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Gene Review

IGFBP4  -  insulin-like growth factor binding protein 4

Homo sapiens

Synonyms: BP-4, HT29-IGFBP, IBP-4, IBP4, IGF-binding protein 4, ...
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Disease relevance of IGFBP4


High impact information on IGFBP4

  • IGFBP-2 and IGFBP-4 are secreted primarily into the basolateral side (71 and 87%, respectively), whereas IGFBP-6 is targeted to the apical surface (76%) as a possible consequence of an active sorting [6].
  • Estrogen receptor expression was positively correlated with BP-2 (Spearman correlation coefficient, rs = .262; P = .0001), BP-4 (rs = .313; P = .0001), and BP-5 (rs = .242; P = .0002) [7].
  • RESULTS: Binding protein (BP)-2, BP-3, BP-4, and BP-5 were identified in breast cancer extracts [7].
  • IMPLICATIONS: These data suggest that the IGFBPs may play a role in breast cancer biology and that BP-4 levels, analyzed in conjunction with tumor size, may have prognostic significance [7].
  • BP-4 was weakly inversely correlated with tumor size (rs = -.141; P = .0295) and S-phase fraction (rs = -.216; P = .0025) [7].

Chemical compound and disease context of IGFBP4


Biological context of IGFBP4


Anatomical context of IGFBP4


Associations of IGFBP4 with chemical compounds


Physical interactions of IGFBP4


Enzymatic interactions of IGFBP4

  • This IGF-regulated loss of IGFBP-4 was inhibited by metalloproteinase inhibitors and appeared to be due to a proteinase that cleaved IGFBP-4 in 18 and 14 kD fragments identified by western immunoblotting [28].
  • Herein, we first determined that PAPP-A cleaves IGFBP-4 at a single site (Met-135/Lys-136), and we analysed the influence of ionic strength, pH and zinc ion concentration on the cleavage reaction [29].

Co-localisations of IGFBP4


Regulatory relationships of IGFBP4

  • Both IGF-I and IGF-II were capable of inducing a decrease in IGFBP-4; however, IGF-II was more effective [28].
  • 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 [31].
  • Proteolysis of radiolabeled IGFBP-4 in conditioned media from OSE(tsT) lines was IGF-dependent and blocked by anti-PAPP-A antisera [32].
  • However, administration of epidermal growth factor (EGF) induced polarized secretion of IGFBP-4 by increasing secretion from the apical surface more than from the basolateral aspect [33].
  • All of the IGFBPs, except the TGF-beta1-regulated IGFBP-4, were modulated at mRNA level [34].
  • We find that PAPP-A-mediated IGF-dependent cleavage of IGFBP-4 is inhibited by IGFBP-5, which sequesters IGF from IGFBP-4, and that cleavage of both IGFBP-4 and -5 is required for the release of bioactive IGF [35].

Other interactions of IGFBP4


Analytical, diagnostic and therapeutic context of IGFBP4


  1. Identification of a novel SP3 binding site in the promoter of human IGFBP4 gene: role of SP3 and AP-1 in regulating promoter activity in CaCo2 cells. Shen, Q., Singh, P. Oncogene (2004) [Pubmed]
  2. Inhibitory insulin-like growth factor-binding protein: cloning, complete sequence, and physiological regulation. LaTour, D., Mohan, S., Linkhart, T.A., Baylink, D.J., Strong, D.D. Mol. Endocrinol. (1990) [Pubmed]
  3. 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. Powell, D.R., Durham, S.K., Brewer, E.D., Frane, J.W., Watkins, S.L., Hogg, R.J., Mohan, S. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  4. 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. Honda, Y., Landale, E.C., Strong, D.D., Baylink, D.J., Mohan, S. J. Clin. Endocrinol. Metab. (1996) [Pubmed]
  5. Insulin-like growth factor-I (IGF-I) regulates IGFBP-3 and IGFBP-4 by multiple mechanisms in A549 human adenocarcinoma cells. Price, W.A., Moats-Staats, B.M., Stiles, A.D. Am. J. Respir. Cell Mol. Biol. (1995) [Pubmed]
  6. Cell polarity of the insulin-like growth factor system in human intestinal epithelial cells. Unique apical sorting of insulin-like growth factor binding protein-6 in differentiated human colon cancer cells. Remacle-Bonnet, M., Garrouste, F., el Atiq, F., Marvaldi, J., Pommier, G. J. Clin. Invest. (1995) [Pubmed]
  7. Prognostic significance of insulin-like growth factor-binding protein expression in axillary lymph node-negative breast cancer. Yee, D., Sharma, J., Hilsenbeck, S.G. J. Natl. Cancer Inst. (1994) [Pubmed]
  8. Cyclic adenosine monophosphate stimulates insulin-like growth factor binding protein-4 and its messenger ribonucleic acid in a clonal endothelial cell line. Yang, Y.W., Pioli, P., Fiorelli, G., Brandi, M.L., Rechler, M.M. Endocrinology (1993) [Pubmed]
  9. Retinoic acid stimulates IGF binding protein (IGFBP)-6 and depresses IGFBP-2 and IGFBP-4 in SK-N-SH human neuroblastoma cells. Chambéry, D., de Gallé, B., Babajko, S. J. Endocrinol. (1998) [Pubmed]
  10. Expression of insulin-like growth factor binding protein-4 (IGFBP-4) by rat neural cells--comparison to other IGFBPs. Chernausek, S.D., Murray, M.A., Cheung, P.T. Regul. Pept. (1993) [Pubmed]
  11. 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. Scharla, S.H., Strong, D.D., Rosen, C., Mohan, S., Holick, M., Baylink, D.J., Linkhart, T.A. J. Clin. Endocrinol. Metab. (1993) [Pubmed]
  12. Alterations in insulin-like growth factor (IGF)-dependent IGF-binding protein-4 proteolysis in transformed osteoblastic cells. Durham, S.K., Riggs, B.L., Harris, S.A., Conover, C.A. Endocrinology (1995) [Pubmed]
  13. 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. Tonin, P., Ehrenborg, E., Lenoir, G., Feunteun, J., Lynch, H., Morgan, K., Zazzi, H., Vivier, A., Pollak, M., Huynh, H. Genomics (1993) [Pubmed]
  14. Localization of the human insulin-like growth-factor-binding protein 4 gene to chromosomal region 17q12-21.1. Bajalica, S., Allander, S.V., Ehrenborg, E., Brøndum-Nielsen, K., Luthman, H., Larsson, C. Hum. Genet. (1992) [Pubmed]
  15. Potential role of insulin-like growth factor binding protein-4 in the uncoupling of bone turnover in multiple myeloma. Feliers, D., Woodruff, K., Abboud, S. Br. J. Haematol. (1999) [Pubmed]
  16. Competition with TATA box-binding protein for binding to the TATA box implicated in human cytomegalovirus IE2-mediated transcriptional repression of cellular promoters. Wang, Y.C., Huang, C.F., Tung, S.F., Lin, Y.S. DNA Cell Biol. (2000) [Pubmed]
  17. Anatomy of the human ovarian insulin-like growth factor system. Zhou, J., Bondy, C. Biol. Reprod. (1993) [Pubmed]
  18. The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A. Lawrence, J.B., Oxvig, C., Overgaard, M.T., Sottrup-Jensen, L., Gleich, G.J., Hays, L.G., Yates, J.R., Conover, C.A. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  19. Purification of a colon cancer cell growth inhibitor and its identification as an insulin-like growth factor binding protein. Culouscou, J.M., Shoyab, M. Cancer Res. (1991) [Pubmed]
  20. Diabetic microangiopathy: IGFBP control endothelial cell growth by a common mechanism in spite of their species specificity and tissue peculiarity. Giannini, S., Cresci, B., Manuelli, C., Pala, L., Rotella, C.M. J. Endocrinol. Invest. (2006) [Pubmed]
  21. Regulation of insulin-like growth factor-binding protein-4 in human endometrial stromal cell cultures: evidence for ligand-induced proteolysis. Irwin, J.C., Dsupin, B.A., Giudice, L.C. J. Clin. Endocrinol. Metab. (1995) [Pubmed]
  22. Insulin-like growth factor-I (IGF-I) enhanced proteolysis of IGF-binding protein-4 in conditioned medium from primary cultures of human decidua: independence from IGF receptor binding. Myers, S.E., Cheung, P.T., Handwerger, S., Chernausek, S.D. Endocrinology (1993) [Pubmed]
  23. Pregnancy-associated plasma protein-a is the insulin-like growth factor binding protein-4 protease secreted by human ovarian granulosa cells and is a marker of dominant follicle selection and the corpus luteum. Conover, C.A., Faessen, G.F., Ilg, K.E., Chandrasekher, Y.A., Christiansen, M., Overgaard, M.T., Oxvig, C., Giudice, L.C. Endocrinology (2001) [Pubmed]
  24. Myocardial insulin-like growth factor-I gene expression during recovery from heart failure after combined left ventricular assist device and clenbuterol therapy. Barton, P.J., Felkin, L.E., Birks, E.J., Cullen, M.E., Banner, N.R., Grindle, S., Hall, J.L., Miller, L.W., Yacoub, M.H. Circulation (2005) [Pubmed]
  25. 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. Byun, D., Mohan, S., Yoo, M., Sexton, C., Baylink, D.J., Qin, X. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  26. Characterization of recombinant human insulin-like growth factor binding proteins 4, 5, and 6 produced in yeast. Kiefer, M.C., Schmid, C., Waldvogel, M., Schläpfer, I., Futo, E., Masiarz, F.R., Green, K., Barr, P.J., Zapf, J. J. Biol. Chem. (1992) [Pubmed]
  27. Effects of estrogen and parathyroid hormone on osteoblastic activity via regulating the binding activity of insulin-like growth factor binding protein-4 in SaOS-2 cells: implications for the pathogenesis of postmenopausal osteoporosis. Kudo, Y., Itatsu, S., Iwashita, M., Iguchi, T., Takeda, Y. Biochim. Biophys. Acta (1995) [Pubmed]
  28. Regulation of insulin-like growth factor binding protein 4 by a specific insulin-like growth factor binding protein 4 proteinase in normal human osteoblast-like cells: implications in bone cell physiology. Durham, S.K., Kiefer, M.C., Riggs, B.L., Conover, C.A. J. Bone Miner. Res. (1994) [Pubmed]
  29. Substrate specificity of the metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) assessed by mutagenesis and analysis of synthetic peptides: substrate residues distant from the scissile bond are critical for proteolysis. Laursen, L.S., Overgaard, M.T., Nielsen, C.G., Boldt, H.B., Hopmann, K.H., Conover, C.A., Sottrup-Jensen, L., Giudice, L.C., Oxvig, C. Biochem. J. (2002) [Pubmed]
  30. Differential expression of IGFBPs by normal and hypertrophic scar fibroblasts. Hathaway, C.L., Arnold, A.M., Rand, R.P., Engrav, L.H., Quinn, L.S. J. Surg. Res. (1996) [Pubmed]
  31. 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. Neely, E.K., Rosenfeld, R.G. Endocrinology (1992) [Pubmed]
  32. Pregnancy-associated plasma protein-A (PAPP-A) expression and insulin-like growth factor binding protein-4 protease activity in normal and malignant ovarian surface epithelial cells. Kalli, K.R., Chen, B.K., Bale, L.K., Gernand, E., Overgaard, M.T., Oxvig, C., Cliby, W.A., Conover, C.A. Int. J. Cancer (2004) [Pubmed]
  33. Insulin-like growth factor binding protein profile secreted by human intestinal epithelial cells varies with polarity. Oguchi, S., Walker, W.A., Sanderson, I.R. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  34. Human glomerular endothelial cells IGFBPs are regulated by IGF-I and TGF-beta1. Giannini, S., Cresci, B., Pala, L., Ciucci, A., Manuelli, C., Fujita-Yamaguchi, Y., Cappugi, P., Rotella, C.M. Mol. Cell. Endocrinol. (1999) [Pubmed]
  35. Regulation of insulin-like growth factor (IGF) bioactivity by sequential proteolytic cleavage of IGF binding protein-4 and -5. Laursen, L.S., Kjaer-Sorensen, K., Andersen, M.H., Oxvig, C. Mol. Endocrinol. (2007) [Pubmed]
  36. Regulation of insulin-like growth factor-binding protein (IGFBP) expression by breast cancer cells: use of IGFBP-1 as an inhibitor of insulin-like growth factor action. McGuire, W.L., Jackson, J.G., Figueroa, J.A., Shimasaki, S., Powell, D.R., Yee, D. J. Natl. Cancer Inst. (1992) [Pubmed]
  37. Insulin-like growth factor-1 and its binding proteins during a low-protein diet in chronic renal failure. Fouque, D., Le Bouc, Y., Laville, M., Combarnous, F., Joly, M.O., Raton, P., Zech, P. J. Am. Soc. Nephrol. (1995) [Pubmed]
  38. The expression of insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) genes in the human placenta and membranes: evidence for IGF-IGFBP interactions at the feto-maternal interface. Han, V.K., Bassett, N., Walton, J., Challis, J.R. J. Clin. Endocrinol. Metab. (1996) [Pubmed]
  39. Molecular cloning of mouse insulin-like growth factor binding protein 4 (IGFBP4) cDNA and expression of a fusion protein with IGF-binding activity. Bethel, C.R., Vitullo, J.C., Miller, R.E., Aron, D.C. Biochem. Mol. Biol. Int. (1994) [Pubmed]
  40. The insulin-like growth factor system in human peritoneal fluid: its effects on endometrial stromal cells and its potential relevance to endometriosis. Giudice, L.C., Dsupin, B.A., Gargosky, S.E., Rosenfeld, R.G., Irwin, J.C. J. Clin. Endocrinol. Metab. (1994) [Pubmed]
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