The Insulin-Like Growth Factor-II/Mannose 6-Phosphate Receptor

  • Constantin Polychronakos


Based on long-existing evidence (reviewed in Ref. 1), it has been known that the insulin-like growth factors (IGF-I and IGF-II) bind with high affinity to two different cell surface receptors. The type I receptor binds IGF-I with high affinity. It also binds IGF-II with somewhat lower affinity, and insulin very weakly. It has a heterotetrameric structure (Fig. 1) very similar to that of the insulin receptor, with which it shares a striking primary sequence homology. Like the insulin receptor, it consists of two identical extracellular alpha chains that contain the IGF binding domain and two identical beta chains that span the cell membrane and whose cytoplasmic domain, like that of insulin, displays ligand-activated tyrosine kinase activity, believed to be important in the transmission of the biologic effects of the IGFs2.


Lysosomal Enzyme Insulin Receptor Kinase Endocytic Tracer Heterotetrameric Structure Polypeptide Hormone Receptor 
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  1. 1.
    Rechler M.M. and Nissley S.P. (1985) Receptors for insulinlike growth factors. In: Polypeptide Hormone Receptors, Posner B.I. (ed), Toronto, Marcel Dekker, Inc., p.227–297.Google Scholar
  2. 2.
    Zick, Y., Sasaki, N., Rees-Jones, R. N., Grumberger, G., Petri, S. P., Rechler, M., 1984, Insulin-like growth factor-I (IGF-I) stimulates tyrosine kinase activity in purified receptor from rat liver cell line, Biochem Biophvs Res Comm, 119:6.CrossRefGoogle Scholar
  3. 3.
    Ewton, D. Z., Falen, S. L., 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 repector, Endocrinology, 120:115.PubMedCrossRefGoogle Scholar
  4. 4.
    Rosenfeld R.G., Conover CA., Hodges D., Lee P.D.K., Misra P., Hintz R.L., Li C.H. 1987 Heterogeneity of IGF-I affinity for the IGF-II receptor Comparison of natural, synthetic and recombinant DNA-derived IGF-I. Biochem Biophys Res Comm. 143:199PubMedCrossRefGoogle Scholar
  5. 5.
    Barenton B., Guyda H.J., Goodyer C.G., Polycrhonakos C, Posner B.I. 1987 Specificity of IGF-II binding to type II IGF receptors in rabbit mammary gland and hypohysectomized rat liver Biochem Biophys Res Comm. 149:555PubMedCrossRefGoogle Scholar
  6. 6.
    Morgan DO, Edman JC, Standring DN, Fried VA, Smith MC, Roth RA, Rutter WJ 1987 Insulin-like growth factor II receptor as a multifunctional binding protein. Nature 329:301PubMedCrossRefGoogle Scholar
  7. 7.
    MacDonald RG, Pfeffer SR, Coussens L, Tepper MA, Brocklebank CM, Mole JE, Anderson JK, Chen E, Czech MP, Ullrich A 1988 A single receptor binds both insulin-like growth factor II and mannose-6-phosphate. Science 239:1134PubMedCrossRefGoogle Scholar
  8. 8.
    Kornfeld, S., 1987, Trafficking of lysosomal enzymes, FASEB J, 1:462.PubMedGoogle Scholar
  9. 9.
    Von Figura K., Hasilik A. 1986 Lysosomal enzymes and their receptors. Ann Rev Biochem 55:167CrossRefGoogle Scholar
  10. 10.
    Tong PY, Tollefsen SE, Kornfeld S 1988 The cation-independent mannose 6-phos-phate receptor binds insulin-like growth factor II. J Biol Chem 263:2585PubMedGoogle Scholar
  11. 11.
    Braulke T., Causin C, Waheed A., Junghans U., Hasilik A., Maly P., Humbel R., von Figura K. 1987 Mannose 6-phosphate/IGF-II receptor: Distinct binding sites for mannose 6-phosphate and IGF-II. Biochem Biophys Res Comm. 150:1287CrossRefGoogle Scholar
  12. 12.
    Kiess W., Blickenstaff G.D., Sklar M.M., Thomas C.L., Nissley S.P., Sahagian G.G. 1988 Biochemical evidence that the type II IGF receptor is identical to the mannose 6-phosphate receptor. J Biol Chem 263:9339PubMedGoogle Scholar
  13. 13.
    Roth R.A, Stover C, Hari J, Morgan D.O, Smith MC, Sara V, Fried V.A. 1987 Interactions of the receptor for insulin-like growth factor II with mannose-6-phosphate and antibodies to the mannose-6-phosphate receptor. Biochem Biophys Res Commun 149:600 PubMedCrossRefGoogle Scholar
  14. 14.
    Adams, S. O., Nissley, S. P., Kasuga, M., Foley, T. P., Rechler, M. M., 1983, Receptors for insulin-like growth factors and growth effects of multiplication-stimulating activity (rat insulin-like growth factor II) in rat embryo fibroblasts, Endocrinology. 112:971.PubMedCrossRefGoogle Scholar
  15. 15.
    Bhaumick B., Bala R.M. 1987 Receptors for IGF-I and II in developing embryonic mouse limb bud Biochim Biophys Acta 927:117PubMedCrossRefGoogle Scholar
  16. 16.
    Sklar, M. M., Kiess, W., Thomas, C. L., Lee, L., Nissley, S. P., 1988, The rat insulin-like growth factor-II (IGF-II)/mannose-6-phosphate (M6P) receptor is developmentally regulated in multiple tissues, 70th Annual Meeting of the Endocrine Society, New Orleans, Louisana, Abstract #516.Google Scholar
  17. 17.
    Alexandrides T., Smith R.J. (1987) Distinct patterns of expression of receptors for insulin, IGF-I and IGF-II in skeletal muscle during development. Abstract #805, Endocrine Society Meeting, Indianapolis 1987.Google Scholar
  18. 18.
    Lee, S. J., Nathans, D., 1988, Proliferin secreted by cultured cells binds to mannose 6-phosphate receptors, J Biol Chem. 263:3521.PubMedGoogle Scholar
  19. 19.
    Adams, S. O., Nissley, S. P., Handwerger, S., Rechler M., 1983, Developmental patterns of of IGF-I and II synthesis and regulation in rat fibroblasts, Nature. 302:150.PubMedCrossRefGoogle Scholar
  20. 20.
    Kiess, W., Greenstein, L. A., Lee, L., White, R. M., Rechler, M. M., Nissley, S. P., 1987, The type II insulin-like growth factor (IGF) receptor is present in rat serum, Proc Natl Acad Sci USA. 84:7720.PubMedCrossRefGoogle Scholar
  21. 21.
    Gelato, M. C., Kiess, W., Lee, L., Malozowski, S., Rechler, M. M., Nissley, P., 1988, The insulin-like growth factor II/mannose-6-phosphate receptor is present in monkey serum, J Clin Endocrinol Metab. 67: 669.PubMedCrossRefGoogle Scholar
  22. 22.
    Causin, C., Waheed, A., Braulke, T., Junghans, U., Maly, P., Humbel, R.E., von Figura, K., 1988, Mannose 6-phosphate/insulin-like growth factor II-binding proteins in human serum and urine. Their relation to the mannose-6-phosphate/insulin-like growth factor II receptor, Biochem J, 252:795.PubMedGoogle Scholar
  23. 23.
    MacDonald, R. G., Tepper, M. A., Clairmont, K. B., Perregaux, S. B., Brocklebank C. M., Czech, M. P., 1988, Antipeptide antibodies as domain-specific probes for cellular and serum forms of the insulin-like growth factor-II/mannose-6-phosphate receptor, 40th Annual Meeting ADA. New Orleans. Louisana. Abstract #34.Google Scholar
  24. 24.
    Polychronakos C., Guyda H.J., Patel B., Posner B.I. 1986 Increase in the number of type II IGF receptors during propylthiouracilinduced hyperplasia in the rat thyroid. Endocrinology 119:1204PubMedCrossRefGoogle Scholar
  25. 25.
    Polychronakos C., Guyda H.J., Posner B.I., 1985 Increase in the type 2 IGF receptors in the rat kidney during compensatory growth. Biochem Biophys Res Commun 132:148CrossRefGoogle Scholar
  26. 26.
    Mottola, C., Czech, M. P., 1984, The type II IGF recptor does not mediate increased DNA synthesis in H-35 hepatoma cells, J Biol Chem 259:12705.PubMedGoogle Scholar
  27. 27.
    Kiess, W., Haskell, J. F., Lee, L., Greenstein, L. A., Miller, B. E., Aarons, A. L., Rechler, M. M., Nissley, S. P., 1987, An antibody that blocks insulinlike growth factor (IGF) binding to the type II IGF receptor is neither an agonist nor an inhibitor of IGF-stimulated biologic responses in L6 myoblasts, J Biol Chem. 262:12745.PubMedGoogle Scholar
  28. 28.
    Furlanetto, R.W., DiCarlo, J. N., Wisehart, C., 1987, The type II insulinlike growth factor receptor does not mediate deoxyribonucleic acid synthesis in human fibroblasts, J Clin Endocrinol Metab. 64:1142.PubMedCrossRefGoogle Scholar
  29. 29.
    Conover C.A., Misra P., Hint Z R.L., Rosenfeld R.G. 1986 Effect of an anti-IGF-I receptor antibody on IGF-II stimulation of DNA synthesis in human fibroblasts Biochem Biophys Res Commun 139:501PubMedCrossRefGoogle Scholar
  30. 30.
    Kadowaki, T., Koyasu, S., Nishida, E., Sakai, H., Takaku, F., Yahara, I., Kasuga, M., 1986, Insulin-like growth factors, insulin, and epidermal growth factor cause rapid cytoskeletal reorganization in KB cells, J Biol Chem. 261:16141.PubMedGoogle Scholar
  31. 31.
    Kojima, I., Nishimoto, I., Taroh, I., Ogata, E., Rosenfeld, R., 1988, Evidence that the type II IGF receptor is coupled to calcium gating system, Biochem Biophys Res Commun. 154:9.PubMedCrossRefGoogle Scholar
  32. 32.
    Hari J, Pierce S.B, Morgan D.O, Sara V, Smith M.C, Roth R.A (1987) The receptor for IGF-II mediates an insulin-like response. EMBO J 6:3367PubMedGoogle Scholar
  33. 33.
    Nishimoto, I., Yutaka, H., Etsuro, O., Kojima, I., 1987, Insulin-like growth factor II stimulates calcium influx in competent BALB/c 3T3 cells primed with epidermal growth factor, J Biol Chem, 262:12120.PubMedGoogle Scholar
  34. 34.
    Lobel P., Dahms N. M., Breitmeyer J., Chirgwin J. M., Kornfeld, S. 1987, Cloning of the bovine 215-kDa cation-independent mannose 6-phosphate receptor, Proc Natl Acad Sci USA. 84:2233.PubMedCrossRefGoogle Scholar
  35. 35.
    Feramisco, J. R., Glass, D. B., Krebs, E. G., 1980, Optimal spatial requirements for the location of basic residues in peptide substrates for the cyclic AMP-dependent protein kinase, J Biol Chem, 255:4240.PubMedGoogle Scholar
  36. 36.
    Haskell J.F., Nissley S.P., Rechler M.M., Sasaki N., Greenstein L., Lee L. 1985 Biochem Biophys Res Commun 130:793PubMedCrossRefGoogle Scholar
  37. 37.
    Corvera S., Roach, P.J., De Paoli-Roach A.A., Czech M.P. 1986 Insulin action inhibits IGF-II receptor phosphorylation in H-35 hepatoma cells. J Biol Chem 263:3116Google Scholar
  38. 38.
    Oshima, A., Nolan, C. M., Kyle, J. W., Grubb, J., Sly, W. S., 1988, The human cation-independent mannose 6-phosphate receptor. Cloning and sequence of the full-length cDNA and expression of functional receptor in COS cells, J Biol Chem. 263:2553.PubMedGoogle Scholar
  39. 39.
    Dahms, N. M., Lobel, P., Breitmeyer, J., Chirgwin, J.M., Kornfeld, S., 1987, 46 kD mannose 6-phosphate receptor: cloning, expression, and homology to the 215 kD mannose 6-phosphate receptor, Cell. 50:181.PubMedCrossRefGoogle Scholar
  40. 40.
    Kornfeld, S. Trafficking of lysosomal enzymes in normal and disease states, 1986, J Clin Invest. 77:1.PubMedCrossRefGoogle Scholar
  41. 41.
    Reitman M.L., Kornfeld S. 1981 Lysosomal enzyme targeting: N-acetyl-glucosaminylphosphotransferase selectively phosphorylates native lysosomal enzymes. J Biol Chem 256:11977PubMedGoogle Scholar
  42. 42.
    Lang, L., Reitman, M. L., Tang, J., Roberts, R. M., Kornfeld, S., 1984, Lysosomal enzyme phosphorylation. Recognition of a protein-dependent determinant allows specific phosphorylation of oligosaccharides present on lysosomal enzymes, J Biol Chem. 259:14663.PubMedGoogle Scholar
  43. 43.
    Griffiths, G., Hoflack, B., Simons, K., Mellman, I., Kornfeld, S., 1988, The mannose 6-phosphate receptor and the biogenesis of lysosomes, Cell. 52:329.PubMedCrossRefGoogle Scholar
  44. 44.
    Posner, B.I., Khan M.N., and Bergeron J.M., Receptor-mediated uptake of peptide hormones and other ligands, in: “Polypeptide Hormone Receptors,” Marcel Dekker, Inc., New York (1985).Google Scholar
  45. 45.
    Basu, S. K, Goldstein, J. L., Anderson, R. G. W., Brown, M. S., 1981, Monensin interrupts the recycling of low density lipoprotein receptors in human fibroblasts, Cell 93:493 CrossRefGoogle Scholar
  46. 46.
    Brown, W.J., Goodhouse, J., Farquhar, M.G., 1986, Mannose-6 phosphate receptors for lysosomal enzymes cycle between the Golgi complex and endosomes, J Cell Biol. 103:1235.PubMedCrossRefGoogle Scholar
  47. 47.
    Fischer HD, Gonzalez-Noriega A, Sly WS 1980 B-glucuronidase binding to phos-phomannosyl-enzyme receptors in membranes from human and rat tissues. J Biol Chem 255:5069PubMedGoogle Scholar
  48. 48.
    Oka, Y., Czech, M.P., 1986, The type II insulin-like growth factor receptor is internalized and recycles in the absence of ligand. J Biol Chem. 261:909013.Google Scholar
  49. 49.
    Braulke, T., Gartung, C., Hasilik, A., Von Figura, K., 1987, Is movement of mannose 6-phosphate-specific receptor triggered by binding of lysosomal enzymes? J Cell Biol, 104:1735.PubMedCrossRefGoogle Scholar
  50. 50.
    Vignon, F. et al., 1983, Autocrine stimulation of the MCF-7 breast cancer cells by the estrogen regulated 52K protein, Endocrinology. 118:1537.CrossRefGoogle Scholar
  51. 51.
    Saunders, P.T., Renegar, R. H., Raub, T.J., Baumbach, G. A., Atkinson, P. H., Bazer, F. W., Roberts, R. M., 1985, The carbohydrate structure of porcine uteroferrin and the role of the high mannose chains in promoting uptake by the reticuloendothelial cells of the fetal liver, J Biol Chem, 260:3658.PubMedGoogle Scholar
  52. 52.
    Sahagian, GG, Neufeld EF 1983 Biosynthesis and turnover of the mannose 6-phosphate receptor in cultured Chinese hamster ovary cells. J Biol Chem 258:7121PubMedGoogle Scholar
  53. 53.
    Sahagian G.G. The Mannose 6-Phosphate receptor. Action, biosynthesis and translocation. Biol Cell 51:207Google Scholar
  54. 54.
    Pfeffer, S. R., 1986, The endosomal concentration of a M6P receptor is unchanged in the absence of ligand synthesis, J Cell Biol. 105:229.CrossRefGoogle Scholar
  55. 55.
    Wardzala, L. J., Simpson, I. A., Rechler, M. M., Cushman, S. W., 1984, Potential mechanism of the stimulatory action of insulin on IGF-II binding to the isolated rat adipose cell, J Biol Chem. 259:8378.PubMedGoogle Scholar
  56. 56.
    Corvera, S., Folander, K., Clairmont, K.B., Czech, M.P., 1988, A highly phos-phorylated subpopulation of insulin-like growth factor II/mannose 6-phos-phate receptors is concentrated in a clathrin-enriched plasma membrane fraction, Proc Natl Acad Sci USA. 85:7567.PubMedCrossRefGoogle Scholar
  57. 57.
    Kadota S., Fantus I.G., Deragon G., Guyda H.J., Posner B.I. 1987 Stimulation of IGF-II receptor binding and insulin receptor kinase activity in rat adipocytes. J Biol Chem 262:8252PubMedGoogle Scholar
  58. 58.
    Polychronakos, C., Piscina, R., Guyda, H., Mannose-6-phosphate increases the affinity of the insulin-like growth factor II for its receptor on rat liver microsomes, Abstract #900, 70th Annual Meeting of the Endocrine Society, New Orleans 1988 Google Scholar
  59. 59.
    Polychronakos C., Guyda H.J., Posner B.I. 1988 Mannose 6-phosphate increases IGF-II receptor binding by displacing endogenous phosphomannosylated ligands. Biochem Biophys Res Commun 157:632PubMedCrossRefGoogle Scholar
  60. 60.
    Kiess, W., Sklar, M. M., Thomas, C. L., Lee, L., Nissley, S. P., Insulin-like growth factor II (IGF-II) inhibits binding of beta calactosidase to the IGF-II/mannose-6-phosphate (M6P) receptor, Abstract #899, 70th Annual Meeting of the Endocrine Society. New Orleans. 1988 Google Scholar
  61. 61.
    Polychronakos C., Piscina R. 1988 Endocytosis of receptor-bound IGF-II is enhanced by mannose 6-phosphate in IM9 cells. Endocrinology 123:2943PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Constantin Polychronakos
    • 1
  1. 1.The Protein and Polypeptide Hormone Laboratory, Department of PediatricsMcGill UniversityMontrealCanada

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