 31% decrease in retinal vessel regrowth compared to controls after returning to room air. There was no difference in IGF1 levels between Ifgbp3 -/- mice and controls. Wildtype mice treated with exogenous Igfbp3 had a significant increase in vessel regrowth, correlating with a 30% increase in endothelial progenitor cells in the retina at postnatal day 15, suggesting that IGFBP3 may serve as a progenitor cell chemoattractant. Lofqvist et al. (2007) concluded that IGFBP3, acting independently of IGF1, helps to prevent oxygen-induced vessel loss and to promote vascular regrowth after vascular destruction in vivo in a dose-dependent manner, resulting in less retinal neovascularization.
See report by Ballard et al. (1989) on the nomenclature of the IGF-binding proteins. IGFBP3 is also known as growth hormone-dependent binding protein, acid-stable subunit of the 140-kD IGF complex, binding protein-53, and binding protein-29.
Ballard, J., Baxter, R., Binoux, M., Clemmons, D., Drop, S.., Hall, K., Hintz, R., Rechler, M., Rutanen, E., Schwander, J. On the nomenclature of the IGF binding proteins. Acta Endocr. 121: 751-752, 1989. [PubMed: 2555997] [Full Text: https://doi.org/10.1530/acta.0.1210751]
Baxter, R. C. Insulin-like growth factor binding protein-3 (IGFBP-3): novel ligands mediate unexpected functions. J Cell Commun Signal 7: 179-189, 2013. [PubMed: 23700234] [Full Text: https://doi.org/10.1007/s12079-013-0203-9]
Buckway, C. K., Wilson, E. M., Ahlsen, M., Bang, P., Oh, Y., Rosenfeld, R. G. Mutation of three critical amino acids of the N-terminal domain of IGF-binding protein-3 essential for high affinity IGF binding. J. Clin. Endocr. Metab. 86: 4943-4950, 2001. [PubMed: 11600567] [Full Text: https://doi.org/10.1210/jcem.86.10.7936]
Chang, K.-H., Chan-Ling, T., McFarland, E. L., Afzal, A., Pan, H., Baxter, L. C., Shaw, L. C., Caballero, S., Sengupta, N., Calzi, S. L., Sullivan, S. M., Grant, M. B. IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development. Proc. Nat. Acad. Sci. 104: 10595-10600, 2007. [PubMed: 17567755] [Full Text: https://doi.org/10.1073/pnas.0702072104]
Cheng, I., Henderson, K. D., Haiman, C. A., Kolonel, L. N., Henderson, B. E., Freedman, M. L., Le Marchand, L. Genetic determinants of circulating insulin-like growth factor (IGF)-I, IGF binding protein (BP)-1, and IGFBP-3 levels in a multiethnic population. J. Clin. Endocr. Metab. 92: 3660-3666, 2007. [PubMed: 17566087] [Full Text: https://doi.org/10.1210/jc.2007-0790]
D'Addio, F., Maestroni, A., Assi, E., Ben Nasr, M., Amabile, G., Usuelli, V., Loretelli, C., Bertuzzi, F., Antonioli, B., Cardarelli, F., El Essawy, B., Solini, A., and 18 others. The IGFBP3/TMEM219 pathway regulates beta cell homeostasis. Nature Commun. 13: 684, 2022. [PubMed: 35115561] [Full Text: https://doi.org/10.1038/s41467-022-28360-2]
Deal, C., Ma, J., Wilkin, F., Paquette, J., Rozen, F., Ge, B., Hudson, T., Stampfer, M., Pollak, M. Novel promoter polymorphism in insulin-like growth factor-binding protein-3: correlation with serum levels and interaction with known regulators. J. Clin. Endocr. Metab. 86: 1274-1280, 2001. [PubMed: 11238520] [Full Text: https://doi.org/10.1210/jcem.86.3.7280]
Ehrenborg, E., Larsson, C., Stern, I., Janson, M., Powell, D. R., Luthman, H. Contiguous localization of the genes encoding human insulin-like growth factor-binding proteins 1 (IGBP1) and 3 (IGBP3) on chromosome 7. Genomics 12: 497-502, 1992. [PubMed: 1373120] [Full Text: https://doi.org/10.1016/0888-7543(92)90440-4]
Ferry, R. J., Jr., Cerri, R. W., Cohen, P. Insulin-like growth factor binding proteins: new proteins, new functions. Horm. Res. 51: 53-67, 1999. [PubMed: 10352394] [Full Text: https://doi.org/10.1159/000023315]
Fraser, H. M., Lunn, S. F., Kim, H., Duncan, W. C., Rodger, F. E., Illingworth, P. J., Erickson, G. F. Changes in insulin-like growth factor-binding protein-3 messenger ribonucleic acid in endothelial cells of the human corpus luteum: a possible role in luteal development and rescue. J. Clin. Endocr. Metab. 85: 1672-1677, 2000. [PubMed: 10770214] [Full Text: https://doi.org/10.1210/jcem.85.4.6497]
Geary, M. P. P., Pringle, P. J., Rodeck, C. H., Kingdom, J. C. P., Hindmarsh, P. C. Sexual dimorphism in the growth hormone and insulin-like growth factor axis at birth. J. Clin. Endocr. Metab. 88: 3708-3714, 2003. [PubMed: 12915659] [Full Text: https://doi.org/10.1210/jc.2002-022006]
Gross, M. B. Personal Communication. Baltimore, Md. 3/20/2023.
Lofqvist, C., Chen, J., Connor, K. M., Smith, A. C. H., Aderman, C. M., Liu, N., Pintar, J. E., Ludwig, T., Hellstrom, A., Smith, L. E. H. IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth. Proc. Nat. Acad. Sci. 104: 10589-10594, 2007. [PubMed: 17567756] [Full Text: https://doi.org/10.1073/pnas.0702031104]
Popovici, R. M., Lu, M., Bhatia, S., Faessen, G. H., Giaccia, A. J., Giudice, L. C. Hypoxia regulates insulin-like growth factor-binding protein 1 in human fetal hepatocytes in primary culture: suggestive molecular mechanisms for in utero fetal growth restriction caused by uteroplacental insufficiency. J. Clin. Endocr. Metab. 86: 2653-2659, 2001. [PubMed: 11397868] [Full Text: https://doi.org/10.1210/jcem.86.6.7526]
Spagnoli, A., Torello, M., Nagalla, S. R., Horton, W. A., Pattee, P., Hwa, V., Chiarelli, F., Roberts, C. T., Jr., Rosenfeld, R. G. Identification of STAT-1 as a molecular target of IGFBP-3 in the process of chondrogenesis. J. Biol. Chem. 277: 18860-18867, 2002. [PubMed: 11886859] [Full Text: https://doi.org/10.1074/jbc.M200218200]
Spoerri, P. E., Caballero, S., Wilson, S. H., Shaw, L. C., Grant, M. B. Expression of IGFBP-3 by human retinal endothelial cell cultures: IGFBP-3 involvement in growth inhibition and apoptosis. Invest. Ophthal. Vis. Sci. 44: 365-369, 2003. [PubMed: 12506097] [Full Text: https://doi.org/10.1167/iovs.02-0309]
Weinzimer, S. A., Gibson, T. B., Collett-Solberg, P. F., Khare, A., Liu, B., Cohen, P. Transferrin is an insulin-like growth factor-binding protein-3 binding protein. J. Clin. Endocr. Metab. 86: 1806-1813, 2001. [PubMed: 11297622] [Full Text: https://doi.org/10.1210/jcem.86.4.7380]
Wood, W. I., Cachianes, G., Henzel, W. J., Winslow, G. A., Spencer, S. A., Hellmiss, R., Martin, J. L., Baxter, R. C. Cloning and expression of the GH dependent IGF binding protein. Molec. Endocr. 2: 1176-1185, 1988. [PubMed: 2464130] [Full Text: https://doi.org/10.1210/mend-2-12-1176]