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Gene Review

IGFBP2  -  insulin-like growth factor binding protein...

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Disease relevance of IGFBP2

  • More moderate undernutrition (80% of requirements) did not affect circulating IGFBP-2 but did alter the response of IGFBP-2 to bST [1].
  • The cDNA for bovine IGFBP-2 was inserted between regions coding for the pelB signal sequence and geneIII product, g3p, of bacteriophage fd in a phagemid vector to generate pGF14 [2].
  • Furthermore, circulating IGFBP-2 appears to be higher in heifers than in bulls, and also appears to be negatively correlated with body weights [3].
  • Thus IGFBP-2 can be secreted in E. coli and displayed on filamentous phage [2].
  • On the other hand, IGFBP-2 was a potent inhibitor of IGF-II action in human breast and ovarian carcinoma cells [4].

High impact information on IGFBP2

  • We have previously used tyrosine iodination to implicate Tyr-60 in the IGF-binding site of bovine IGFBP-2 (Hobba, G. D., Forbes, B. E., Parkinson, E. J., Francis, G. L., and Wallace, J. C. (1996) J. Biol. Chem. 271, 30529-30536) [5].
  • FSH inhibited the expression of IGFBP-2 mRNA in granulosa cells, whereas LH stimulated IGFBP-4 mRNA expression in theca cells [6].
  • The regulation of IGFBP-2 and -4 mRNA expression in granulosa and theca cells was analyzed using a serum-free cell culture system [6].
  • We conclude that low amounts of IGFBP-2 and increased thecal binding sites for hCG/LH appear to be related to establishment of the dominant follicle during the first follicular wave in cattle exhibiting regular estrous cycles during late lactation [7].
  • Thus, RA is a potent but transient inhibitor of bovine mammary epithelial cell proliferation, and this growth inhibition is correlated with increased IGFBP-2 accumulation and inhibition of IGF-I stimulated IGFBP-3 protein secretion [8].

Biological context of IGFBP2

  • Immunolocalization studies showed that spatial and temporal patterns of expression of IGFBP-2 and -3 were markedly altered in the placentomes of NT pregnancies compared to AI/IVP controls [9].
  • The opposite pattern of IGFBP-2 gene expression in SF and some NRF may lead to follicular atresia [10].
  • In conclusion, the reduced expression of IGFBP-2 mRNA in severe NEB cows may alter the bioavailability of circulating IGF-I and locally produced IGF-II to modulate the pre-recruitment stages of follicles required to maintain normal post partum ovarian cyclicity [11].
  • The predicted protein sequence shares extensive sequence similarity with both the rat (82%) and human (89%) IGFBP-2s, so that the MDBK binding protein is clearly the bovine counterpart of IGFBP-2 [12].
  • Levels of endometrial IGFBP-2 mRNA increased (p less than 0.05) between Days 10 and 18 of the estrous cycle and early pregnancy [13].

Anatomical context of IGFBP2


Associations of IGFBP2 with chemical compounds

  • In experiment 2, E2 concentrations in large E-A follicles increased (p < 0.01) from 0 to 48 h after the PGF injection for control cows but decreased (p < 0.01) for FSH cows, whereas follicular fluid IGFBP-2 binding activity decreased from 0 to 48 h after PGF in controls and increased in FSH cows (treatment x time, p < 0.05) [18].
  • Both IGFBP-2 and IGFBP-4 mRNA levels were consistently reduced in stretched cells but remained comparable to those of the control cells when the angiotensin II transducing pathway was blocked by inhibitors prior to the application of mechanical strain [19].
  • Levels of IGFBP-2 and -5 mRNA were severalfold greater (P < 0.05) in subordinate than dominant follicles [20].
  • Other features deduced from the bovine IGFBP-2 cDNA include: an abundance of leucine in the pre-peptide, an Arg-Gly-Asp sequence, absence of N-linked glycosylation sites, and an imperfect polyadenylation signal as well as an ATTTA motif in the 3' non-coding DNA [12].
  • However, retinoic acid (10(-6) M) stimulated both IGFBP-2 and IGFBP-6 protein and mRNA levels, but it decreased IGFBP-3 mRNA levels relative to controls [21].

Physical interactions of IGFBP2

  • IGF-II ligand blots confirm these tissue-specific differences in binding and show that each ocular tissue contains IGFBP-2 [22].

Regulatory relationships of IGFBP2


Other interactions of IGFBP2

  • In contrast, release of both IGFBP-2 and IGFBP-3 was greater (3.1-fold and 3.5-fold, respectively) from basal as compared to apical surfaces of the MDBKpMONBP-3 cells [25].
  • Primary bovine mammary cells express the two IGF receptors (IGF-IR, IGF-IIR), insulin receptor, and four IGFBPs (IGFBP-2, -3, -4, and -5) [26].
  • Intensities of the 34-kDa (IGFBP-2), 29-27-kDa, and 22-kDa IGFBP bands in follicular fluid were nondetectable or were lower (p < 0.01) in the fluid of large (> or = 8 mm) E-active (E-A; E2 > 50 ng/ml and > P4) follicles than in large E-inactive (E-I), medium (5-7 mm), or small (< 5 mm) follicles [18].
  • Levels of GH receptor, the type 1 IGF receptor, and IGF binding protein-2 (IGFBP-2) mRNAs were unchanged across the growth-plate [27].
  • The disappearance of binding activities for IGFBP-2 and smaller-molecular-mass IGFBPs in E-A follicles suggests a possible regulatory role for IGFBPs in follicular maturation and on aromatase activity.(ABSTRACT TRUNCATED AT 400 WORDS)[18]

Analytical, diagnostic and therapeutic context of IGFBP2


  1. Nutritional modulation of the somatotropin/insulin-like growth factor system: response to feed deprivation in lactating cows. McGuire, M.A., Bauman, D.E., Dwyer, D.A., Cohick, W.S. J. Nutr. (1995) [Pubmed]
  2. Secretion in Escherichia coli and phage-display of recombinant insulin-like growth factor binding protein-2. Lucic, M.R., Forbes, B.E., Grosvenor, S.E., Carr, J.M., Wallace, J.C., Forsberg, G. J. Biotechnol. (1998) [Pubmed]
  3. Evaluation of serum insulin-like growth factor binding proteins (IGFBP) in Angus cattle divergently selected for serum IGF-I concentration. Pagan, M., Davis, M.E., Stick, D.A., Simmen, R.C., Raney, N.E., Tempelman, R.J., Ernst, C.W. Domest. Anim. Endocrinol. (2003) [Pubmed]
  4. Role of extracellular matrix in insulin-like growth factor (IGF) binding protein-2 regulation of IGF-II action in normal human osteoblasts. Conover, C.A., Khosla, S. Growth Horm. IGF Res. (2003) [Pubmed]
  5. Alanine screening mutagenesis establishes tyrosine 60 of bovine insulin-like growth factor binding protein-2 as a determinant of insulin-like growth factor binding. Hobba, G.D., Löthgren, A., Holmberg, E., Forbes, B.E., Francis, G.L., Wallace, J.C. J. Biol. Chem. (1998) [Pubmed]
  6. Insulin-like growth factor binding protein -2 and -4 messenger ribonucleic acid expression in bovine ovarian follicles: effect of gonadotropins and developmental status. Armstrong, D.G., Baxter, G., Gutierrez, C.G., Hogg, C.O., Glazyrin, A.L., Campbell, B.K., Bramley, T.A., Webb, R. Endocrinology (1998) [Pubmed]
  7. Levels of insulin-like growth factor (IGF) binding proteins, luteinizing hormone and IGF-I receptors, and steroids in dominant follicles during the first follicular wave in cattle exhibiting regular estrous cycles. Stewart, R.E., Spicer, L.J., Hamilton, T.D., Keefer, B.E., Dawson, L.J., Morgan, G.L., Echternkamp, S.E. Endocrinology (1996) [Pubmed]
  8. Inhibition of cellular proliferation and modulation of insulin-like growth factor binding proteins by retinoids in a bovine mammary epithelial cell line. Woodward, T.L., Turner, J.D., Hung, H.T., Zhao, X. J. Cell. Physiol. (1996) [Pubmed]
  9. Insulin-like growth factor-I and binding proteins 1, 2, and 3 in bovine nuclear transfer pregnancies. Ravelich, S.R., Breier, B.H., Reddy, S., Keelan, J.A., Wells, D.N., Peterson, A.J., Lee, R.S. Biol. Reprod. (2004) [Pubmed]
  10. Follicular dominance in cattle is associated with divergent patterns of ovarian gene expression for insulin-like growth factor (IGF)-I, IGF-II, and IGF binding protein-2 in dominant and subordinate follicles. Yuan, W., Bao, B., Garverick, H.A., Youngquist, R.S., Lucy, M.C. Domest. Anim. Endocrinol. (1998) [Pubmed]
  11. Effect of negative energy balance on the insulin-like growth factor system in pre-recruitment ovarian follicles of post partum dairy cows. Llewellyn, S., Fitzpatrick, R., Kenny, D.A., Murphy, J.J., Scaramuzzi, R.J., Wathes, D.C. Reproduction (2007) [Pubmed]
  12. Characterization and cloning of a bovine insulin-like growth factor-binding protein. Upton, F.Z., Szabo, L., Wallace, J.C., Ballard, F.J. J. Mol. Endocrinol. (1990) [Pubmed]
  13. Expression of messenger RNAs encoding insulin-like growth factor-I, -II, and insulin-like growth factor binding protein-2 in bovine endometrium during the estrous cycle and early pregnancy. Geisert, R.D., Lee, C.Y., Simmen, F.A., Zavy, M.T., Fliss, A.E., Bazer, F.W., Simmen, R.C. Biol. Reprod. (1991) [Pubmed]
  14. The effect of an acute energy deficit on the hormone profile of dominant follicles in dairy cows. Comin, A., Gerin, D., Cappa, A., Marchi, V., Renaville, R., Motta, M., Fazzini, U., Prandi, A. Theriogenology (2002) [Pubmed]
  15. Characterization of insulin-like growth factor-binding proteins in the uterus and conceptus during early conceptus elongation in cattle. Keller, M.L., Roberts, A.J., Seidel, G.E. Biol. Reprod. (1998) [Pubmed]
  16. Bovine oviductal and embryonic insulin-like growth factor binding proteins: possible regulators of "embryotrophic" insulin-like growth factor circuits. Winger, Q.A., de los Rios, P., Han, V.K., Armstrong, D.T., Hill, D.J., Watson, A.J. Biol. Reprod. (1997) [Pubmed]
  17. Effect of insulin-like growth factors (IGF), FSH, and leptin on IGF-binding-protein mRNA expression in bovine granulosa and theca cells: quantitative detection by real-time PCR. Voge, J.L., Aad, P.Y., Santiago, C.A., Goad, D.W., Malayer, J.R., Allen, D., Spicer, L.J. Peptides (2004) [Pubmed]
  18. Relationships among concentrations of steroids, insulin-like growth factor-I, and insulin-like growth factor binding proteins in ovarian follicular fluid of beef cattle. Echternkamp, S.E., Howard, H.J., Roberts, A.J., Grizzle, J., Wise, T. Biol. Reprod. (1994) [Pubmed]
  19. Mechanical regulation of IGF-I and IGF-binding protein gene transcription in bladder smooth muscle cells. Chaqour, B., Han, J.S., Tamura, I., Macarak, E. J. Cell. Biochem. (2002) [Pubmed]
  20. Pregnancy-associated plasma protein-A and insulin-like growth factor binding protein mRNAs in granulosa cells of dominant and subordinate follicles of preovulatory cattle. Santiago, C.A., Voge, J.L., Aad, P.Y., Allen, D.T., Stein, D.R., Malayer, J.R., Spicer, L.J. Domest. Anim. Endocrinol. (2005) [Pubmed]
  21. Regulation of IGF binding protein synthesis by a bovine mammary epithelial cell line. Cohick, W.S., Turner, J.D. J. Endocrinol. (1998) [Pubmed]
  22. Distribution of IGF-I and -II, IGF binding proteins (IGFBPs) and IGFBP mRNA in ocular fluids and tissues: potential sites of synthesis of IGFBPs in aqueous and vitreous. Arnold, D.R., Moshayedi, P., Schoen, T.J., Jones, B.E., Chader, G.J., Waldbillig, R.J. Exp. Eye Res. (1993) [Pubmed]
  23. A homologous radioimmunoassay for quantification of insulin-like growth factor-binding protein-2 in blood from cattle. Vleurick, L., Renaville, R., VandeHaar, M., Hornick, J.L., Istasse, L., Parmentier, I., Bertozzi, C., Van Eenaeme, C., Portetelle, D. J. Dairy Sci. (2000) [Pubmed]
  24. The influence of level of feeding on growth and serum insulin-like growth factor I and insulin-like growth factor-binding proteins in growing beef cattle supplemented with somatotropin. Rausch, M.I., Tripp, M.W., Govoni, K.E., Zang, W., Webert, W.J., Crooker, B.A., Hoagland, T.A., Zinn, S.A. J. Anim. Sci. (2002) [Pubmed]
  25. Enhanced expression of dihydrofolate reductase by bovine kidney epithelial cells results in altered cell morphology, IGF-I responsiveness, and IGF binding protein-3 expression. Cohick, W.S., Clemmons, D.R. J. Cell. Physiol. (1994) [Pubmed]
  26. Insulin-like growth factor (IGF) system in the bovine mammary gland and milk. Baumrucker, C.R., Erondu, N.E. Journal of mammary gland biology and neoplasia. (2000) [Pubmed]
  27. Expression of the components of the insulin-like growth factor axis across the growth-plate. Olney, R.C., Mougey, E.B. Mol. Cell. Endocrinol. (1999) [Pubmed]
  28. Regulation of insulin-like growth factor-binding proteins in serum and lymph of lactating cows by somatotropin. Cohick, W.S., McGuire, M.A., Clemmons, D.R., Bauman, D.E. Endocrinology (1992) [Pubmed]
  29. Insulin-like growth factor I and insulin-like growth factor-binding proteins in bovine serum and follicular fluid before and after the preovulatory surge of luteinizing hormone. Funston, R.N., Seidel, G.E., Klindt, J., Roberts, A.J. Biol. Reprod. (1996) [Pubmed]
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