Summary
Insulin-like growth factor II (IGF-II) belongs to the insulin family of peptides and acts as a growth factor in many fetal tissues and tumors. The gene expression of IGF-II is initiated at three different promoters which gives rise to multiple transcripts. In a human rhabdomyosarcoma cell line IN 157 IGF-II mRNAs of 6.0-kb, 4.8-kb, and 4.2-kb are present. Fractionation of cellular extracts on sucrose gradients and Northern blot analysis showed that only the 4.8-kb mRNA was associated with polysomes, whereas the other transcripts co-sedimented with monosomal particles. This suggests that only the 4.8-kb mRNA is translated to IGF-II. The cell line secretes two forms of immunoreactive and bioactive IGF-II to the medium of molecular size 10 kd and 7.5 kd which may be involved in autocrine control of cell growth. IGF-II binds to two receptors on the surface of many cell types: the IGF-I receptor and the mannose-6-phosphate (Man-6-P)/IGF-ll receptor. There is consensus that the cellular effects of IGF-II are mediated by the IGF-I receptor via activation of its intrinsic tyrosine kinase. The Man-6-P/IGF-ll receptor is involved in endocytosis of lysosomal enzymes and IGF-II. In selected cell types, however, Man-6-P induces cellular responses. We have studied rat brain neuronal precursor cells where Man-6-P acted as a mitogen suggesting that phosphomannosylated proteins may act as growth factors via the Man-6-P/IGF-ll receptor. In conclusion, the gene expression and mechanism of action of IGF-II is very complex suggesting that its biological actions can be regulated at different levels including the transcription, translation, posttranslational processing, receptor binding and intracellular signalling.
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References
Andersen, A. S., Kjeldsen, T., Wiberg, F. C., Christensen, P.M., Rasmussen J. S., Norris, K., Møller, K. B., and Møller N. P. H., 1990, Changing of the insulin receptor to possess insulin-like growth factor I ligand-specificity. Biochemistry, in print.
Auletta, M., Nielsen, F. C, and Gammeltoft, S., 1990, Receptor-mediated endocytosis and degradation of insulin-like growth factors in neonatal rat astrocytes. J. Neuroscience Research, submitted.
Ballotti, R., Nielsen, F. C, Pringle, N., Kowalski, A., Richardson, W. D., Van Obberghen, E., and Gammeltoft, S., 1987, Insulin-like growth factor I in cultured rat astrocytes: expression of the gene, and receptor tyrosine kinase. EMBO J.. 6:3633.
Baumbach, G. A., Saunders, P. T. K., Bazer, F. W., and Roberts, R. M., 1984, Uteroferrin has N-asparagine-linked high-mannose-type oligosaccharides that contain mannose-6-phosphate. Proc. Natl. Acad. Sci. USA. 81: 2985.
Beguinot, F., Kahn, C. R., Moses, A. C., and Smith, R. J., 1985, Distinct biologically active receptors for insulin, insulin-like growth factor I, and insulin-like growth factor II in cultured skeletal muscle cells. J. Biol. Chem.. 260:15892.
Blundell, T. L, Bedarkar, S., Rinderknecht, E., and Humbel, R. E., 1978, Insulinlike growth factor: a model for tertiary structure accounting for immunoreactivity and receptor binding. Proc. Natl. Acad. Sci. USA. 75:180.
Braulke, T., Tippmer, S., Neher, E., and Von Figura, K., 1989, Regulation of the mannose 6-phosphate/IGF II receptor expression at the cell surface by mannose 6-phosphate, insulin like growth factors and epidermal growth factor. EMBO J.. 8:686.
Corvera, S., and Czech, M. P., 1985, Mechanism of insulin action on membrane protein recycling: a selective decrease in the phosphorylation state of insulin-like growth factor II receptors in the cell surface membrane. Proc. Natl. Acad. Sci. USA. 82:7314.
Czech, M. P., 1989, Signal transmission by the insulin-like growth factors. Cell, 59:235.
Dahms, N. M., Lobel, P., and Komfeld, S., 1989, Mannose 6-phosphate receptors and lysosomal enzyme targeting. J. Biol. Chem., 264:12115.
Daughaday, W. H., Rotwein, P., 1989, Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum and tissue concentrations. Endocrine Rev., 10:68.
de Pagter-Holthuizen, P., Jansen, M., van der Kammen, R. A., van Schaik, F. M. A., and Sussenbach, J. S., 1988, Differential expression of the human insulin-like growth factor II gene. Characterization of the IGF-II mRNAs and mRNA encoding a putative IGF-ll-associated protein. Biochim. Biophys. Acta. 950:282.
Ewton, D. Z., Falen, S. L, and Florini, J. R., 1987, The type II insulin-like growth factor (IGF) receptor has low affinity for IGF-I analogs: Pleiotypic actions of IGFs on myoblasts are apparently mediated by the type I receptor. Endocrinology. 120:115.
Faust, P. L, Chirgwin, J. M., and Komfeld, S., 1987,Renin, a secretory glycoprotein, acquires phosphomannosyl residues. J. Cell Biol., 105:1947.
Flier, J. S., Usher, P. A., Moses, A. C, 1986, Monoclonal antibody to the type I insulin-like growth factor (IGF-I) receptor blocks IGF-I receptor-mediated DNA synthesis: clarification of the mitogenic mechanisms of IGF-I and insulin in human skin fibroblasts. Proc. Natl. Acad. Sci. USA. 83:664.
Froesch, E. R., Schmid, C., Schwander, J., and Zapf, J., 1986, Actions of insulin-like growth factors. Ann. Rev. Physiol.. 47:443.
Frunzio, R., Chiariotti, L, Brown, A. L, Graham, D. E., Rechler, M. M., and Bruni, C. B., 1986, Structure and expression of the rat insulin-like growth factor II (rIGF-ll) gene. J. Biol. Chem.. 261:138.
Gammeltoft, S., 1989, Insulin-like growth factors and insulin: gene expression, receptors and biological actions,in: “Peptide hormones as prohormones”, Martinez, ed., Ellis Horwood Limited, pp. 176–210.
Gammeltoft, S., and van Obberghen, E., 1986, Protein kinase activity of the insulin receptor. Biochem. J.. 235:1.
Gammeltoft, S., Haselbacher, G. K., Humbel, R. E., Fehlmann, M., and Van Obberghen, E., 1985, Two types of receptor for insulin-like growth factors in mammalian brain. EMBO J, 4:3407.
Gray, A., Tarn, A. W., Dull, T. J., Hayflick, J., Pintar, J., Cavanee, W. K., Koufos, A., and Ullrich, A., 1987, Tissue-specific and developmentally regulated transcription of the insulin-like growth factor 2 gene. DNA. 6:283.
Grey, V., Rouyer-Fessard, C., Gammeltoft, S., Bourque, M., Morin, C., and Laburthe, M., 1991, IGF-ll/Man-6-P receptors are transiently increased in the rat distal intestinal epithelium after resection. Mol. Cell. Endocrinol.. in print.
Hari, J., Pierce, S. B., Morgan, D. O., Sara, V., Smith, M. C., and Roth, R. A., 1987, The receptor for insulin-like growth factor II mediates an insulin-like response. EMBO J.. 6:3367.
Haselbacher, G. K., and Humbel, R., 1982, Evidence for two species of insulinlike growth factor II (IGF-II and “big” IGF-II) in human spinal fluid. Endocrinology. 110:1822.
Hedley, P. E., Dalin, A. M., Engstromm, W., 1989, Developmental regulation of insulin like growth factor II gene expression in the pig. Cell Biol. Int. Reports. 13:857.
Herzog, V., Neumuller, W., Holzmann, B., 1987, Thyroglobulin, the major and obligatory exportable protein of thyroid follicle cells, carries the lysosomal recognition marker mannose-6-phosphate. EMBO J, 6:555.
Humbel, R. E., 1984, Insulin-like growth factors, somatomedins, and multiplication stimulating activity: chemistry, in: “Hormonal proteins and peptides”, C.H. Li, ed., Academic Press, New York, pp. 57–59.
Hylka, V. W., Teplow, D. B., Kent, S. B. H, and Straus, D. S.,1985, Identification of a peptide fragment from the carboxyl-terminal extension region (E-domain) of rat proinsulin-like growth factor-ll. J. Biol. Chem., 260:417.
Kiess, W., Haskell, J. F., Lee, L, Greenstein, L. A., Miller, B. E., Aarons, A. L., Rechler, M. M., and Nissley, S. P., 1987, An antibody that blocks insulinlike growth factor (IGF) binding to the type II IGF receptor is neither an antagonist nor an inhibitor of IGF-stimulated biologic responses in L6 myoblasts. J. Biol. Chem., 262:12745.
Lammers, R., Gray, Alane, Schlessinger, J., and Ullrich A., 1989, Differential signalling potential of insulin-and IGF-1 -receptor cytoplasmic domains. EMBO J, 8:1369.
Lee, S.-J., and Nathans, D., 1988, Proliferin secreted by cultured cells binds to mannose 6-phosphate receptors. J. Biol. Chem.. 263:3521.
Marquardt, H., Todaro, G. J., Hendersen, L. E., and Oroszlan, S., 1981, Purification and primary structure of a polypeptide with multiplication-stimulating activity from rat liver cell cultures. J. Biol. Chem.. 256:6859.
Morgan, D. O., Edman, J. C., Standring, D. N., Fried, V. A., Smith, M.C., Roth, R. A., and Rutter, W. J., 1987, Insulin-like growth fartor II receptor as a multifunctional binding protein. Nature. 329:301.
Nielsen, F. C., and Gammeltoft, S., 1988, Insulin-like growth factors are mitogens for rat pheochromocytoma PC 12 cells. Biochem. and Biophys. Res. Com., 154:1018.
Nielsen, F. C., and Gammeltoft, S., 1990, Mannose-6-phosphate stimulates proliferation of neuronal precursor cells. FEBS Letters. 262:142.
Nielsen, F. C., Gammeltoft, S., and Christiansen, J., 1990,Translational discrimination of mRNAs coding for human insulin-like growth factor II. J. Biol. Chem.. 265: 13431.
Nielsen, F. C., Wang, E., and Gammeltoft, S., 1990, Receptor binding, endocytosis, and mitogenesis of insulin-like growth factors I and II infetal rat brain neurons. J. Neurochem.. in press.
Nielsen, F. C., Haselbacher, G. K., and Gammeltoft, S., 1991, Biosynthesis of insulin-like growth factor II in a human rhabdomyosarcoma cell line. Mol. Cell. Endocrinol., submitted.
Nishimoto, I., Hata, Y., Ogata, E., and Kojuma, I., 1987, Insulin-like growth factor II stimulates calcium influx in compentent BALB/c 3T3 cells primed with epidermal growth factor. J. Biol. Chem., 262:12120.
Oka, Y., Rozek, L. M., and Czech, M. P., 1985, Direct demonstration of rapid insulin-like growth factor II receptor internalizatioand recycling in rat adipocytes. J. Biol. Chem.. 260:9435.
Okamoto, T., Katada, T., Murayama, Y., Ui, M., Ogata, E., and Nishimoto, I, 1990, A simple structure encodes G protein-activating function of the IGF-ll/Mannose 6-phosphate receptor. Cell, 62:709.
Polychronakos, C., Guyda, H. J., Patel, B., and Posner B. I., 1986, Increase in the number of type II insulin-like growth factor receptors during propylthiouracil-induced hyperplasia in the rat thyroid. Endocrinology. 119:1204.
Purchio, A. F., Cooper, J. A., Brunner, A. M., Lioubin, M. N., Gentry, L. E., Kovacina, K. S., Roth, R. A., and Marquardt, H., 1988, Identification of Mannose 6-phosphate in two asparagine-linked sugar chains of recombinant transforming growth factor-β1 precursor. J. Biol. Chem.. 263:14211.
Rosen, O. M., 1990, Insulin-receptor approaches to studying protein kinase domain. Diabetes Care. 13:1990.
Roth, R. A., 1988, Structure of the receptor for insulin-like growth factor II: the puzzle amplified. Science. 239:1269.
Schwartz, T. W., 1986, The processing of peptide precursors. Proline-directed arginyl cleavage and other monobasic processing mechanisms. FEBS Lett., 200:1.
Scott, C. D., and Baxter, R. C., 1990, Insulin-like growth factor-ll/Mannose-6-phosphate receptors are increased in hepatocytes from regenerating rat liver. Endocrinology. 126:2543.
Steiner, D. F., Quinn, P. S., Chan, S. J., Marsh, J., and Tager, H. S., 1980, Processing mechanisms in the biosynthesis of proteins. Ann. NY Acad. Sci., 343:1.
Sussenbach, J. S., 1989, The gene structure of the insulin-like growth factor family. Progress in Growth Factor Res , 1:331
Ullrich, A., Bell, J. R., Chen, E. Y., Herrera, R., Petruzelli, L. M., Dull, T. J., Gray, A., Coussens, L, Liao, Y.-C., Tsubokawa, M., Mason, A., Seeburg, P. H., Grunfeld, C., Rosen, O. M., and Ramachandran, J., 1985, Human insulin receptor and its relationship to the tyrosine kianse family of oncogenes. Nature. 313:756.
Ullrich, A., Gray, A., Tam, A. W., Yang-Feng, T., Tsubokawa, M., Collins, C., Henzel, W., Le Bon, T., Kathuria, S., Chen, E., Jacobs, S., Francke, U., Ramachandran, J., and Fujita-Yamaguchi, Y., 1986, Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specifiqity. EMBOJ,, 5:2503.
Ullrich, A., and Schlessinger, J., 1990, Signal transduction by receptors with tyrosine kinase activity. Cell. 61:203.
Verland, S., and Gammeltoft, S., 1989, Functional receptors for insulin-like growth factors I and II in rat thymocytes and mouse thymoma cells. Mol. Cel. Endocrinol.. 67:207.
Verland, S., Nielsen, F: C., and Gammeltoft, S., 1990, Gamma-interferon induces expression of mannose-6-phosphate/insulin-like growth factor II receptor gene in rat thymocytes. Endocrinology, submitted.
Von Figura, K., and Hasilik, A., 1986, Lysosomal enzymes and their receptors. Ann. Rev. Biochem., 55:167.
Yang, Y. W. H., Romanus, J. A., Liu, T. Y., Nissley, S. P., and Rechler, M. M., 1985a, Biosynthesis of rat insulin-like growth factor II. I. Immunochemical demonstration of A ~ 20-kilodalton biosynthesis precursor of rat insulinlike growth factor II in metabolically labelled BRL-3A rat liver cells. J. Biol. Chem.. 260:2570.
Yu K.-T., Peters, M. A., and Czech, M. P., 1986, Similar control mechanisms regulate the insulin and type I insulin-like growth factor receptor kinases. J. Biol. Chem.. 261:11349.
Zumstein, P. P., Lüthi, C., and Humbel, R. E., 1985, Amino acid sequence of a variant pro-form of insulin-like growth factor II. Proc. Natl. Acad. Sci.USA. 82:3169.
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Gammeltoft, S., Christiansen, J., Nielsen, F.C., Verland, S. (1991). Insulin-Like Growth Factor II: Complexity of Biosynthesis and Receptor Binding. In: Raizada, M.K., LeRoith, D. (eds) Molecular Biology and Physiology of Insulin and Insulin-Like Growth Factors. Advances in Experimental Medicine and Biology, vol 293. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5949-4_4
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