The Insulin-Like Growth Factor-II/Mannose-6-Phosphate Receptor: Structure, Function and Differential Expression

  • Wieland Kiess
  • Andreas Hoeflich
  • Yi Yang
  • Ulrike Kessler
  • Allan Flyvbjerg
  • Bruno Barenton
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 343)


The insulin like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor is a bifunc-tional binding protein that binds lysosomal enzymes bearing the M6P recognition marker and IGF-II at distinct binding sites (45, 52). In addition, transforming growth factor (TGF) beta precursor, thyroglobulin and proliferin, a protein which is expressed in rapidly proliferating cells are also recognized by this receptor (Table 1). In avian and amphibian cells the receptor lacks the binding site for IGF-II but serves as a binding protein for M6P bearing ligands (7,9,76). Almost all mammalian cells described until today express IGF-II/M6P receptors that bind both classes of ligands, namely M6P-containing glycoproteins and IGF-II (55–59).


Lysosomal Enzyme MCF7 Mammary Carcinoma Cell MCF7 Mammary Carcinoma Trisphosphate Formation Extracytoplasmic Region 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Barlow DP, Stoeger R, Herrmann BG, Saito K, Schweifer N. The mouse IGF-2 receptor is imprinted and closely linked to the Tme locus. Nature 349:84–87 (1991)PubMedCrossRefGoogle Scholar
  2. 2.
    Beukers MW, Oh Y, Zhang H, Ling N, Rosenfeld RG. (Leu 27)-IGF-H is highly selective for the type II IGF receptor in binding, crosslinking and thymidine incorporation experiments. Endocrinology 128:1201–1203 (1991)PubMedCrossRefGoogle Scholar
  3. 3.
    Braulke T., Bresciani R., Buergisser D.M., K. von Figura. IGF-II overexpression does not affect sorting of lysosomal enzymes in NIH 3T3 cells. Biochem Biophys Res Commun 179: 108–115 (1991)PubMedCrossRefGoogle Scholar
  4. 4.
    Braulke T, Mieskes G. Role of protein phosphatases in IGF-H-stimulated M6P/IGF-II receptor redistribution. J Biol Chem. 267:17347–17353 (1992)PubMedGoogle Scholar
  5. 5.
    B_rgisser DM, Roth BV, Giger R. Mutants of human IGF-II with altered affinities for the type I and type II IGF receptor. J Biol Chem. 266:1029–1033 (1991)Google Scholar
  6. 6.
    Burguera B, Werner H, Sklar M, Shen-Orr Z, Stannard B, Roberts CT, Nissley SP, Vore SJ, Caro JF, LeRoith D. Liver regeneration is associated with increased expression of the IGF-II/M6P receptor. Molec. Endocrinol 4:1539–1545 (1990)CrossRefGoogle Scholar
  7. 7.
    Canfield WM, Kornfeld S. The chicken liver cation-independent M6P receptor lacks the high affinity binding site for IGF-II. J Biol Chem. 264: 7100–7103 (1989)PubMedGoogle Scholar
  8. 8.
    Cassella SJ, Han VK, D’Creole AJ, Svoboda ME, Van Wyk JJ. IGF-II binding to the type I somátomedin receptor. J. Biol. Chem. 261:9268–9273 (1986)Google Scholar
  9. 9.
    Clairmont KB, Czech MP. Chicken and Xenopus M6P-receptors fail to bind IGF-II. J Biol Chem. 264: 16390–16392 (1989)PubMedGoogle Scholar
  10. 10.
    Clairmont KB, Czech MR Insulin injection increases the levels of serum receptors for transferrin and IGF-II/M6P in intact rats. Endocrinology 127:1568–1573 (1990)PubMedCrossRefGoogle Scholar
  11. 11.
    Clairmont KB, Czech MP. Extracellular release as the major degradative pathway of the IGF-II/M6P receptor. J Biol Chem. 266:12131–12134 (1991)PubMedGoogle Scholar
  12. 12.
    Cormont M, Gremeaux T, Tanti JF, Van Obberghen E, Le Marchand-Brustel Y. Polymyxin B inhibits insulin-induced glucose transporter and IGF-II receptor trañslocation in isolated adipocytes. Eur. J. Biochem. 207:185–193 (1992)PubMedCrossRefGoogle Scholar
  13. 13.
    Corvera S, Folander K, Clairmont KB, Czech MP. A highly phosphorylated sübpopulation of IGF-II/M6P receptors is concentrated in a clathrin-enriched plasma membrane fraction. Proc. Natl. Acad. Sci. USA 85:7567 (1988)PubMedCrossRefGoogle Scholar
  14. 14.
    Cui S, Flyvbjerg A, Nielsen S, Kiess W, Christensen El. Distribution of IGF-II/M6P receptors in rat kidney: evidence for apical localization in proximal tubule cells. Kidney Intern. 43:796–807 (1993)CrossRefGoogle Scholar
  15. 15.
    Dahms N.M., P. Lobel, S. Kornfeld. Mannose-6-phosphate receptors and lysosomal enzyme targeting. J Biol Chem 264:12115–12118 (1989)PubMedGoogle Scholar
  16. 16.
    Damke H., Klumpermann J., von Figura K., Braulke T. Effects of Brefeldin A on the endocytic route. Redistribution of M6P/IGF-II receptors to the cell surface. J Biol Chem. 266:24829–24833 (1991)PubMedGoogle Scholar
  17. 17.
    Damke H, von Figura K, Braulke T. Simultaneous redistribution of M6P and transferrin receptors by IGFs and phorbol ester. Biochem J. 281:225–229 (1992)PubMedGoogle Scholar
  18. 18.
    Damke H, Klumperman J, von Figura K, Braulke T. Brefeldin A affects the cellular distribution of endocytic receptors differentially. Biochem Biophys. Res Commun. 185:719–727 (1992)PubMedCrossRefGoogle Scholar
  19. 19.
    DeChiara T.M., A. Efstradiadis , EJ. Robertson . A growth-deficiency phenotype in heterozygous mice carrying an IGF-II gene disrupted by targeting. Nature 345: 78–80 (1990)PubMedCrossRefGoogle Scholar
  20. 20.
    DeChiara TM, Robertson EJ, Efstradiadis A. Parental imprinting of the mouse IGF-II gene. Cell 64:849–859 (1991)PubMedCrossRefGoogle Scholar
  21. 21.
    Domeyne A, Pinset C, Montarras D, Garandel V, Rosenfeld RG, Barenton B. Preferential binding of IGF-II to a putative alpha2beta2 IGF-II receptor type in C2 myoblasts. Eur J Biochem. 208:273–279 (1992)PubMedCrossRefGoogle Scholar
  22. 22.
    Figura von K., A. Hasilik. Lysosomal enzymes and their receptors. Ann. Rev. Biochem. 55:167–193 (1986)CrossRefGoogle Scholar
  23. 23.
    Figura von K. Molecular recognition and targeting of lysosomal proteins. Curr Opinionin Biol 3:642–646 (1991)CrossRefGoogle Scholar
  24. 24.
    Florini J, Magri KA, Ewton ZA, James PL, Grindstaff K, Rotwein PS. Spontaneous differentiation of skeletal myoblasts is dependent upon autocrine secretion of IGF-II. J. Biol. Chem. 266:15917–15923 (1991)PubMedGoogle Scholar
  25. 25.
    Flyvbjerg A, Kessler U, Funk B, Dorka B, Orskov H, Kiess W. Transient increase of IGF-II/M6P receptor protein content in diabetic rat kidney and liver tissue. Diabetologia (submitted) (1993)Google Scholar
  26. 26.
    Funk B, Kessler U, Eisenmenger W, Hansmann A, Kolb H, Kiess W. Expression of the human IGF-Ü/M6P receptor during fetal life and early infancy. J. Clin Endocrinol. Metab. 75:424–431 (1992)PubMedCrossRefGoogle Scholar
  27. 27.
    Gallaher BW, Oliver MH, Eichorn K, Kessler U, Kiess W, Harding JE, Gluckman PD, Breier BH. The circulating IGF-II/M6P receptor and IGFBPs in fetal sheep plasma are regulated by glucose and insulin. Endocrinology (submitted) (1993)Google Scholar
  28. 28.
    Garafalo RS, Barenton B. Functional and immunological distinction between IGF-I receptor subtypes in KB cells. J Biol Chem 275: 7735–7738 (1992)Google Scholar
  29. 29.
    Guse A, Kiess W, Funk B, Kessler U, Berg I, Gercken G. Identification and harcterization of IGF receptors on adult rat cardiac myocytes: linkage to inositol 1,4,5 trisphosphate formation. Endocrinology 130:145–151 (1992)PubMedCrossRefGoogle Scholar
  30. 30.
    Haig D, Graham C. Genomic imprinting and the strange case of the IGF-II receptor. Cell 64:1045–1046 (1991)PubMedCrossRefGoogle Scholar
  31. 31.
    Hartmann H, Meyer-Alber A, Braulke T. Metabolic actions of IGF-II in cultured adult rat hepatocytes are not mediated through the IGF-II receptor. Diabetologia 35:216–223 (1992)PubMedCrossRefGoogle Scholar
  32. 32.
    Harvey MB, Kaye PL. IGF-II receptors are first expressed at the 2-cell stage of mouse development. Development 111:1057–1060 (1991)PubMedGoogle Scholar
  33. 33.
    Hu K-Q, Backer JM, Sahagian G, Feener EP, King GL. Modulation of the IGF-D/M6P receptor in microvascular endothelial cells by phorbol ester via protein kinase C. J Biol Chem 265:13864–13870 (1990)PubMedGoogle Scholar
  34. 34.
    Jonas HA, Cox AJ. IGF binding to the atypical insulin receptors of a human lymphoid-derived cell line (IM-9). Biochem. J. 266:737–742 (1990)PubMedGoogle Scholar
  35. 35.
    Kessler U, Aumeier S, Funk B, Kiess W. Biosynthetic labeling of beta-hexosaminidase B: inhibition of the cellular uptake of 3H hexosaminidase B by IGF-II in rat C6 glial cells. Mol Cell. Endocrinol 90:147–153 (1992)PubMedCrossRefGoogle Scholar
  36. 36.
    Kiess W, Greenstein LA, White RM, Lee L, Rechler MM, Nissley SP. Type II IGF receptor is present in rat serum. Proc Natl Acad Sci USA 84:7720–7724 (1987)PubMedCrossRefGoogle Scholar
  37. 37.
    Kiess W, Thomas CL, Greenstein L, Lee L, Sklar MM, Rechler MM, Sahagian GG, SP Nissley SP. IGF-II inhibits both the cellular uptake of beta-galactosidase and the binding of beta-galactosidase to purified IGF-II/M6P receptor. J.Biol.Chem. 264:4710–4714 (1989)PubMedGoogle Scholar
  38. 38.
    Kiess W, Thomas CL, Sklar MM, Nissley SP. Beta-galactosidase decreases the binding affinity of the IGF-II/M6P receptor for IGF-II. Eur J. Biochem 190:71–77 (1990)PubMedCrossRefGoogle Scholar
  39. 39.
    Kojima I, Nishimoto I., Iiri T, Ogata E, Rosenfeld RG. Evidence that the type II IGF receptor is coupled to calcium gating system. Biochem. Biophys. Res. Commun. 154:9 (1988)PubMedCrossRefGoogle Scholar
  40. 40.
    Kornfeld S. Structure and function of the M6P/IGF-II receptors. Ann.Rev.Biochem. 61:307–330 (1992)PubMedCrossRefGoogle Scholar
  41. 41.
    Laureys G, Barton DE, Ullrich A, Francke U. Chromosomal mapping of the gene for the type II IGF receptor/ cation-independent M6P receptor in man and mouse.Genomics 3:224–229 (1988)PubMedCrossRefGoogle Scholar
  42. 42.
    Lobel P, Fujimoto K, Ye RD, Griffiths G, Kornfeld S. Mutations in the cytoplasmic domain of the 215 kDa M6P receptor differentially alter lysosomal enzyme sorting and endocytosis.Cell 57:787 (1989)PubMedCrossRefGoogle Scholar
  43. 43.
    Lonroth P, Assmundsson K, Eden S, Enberg G, Gause I, Hall K, Smith U. Regulation of IGF-II receptors by GH and insulin in rat adipocytes. Proc. Natl. Scad. Sci. USA 84:3619 (1987)CrossRefGoogle Scholar
  44. 44.
    Lonroth P, Appell KC, Wesslau C, Cushman SW, Simpson IA, Smith U. Insulin-induced subcellular redistribution of IGF-II receptors in the rat adipose cell. Counterregulatory effects of isoproterenol, adenosine, and cAMP analogues. J Biol Chem. 263:15386 (1988)Google Scholar
  45. 45.
    MacDonald R., Pfeffer ,S.R., Coussens, L., Tepper, M.A., Brocklebank,C.M., Mole, J.E., Anderson, J.K., Chen, E., Czech, M.P., Ullrich , A. A single receptor binds both IGF-II and mannose-6-phosphate. Science 239: 1134–1136 (1988)PubMedCrossRefGoogle Scholar
  46. 46.
    MacDonald RG, Trepper MA; Clairmont KB, Perregaux SB, Czech MP. Serum form of the rat IGF-II/M6P receptor is truncated in the carboxyl-terminal domain. J Biol Chem. 264:3256–3261 (1989)PubMedGoogle Scholar
  47. 47.
    Mathieu M, Rochefort H, Barenton B, Prebois C, Vignon F. Interactions of cathepsin D and IGF-II on the IGF-II/M6P receptor in human breast cancer cells and possible consequences on mitogenic activity of IGF-II. Mol.Endocrinol. 4:1327–1335 (1990)PubMedCrossRefGoogle Scholar
  48. 48.
    Mathieu M. Vignon F, Capony F, Rochefort H. Estradiol down-regulates the M6P/IGF-II receptor gene and induces cathepsin-D in breast cancer cells: a receptor saturation mechanism to increase the secretion of lysosomal proenzymes. Mol. Endocrinology 4: 1327–1335 (1991)CrossRefGoogle Scholar
  49. 49.
    Melancon P, Glick BS, Malhotra V, Weidman PJ, Serafini T, Gleason ML, Orci L, Rothman JE. Involvement of GTP-binding Gproteins in transport through the Golgi stack. Cell 51:1053–1062 (1987)PubMedCrossRefGoogle Scholar
  50. 50.
    Minniti CP, Kohn EC, Grubb JH, Sly WS, Y. Oh, HL Miller, RG Rosenfeld, LJ Helman. The IGF-II/M6P receptor mediates IGF-II induced motility in human rhabdomyosarcoma cells. J.Biol.Chem. 267:9000–9004 (1992)PubMedGoogle Scholar
  51. 51.
    Misra P, Hintz R, Rosenfeld RG. Structural and immunological characterization of IGF-II binding to IM-9 cells. J Clin Endocrinol Metab. 63:1400 (1986)PubMedCrossRefGoogle Scholar
  52. 52.
    Morgan, D.O., J. C. Edman, D.N. Standring, V.A. Fried, M.C. Smith, R.A. Roth, W.J. Rutter. Insulin-like growth factor-II receptor as a multifunctional binding protein. Nature 329:301–307 (1987)PubMedCrossRefGoogle Scholar
  53. 53.
    Murayama Y, Okamoto T, Ogata E, Asano T, Iiri T, Katada T, Ui M, Grubb JH, Sly WS, Nishimoto I.Distinctive regulation of the functional linkage between the human cation-independent mannose-6-phosphate receptor and GTP-binding proteins by IGF II and M6P. J Biol Chem 265:17456–17462 (1990)PubMedGoogle Scholar
  54. 54.
    Nishimoto I, Ogata E, Okamoto T. Guanine nucleotide-binding protein interacting but unstimulating sequence located in IGF-II receptor. J Biol Chem 266:12747–12751 (1991)PubMedGoogle Scholar
  55. 55.
    Nissley SP, Kiess W, Sklar MM. The IGF-II/M6P receptor. In: LeRoith D, Raiszada M, (Eds.), Molecular and cellular biology of IGFs and their receptors. Plenum Press, New York, pp 359–368.(1990)Google Scholar
  56. 56.
    Nissley SP, Kiess W, Sklar MM. The IGF-II/mannose-6-phosphate receptor, in: IGFs: molecular and cellular aspects. Ed. D.LeRoith . CRC Press, Boca Raton, pp 111–150 (1991)Google Scholar
  57. 57.
    Nissley SP, Kiess W. Reciprocal modulation of binding of lysosomal enzymes and IGF-II to the M6P/IGF-II receptor. In: Molecular biology of insulin, IGFs and their receptors. Eds. D.LeRoith, MK Raizada, Plenum Press, New York, (1991)Google Scholar
  58. 58.
    Nissley SP, Kiess W. Binding of IGF-II and lysosomal enzymes to the IGF-II/M6P receptor.In: Modern concepts of IGFs. Ed. M. Spencer, pp 419–430, Elsevier Publisher, Amsterdam (1991)Google Scholar
  59. 59.
    Nissley SP, Lopeszinsky W. IGF receptors. Growth factors 5:29–43 (1991)PubMedCrossRefGoogle Scholar
  60. 60.
    Nissley P, Kiess W, Sklar MM The developmental expression of the IGF-II/M6P receptor. Molecular Reproduction &Developm (in press) (1993)Google Scholar
  61. 61.
    Nolan CM , JW Kyle , H Watanabe, WS Sly. Binding of IGF-II by human cation-independent mannose-6-phosphate receptor/IGF-II receptor expressed in receptordeficient mouse L cells. Cell Regulation 1:197–213 (1990)PubMedGoogle Scholar
  62. 62.
    Okamoto T , Katada T , Murayama Y , Ui M , Ogata E , Nishimoto I A simple structure encodes G protein-activating function of the IGF-D/mannose-6-phosphate receptor. Cell 62:709–717 (1990)PubMedCrossRefGoogle Scholar
  63. 63.
    Okamoto T, Ohkuni Y, Ogata E, Nishimoto I. Distinct mode of G protein activation due to single residue substitution of active IGF-II receptor peptide Arg2410-Lys2423: evidence for stimulation acceptor region other than C-terminus of Gialpha. Biochem Biophys Res Commun. 179:10–16 (1991)PubMedCrossRefGoogle Scholar
  64. 64.
    Pfeffer SR. Mannose-6-phosphate receptors and their role in targeting proteins to lysosomes. J Membr Biol 103:7 (1988)PubMedCrossRefGoogle Scholar
  65. 65.
    Polychronakos C, Guyda HJ, Posner BI. Increase in the type 2 IGF receptors in the rat kidney during compensatory growth. Biochem Biophys Res. Commun. 132: 418–423 (1985)PubMedCrossRefGoogle Scholar
  66. 66.
    Polychronakos C, Guyda HJ, Patel B, Posner BI.Increase in the number of type II IGF receptors during propylthiouracil-induced hyperplasia in the rat thyroid. Endocrinology 119: 1204(1986)PubMedCrossRefGoogle Scholar
  67. 67.
    Polychronakos C, Guyda HJ, Janthly U, Posner BI. Effects of M6P on receptor-mediated endocytosis of IGF-H. Endocrinology 127:1861–1866 (1990)PubMedCrossRefGoogle Scholar
  68. 68.
    Rechler MM , Nissley SP .Insulin-like growth factors. In: Sporn MB, Roberts AB,eds. Peptide growth factors and their receptors I. Handbook of Pharmacology, Heidelberg, New York, Springer Publisher; 263–367 (1990)CrossRefGoogle Scholar
  69. 69.
    Roth RA. Structure of the receptor for IGF-H: the puzzle amplified. Science 239:1269– 1271 (1988)PubMedCrossRefGoogle Scholar
  70. 70.
    Senior PV, Byrne S, Brammar WJ, Beck F. Expression of the IGF-II/M6P receptor mRNA and protein in the developing rat. Development 109:67–73 (1990)PubMedGoogle Scholar
  71. 71.
    Shier P, Watt VM. Primary structure of a putative receptor for a ligand of the insulin family. J Biol Chem. 264:14605–14608 (1989)PubMedGoogle Scholar
  72. 72.
    Tollefsen SE, Sadow JL, Rotwein P. Coordinate expression of IGF-II and its receptor during muscle differentiation. Proc. Natl Acad Sci USA 86:1543–1547 (1989)PubMedCrossRefGoogle Scholar
  73. 73.
    Werner H, Shen-Orr Z, Stannard B, Burguera B, Roberts CT, LeRoith D. Experimental diabetes increases IGF-I and IGF-H receptor concentration and gene expression in kidney. Diabetes 39:1490–1497 (1990)PubMedCrossRefGoogle Scholar
  74. 74.
    Westlund B, Dahms NM, Kornfeld S. The bovine M6P/IGF-n receptor: localization of M6P binding sites to domains 1–3 and 7–11 of the extracytoplasmic region. J. Biol. Chem. 266:23233–23239 (1991)PubMedGoogle Scholar
  75. 75.
    Willison K. Opposite imprinting of the mouse IGF-H and IGF-H receptor genes. Trends in Genetics 7:107–108 (1991)PubMedGoogle Scholar
  76. 76.
    Yang YWH, Robbins AR, Nissley SP, Rechler MM. The chick embryo fibroblast cation-independent M6P receptor is functional and immunologically related to the mammalian IGF-II/M6P receptor but does not bind IGF-II. Endocrinology 126:1177–1189(1991)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Wieland Kiess
    • 1
  • Andreas Hoeflich
    • 1
  • Yi Yang
    • 2
  • Ulrike Kessler
    • 1
  • Allan Flyvbjerg
    • 3
  • Bruno Barenton
    • 4
  1. 1.Cell Biology Laboratory, Dept. Pediatric Endocrinology, Children’s HospitalUniversity of MunichMunich 2Germany
  2. 2.Children’s HospitalMedical UniversityShanghaiPeople’s Republic of China
  3. 3.Institute of Experimental Clinical ResearchKommunehospitalet University of AarhusAarhusDenmark
  4. 4.Laboratoire de Croissance et Differenciation CellulaireINRAF-Montpellier CedexFrance

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