Alternative titles; symbols
HGNC Approved Gene Symbol: IGFBP4
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:40,443,450-40,457,725 (from NCBI)
Insulin-like growth factor (see IGF1; 147440)-binding proteins (IGFBPs), such as IGFBP4, are involved in the systemic and local regulation of IGF activity. IGFBPs contain 3 structurally distinct domains each comprising approximately one-third of the molecule. The N-terminal domain 1 and the C-terminal domain 3 of IGFBPs show moderate to high levels of sequence identity, including 12 and 6 invariant cysteines in domains 1 and 3, respectively (IGFBP6 (146735) contains 10 cysteines in domain 1), and are thought to be the IGF-binding domains. Domain 2 is defined primarily by a lack of sequence identity among the IGFBPs and by a lack of cysteines, though it does contain 2 cysteines in IGFBP4. Domain 3 is homologous to the thyroglobulin type I repeat unit (Kiefer et al., 1992).
Based on peptide sequences of a purified IGFBP, Shimasaki et al. (1990) cloned rat Igfbp4 using PCR. They used the rat cDNA to clone the human ortholog from a liver cDNA library. Human IGFBP4 encodes a 258-amino acid polypeptide, which includes a 21-amino acid signal sequence. The protein is very hydrophilic, which may facilitate its ability as a carrier protein for the IGFs in blood. Northern blot analysis of rat tissues revealed expression in all tissues examined, with highest expression in liver.
Shimasaki et al. (1990) stated that IGFBP4 acts as an inhibitor of IGF-induced bone cell proliferation.
Kiefer et al. (1992) characterized recombinant human IGFBP4, IGFBP5 (146734), and IGFBP6 by their expression in yeast as fusion proteins with ubiquitin (see 191339). Results of the study indicated the primary effect of the 3 proteins is the attenuation of IGF activity and suggested that they contribute to the control of IGF-mediated cell growth and metabolism.
Zhu et al. (2008) reported a theretofore unknown function for IGFBP4 as a cardiogenic growth factor. In mouse stem cells, Igfbp4 enhanced cardiomyocyte differentiation in vitro, and knockdown of Igfbp4 attenuated cardiomyogenesis both in vitro and in vivo in mouse stem cells and in Xenopus embryos, respectively. The cardiogenic effect of IGFBP4 was independent of its IGF-binding activity but was mediated by the inhibitory effect on canonical Wnt signaling. IGFBP4 physically interacted with a Wnt receptor, Frizzled-8 (FZD8; 606146), and a Wnt coreceptor, low-density lipoprotein receptor-related protein-6 (LRP6; 603507), and inhibited the binding of Wnt3a (606359) to Frz8 and Lrp6. Although IGF-independent, the cardiogenic effect of IGFBP4 was attenuated by IGFs through IGFBP4 sequestration. IGFBP4 is therefore an inhibitor of the canonical Wnt signaling required for cardiogenesis and provides a molecular link between IGF signaling and Wnt signaling.
Zazzi et al. (1998) examined the genomic region containing the IGFBP gene. The gene consists of 4 exons spanning approximately 15 kb of genomic DNA. The upstream region of the gene contains a TATA box and a cAMP-responsive promoter.
By in situ hybridization, Bajalica et al. (1992) mapped the IGFBP4 gene to chromosome 17q12-q21. Because the hereditary breast-ovarian cancer gene BRCA1 (113705) had been mapped to the same region, Tonin et al. (1993) investigated IGFBP4 as a candidate gene by linkage analysis of 22 BRCA1 families; the finding of genetic recombination suggested that it is not the BRCA1 gene.
Zhang et al. (2002) created transgenic mice expressing a protease-resistant rat Igfbp4 cDNA targeted to smooth muscle cells. Transgenic mice had lower aortic, bladder, and stomach weight and shorter intestinal length relative to control animals. The authors concluded that proteolysis of IGFBP4 may be required to release free IGF1 in smooth muscle and that the growth factor may be sequestered if the binding protein cannot be readily degraded.
Bajalica, S., Allander, S. V., Ehrenborg, E., Brondum-Nielsen, K., Luthman, H., Larsson, C. Localization of the human insulin-like growth-factor-binding protein 4 gene to chromosomal region 17q12-21.1. Hum. Genet. 89: 234-236, 1992. [PubMed: 1375185] [Full Text: https://doi.org/10.1007/BF00217129]
Kiefer, M. C., Schmid, C., Waldvogel, M., Schlapfer, I., Futo, E., Masiarz, F. R., Green, K., Barr, P. J., Zapf, J. Characterization of recombinant human insulin-like growth factor binding proteins 4, 5, and 6 produced in yeast. J. Biol. Chem. 267: 12692-12699, 1992. [PubMed: 1377672]
Shimasaki, S., Uchiyama, F., Shimonaka, M., Ling, N. Molecular cloning of the cDNAs encoding a novel insulin-like growth factor-binding protein from rat and human. Molec. Endocr. 4: 1451-1458, 1990. [PubMed: 1704481] [Full Text: https://doi.org/10.1210/mend-4-10-1451]
Tonin, P., Ehrenborg, E., Lenoir, G., Feunteun, J., Lynch, H., Morgan, K., Zazzi, H., Vivier, A., Pollak, M., Huynh, H., Luthman, H., Larsson, C., Narod, S. The human insulin-like growth factor-binding protein 4 gene maps to chromosome region 17q12-q21.1 and is close to the gene for hereditary breast-ovarian cancer. Genomics 18: 414-417, 1993. [PubMed: 7507078] [Full Text: https://doi.org/10.1006/geno.1993.1487]
Zazzi, H., Nikoshkov, A., Hall, K., Luthman, H. Structure and transcription regulation of the human insulin-like growth factor binding protein 4 gene (IGFBP4). Genomics 49: 401-410, 1998. [PubMed: 9615225] [Full Text: https://doi.org/10.1006/geno.1998.5283]
Zhang, M., Smith, E. P., Kuroda, H., Banach, W., Chernausek, S. D., Fagin, J. A. Targeted expression of a protease-resistant IGFBP-4 mutant in smooth muscle of transgenic mice results in IGFBP-4 stabilization and smooth muscle hypotrophy. J. Biol. Chem. 277: 21285-21290, 2002. [PubMed: 11923290] [Full Text: https://doi.org/10.1074/jbc.M112082200]
Zhu, W., Shiojima, I., Ito, Y., Li, Z., Ikeda, H., Yoshida, M., Naito, A. T., Nishi, J., Ueno, H., Umezawa, A., Minamino, T., Nagai, T., Kikuchi, A., Asashima, M., Komuro, I. IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis. Nature 454: 345-349, 2008. Note: Erratum: Nature 506: 254 only, 2014. [PubMed: 18528331] [Full Text: https://doi.org/10.1038/nature07027]