New Perspectives in Shh Signalling?

Part of the Molecular Biology Intelligence Unit book series (MBIU)


The Shh-Ptc signalling pathway and its components have been the subject of much research. Previous chapters of this book have illustrated the importance of this pathway and its activation in many aspects of development, regeneration of adult organs, and pathology. The role of Ptc as the primary receptor for Shh and its analogues has been emphasised in these chapters. However, there is mounting evidence that megalin [also known as glycoprotein 330 (gp330) or low-density lipoprotein receptor-related protein 2 (LPR2)], a 600kDa transmembrane glycoprotein belonging to the low density lipoprotein (LDL) receptor family, may be a second receptor for Shh. In this chapter I shall review this evidence; but I shall preface this discussion with an outline of the known properties and biological functions of megalin.


Lung Development Heymann Nephritis Pulmonary Development LDLR Family Megalin Expression 
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  1. 1.
    Kerjaschki D, Farquhar MG. The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proc Nad Acad Sci USA 1982; 79(18):5557–5561.CrossRefGoogle Scholar
  2. 2.
    Saito A, Pietromonaco S, Loo AK et al. Complete cloning and sequencing of rat gp330/‘megalin,’ a distinctive member of the low density lipoprotein receptor gene family. Proc Natl Acad Sci USA 1994; 91:9725–9729.PubMedCrossRefGoogle Scholar
  3. 3.
    Hjälm G, Murray E, Crumley G et al. Cloning and sequencing of human gp330, a Ca2+-binding receptor with potential intracellular signaling properties. Eur J Biochem 1996; 239:132–137.PubMedCrossRefGoogle Scholar
  4. 4.
    Xia YR, Bachinsky DR, Smith JA et al. Mapping of the glycoprotein 330 (Gp330) gene to mouse chromosome 2. Genomics 1993; 17:780–781.PubMedCrossRefGoogle Scholar
  5. 5.
    Kounnas MZ, Haudenschild CC, Strickland DK et al. Immunological localization of glycoprotein 330, low density lipoprotein receptor related protein and 39 kDa receptor associated protein in embryonic mouse tissues. In Vivo 1994; 8:343–352.PubMedGoogle Scholar
  6. 6.
    Lundgren S, Carling T, Hjalm G et al. Tissue distribution of human gp330/megalin, a putative Ca(2+)-sensing protein. J Histochem Cytochem 1997; 45:383–392.PubMedGoogle Scholar
  7. 7.
    Yammani RR, Seetharam S, Seetharam B. Cubilin and megalin expression and their interaction in the rat intestine: Effect of thyroidectomy. Am J Physiol Endocrinol Metab 2001; 281:E900–E907.PubMedGoogle Scholar
  8. 8.
    Van Praet O, Argraves WS, Morales CR. Coexpression and interaction of cubilin and megalin in the adult male rat reproductive system. Mol Reprod Dev 2003; 64:129–135.PubMedCrossRefGoogle Scholar
  9. 9.
    Argraves WS, Morales CR. Immunolocalization of cubilin, megalin, apolipoprotein J, and apolipoprotein A-I in the uterus and oviduct. Mol Reprod Dev 2004; 69:419–427.PubMedCrossRefGoogle Scholar
  10. 10.
    Erranz B, Miquel JF, Argraves WS et al. Megalin and cubilin expression in gallbladder epithelium and regulation by bile acids. J Lipid Res 2004; 45:2185–2198.PubMedCrossRefGoogle Scholar
  11. 11.
    Stefansson S, Kounnas MZ, Henkin J et al. Gp330 on type II pneumocytes mediates endocytosis leading to degradation of pro-urokinase, plasminogen activator inhibitor-1 and urokinase-plasminogen activatior inhibitor-1 complex. J Cell Sci 1995; 108:2361–2368.PubMedGoogle Scholar
  12. 12.
    Zheng G, Bachinsky DR, Stamenkovic I et al. Organ distribution in rats of two members of the low-density lipoprotein receptor gene family, gp330 and LRP/alpha 2MR, and the receptor associated protein (RAP). J Histochem Cytochem 1994; 42:531–542.PubMedGoogle Scholar
  13. 13.
    Chatelet F, Brianti E, Ronco P et al. Ultrastructural localization by monoclonal antibodies of brush border antigens expressed by glomeruli. II. Extrarenal distribution. Am J Pathol 1986; 122:512–519.PubMedGoogle Scholar
  14. 14.
    Lundgren S, Carling T, Hjälm G et al. Tissue distribution of human gp330/megalin, a putative Ca2+-sensing protein. J Histochem Cytochem 1997; 45:383–392.PubMedGoogle Scholar
  15. 15.
    Kolleck I, Sinha P, Rustow B. Vitamin E as an antioxidant of the lung: mechanisms of vitamin E delivery to alveolar type II cells. Am J Respir Crit Care Med 2002; 166:S62–S66.PubMedCrossRefGoogle Scholar
  16. 16.
    Biemesderfer D, Nagy T, DeGray B et al. Specific association of megalin and the Na+/H+ exchanger isoform NHE3 in the proximal tubule. J Biol Chem 1999; 274:17518–17524.PubMedCrossRefGoogle Scholar
  17. 17.
    Gonzalez-Villalobos R, Klassen RB, Allen PL et al. Megalin binds and internalizes Angiotensin II. Am J Physiol Renal Physiol 2005; 288(2):F420–427.PubMedCrossRefGoogle Scholar
  18. 18.
    Frick KK, Bushinsky DA. Molecular mechanisms of primary hypercalciuria. J Am Soc Nephrol 2003; 14:1082–1095.PubMedCrossRefGoogle Scholar
  19. 19.
    Hilpert J, Wogensen L, Thykjaer T et al. Expression profiling confirms the role of endocytic receptor megalin in renal vitamin D3 metabolism. Kidney Int 2002; 62:1672–1681.PubMedCrossRefGoogle Scholar
  20. 20.
    Gotthardt M, Trommsdorff M, Nevitt MF et al. Interactions of the low density lipoprotein receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions in cellular communication and signal transduction. J Biol Chem 2000; 275:25616–25624.PubMedCrossRefGoogle Scholar
  21. 21.
    Kozyraki R, Kristiansen M, Silahtaroglu A et al. The human intrinsic factor-vitamin B12 receptor, cubilin: Molecular characterization and chromosomal mapping of the gene to 10p within the auto-somal recessive megaloblastic anemia (MGA1) region. Blood 1998; 91:3593–3600.PubMedGoogle Scholar
  22. 22.
    Moestrup SK, Verroust PJ. Megalin-and cubilin-mediated endocytosis of protein-bound vitamins, lipids, and hormones in polarized epithelia. Ann Rev Nutr 2001; 21:407–428.CrossRefGoogle Scholar
  23. 23.
    Hammad SM, Barth JL, Knaak C et al. Megalin acts in concert with cubilin to mediate endocytosis of HDL. J Biol Chem 2000; 275:12003–12008.PubMedCrossRefGoogle Scholar
  24. 24.
    Argraves WS, Barth JL. Cubilin and megalin: Partners in lipoprotein and vitamin metabolism. Trends in Cardiovascular Medicine 2001; 11:26–31.PubMedCrossRefGoogle Scholar
  25. 25.
    Birn H, Fyfe JC, Jacobsen C et al. Cubilin is an albumin binding protein important for renal tubular albumin reabsorption. J Clin Invest 2000a; 105:1353–1361.PubMedCrossRefGoogle Scholar
  26. 26.
    Nykjaer A, Fyfe JC, Kozyraki R et al. Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3). Proc Natl Acad Sci USA 2001; 98:13895–13900.PubMedCrossRefGoogle Scholar
  27. 27.
    Christensen EI, Devuyst O, Dom G et al. Loss of chloride channel C1C-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules. Proc Natl Acad Sci USA 2003; 100:8472–8477.PubMedCrossRefGoogle Scholar
  28. 28.
    Bork P, Beckmann G. The CUB domain. A widespread module in developmentalry regulated proteins. J Mol Biol 1993; 231:539–545.PubMedCrossRefGoogle Scholar
  29. 29.
    Kristiansen M, Kozyraki R, Jacobsen C et al. Molecular dissection of the intrinsic factor-vitamin B12 receptor, cubilin, discloses regions important for membrane association and ligand binding. J Biol Chem 1999; 274:20540–20544.PubMedCrossRefGoogle Scholar
  30. 30.
    Christensen EI, Birn H, Verroust P et al. Membrane receptors for endocytosis in the renal proximal tubule. Int Rev Cytol 1998; 180:237–284.PubMedCrossRefGoogle Scholar
  31. 31.
    Marzolo MP, Yuseff MI, Retamal C et al. Differential distribution of low-density lipoprotein-receptor-related protein (LRP) and megalin in polarized epithelial cells is determined by their cytoplasmic domains. Traffic 2003; 4:273–288.PubMedGoogle Scholar
  32. 32.
    Nagai M, Meerloo T, Takeda T et al. The adaptor protein ARH escorts megalin to and through endosomes. Mol Biol Cell 2003; 14:4984–4996.PubMedCrossRefGoogle Scholar
  33. 33.
    Bu G, Geuze HJ, Strous GJ et al. 39 kDa receptor-associated protein is an ER resident protein and molecular chaperone for LDL receptor-related protein. EMBO J 1995; 14:2269–2280.PubMedGoogle Scholar
  34. 34.
    Willnow TE, Armstrong SA, Hammer RE et al. Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo. Proc Natl Acad Sci USA 1995; 92:4537–4541.PubMedCrossRefGoogle Scholar
  35. 35.
    Furukawa T, Ozawa M, Huang R-P et al. A heparin binding protein whose expression increases during differentiation of embryonal carcinoma cells to parietal endoderm cells: cDNA cloning and sequence analysis. J Biochem (Tokyo) 1990; 108(2):297–302.PubMedGoogle Scholar
  36. 36.
    Czekay RP, Orlando RA, Woodward L et al. Endocytic trafficking of megalin/RAP complexes: Dissociation of the complexes in late endosomes. Mol Biol Cell 1997; 8:517–532.PubMedGoogle Scholar
  37. 37.
    Birn H, Vorum H, Verroust PJ et al. Receptor-associated protein is important for normal processing of megalin in kidney proximal tubules. J Am Soc Nephrol 2000b; 11:191–202.PubMedGoogle Scholar
  38. 38.
    Kounnas MZ, Argraves WS, Strickland DK. The 39-kDa receptor-associated protein interacts with two members of the low density lipoprotein receptor family, α2-macroglobulin receptor and glycoprotein 330. J Biol Chem 1992; 267:21162–21166.PubMedGoogle Scholar
  39. 39.
    Orlando RA, Kerjaschki D, Kurihara H et al. Gp330 associates with a 44-kDa protein in the rat kidney to form the Heymann nephritis antigenic complex. Proc Natl Acad Sci USA 1992; 89:6698–6702.PubMedCrossRefGoogle Scholar
  40. 40.
    Christensen El, Gliemann J, Moestrup SK. Renal tubule gp330 is a calcium binding receptor for endocytic uptake of protein. J Histochem Cytochem 1992; 40(10):1481–1490.PubMedGoogle Scholar
  41. 41.
    Biemesderfer D, Dekan G, Aronson PS et al. Biosynthesis of the gp330/44-kDa Heymann nephritis antigenic complex: Assembly takes place in the ER. Am J Physiol 1993; 264(6 pt 2):F1011–F1020.PubMedGoogle Scholar
  42. 42.
    Orlando RA, Farquhar MG. Functional domains of the receptor-associated protein (RAP). Proc Natl Acad Sci USA 1994; 91:3161–3165.PubMedCrossRefGoogle Scholar
  43. 43.
    Orlando RA, Exner M, Czekay R-P et al. Identification of the second cluster of ligand-binding repeats in megalin as a site for receptor-ligand interactions. Proc Natl Acad Sci USA 1997; 94:2368–2373.PubMedCrossRefGoogle Scholar
  44. 44.
    McCarthy RA, Barth JL, Chintalapudi MR et al. Megalin functions as an endocytic sonic hedgehog receptor. J Biol Chem 2002; 277:25660–25667.PubMedCrossRefGoogle Scholar
  45. 45.
    Herz J. The LDL receptor gene family: (Un)expected signal transducers in the brain. Neuron 2001; 29:571–581.PubMedCrossRefGoogle Scholar
  46. 46.
    Williams SE, Ashcom JD, Argraves WS et al. A novel mechsanism for controlling the activity of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein. Multiple regulatory sites for 39-kDa receptor-associated protein. J Biol Chem 1992; 267:9035–9040.PubMedGoogle Scholar
  47. 47.
    Gueth-Hallonet C, Santa-Maria A, Verroust P et al. Gp330 is specifically expressed in outer cells during epithelial differentiation in the preimplantation mouse embryo. Development 1994; 120:3289–3299.PubMedGoogle Scholar
  48. 48.
    Christiensen EI, Verroust PJ. Megalin and cubilin, role in proximal tubule function and during development. Pediatr Nephrol 2002; 17:993–999.CrossRefGoogle Scholar
  49. 49.
    Willnow TE, Hilpert J, Armstrong SA et al. Defective forebrain development in mice lacking gp330/megalin. Proc Natl Acad Sci USA 1996; 93:8460–8464.PubMedCrossRefGoogle Scholar
  50. 50.
    Sahali D, Mulliez N, Chatelet F et al. Characterization of a 280-kD protein restricted to the coated pits of the renal brush border and the epithelial cells of the yolk sac. Teratogenic effect of the specific monoclonal antibodies. J Exp Med 1988; 167:213–218.PubMedCrossRefGoogle Scholar
  51. 51.
    Drake CJ, Fleming PA, Larue AC et al. Differential distribution of cubilin and megalin expression in the mouse embryo. Anat Rec A Discov Mol Cell Evol Biol 2004; 277:163–170.PubMedCrossRefGoogle Scholar
  52. 52.
    Herz J, Bock HH. Lipoprotein receptors in the nervous system. Ann Rev Biochem 2002; 71:405–434.PubMedCrossRefGoogle Scholar
  53. 53.
    McCarthy RA, Argraves WS. Megalin and the neurodevelopmental biology of sonic hedgehog and retinol. J Cell Sci 2003; 116:955–960.PubMedCrossRefGoogle Scholar
  54. 54.
    Cohen MM. The hedgehog signaling network. Am J Med Genet A 2003; 123:5–28.CrossRefGoogle Scholar
  55. 55.
    Orlando RA, Farquhar, MG. Identification of a cell line that expresses a cell surface and a soluble form of the gp330/receptor-associated protein (RAP) Heymann nephritis antigenic complex. Proc Natl Acad Sci USA 1993; 90(9):4082–4086.PubMedCrossRefGoogle Scholar
  56. 56.
    Lisi S, Pinchera A, McClusky RT et al. Preferential megalin-mediated transcytosis of low hormonogenic thyroglobulin: A control mechanism for thyroid hormone release. Proc Natl Acad Sci USA 2003; 100(25):14858–14863.PubMedCrossRefGoogle Scholar
  57. 57.
    Hislop AA. Airway and blood vessel interaction during lung development. J Anat 2002; 201:325–334.PubMedCrossRefGoogle Scholar
  58. 58.
    McMurtry IF. Introduction: Pre and postnatal lung development, maturation, and plasticity. Am J Physiol Lung Cell Mol Physiol 2002; 282(3):L34l–L344.Google Scholar
  59. 59.
    Burri PH. The postnatal growth of the rat lung III Morphology. Anat Rec 1974; 180:77–98.PubMedCrossRefGoogle Scholar
  60. 60.
    Pietromonaco S, Kerjaschki D, Binder R et al. Molecular cloning of a cDNA encoding a major pathogenic domain of the Heymann nephritis antigen gp330. Proc Natl Acad Sci USA 1990; 87(5):1811–1815.PubMedCrossRefGoogle Scholar
  61. 61.
    Strickland DK, Ashcom JD, Williams S et al. Sequence identity between the alpha 2-macroglobu-lin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J Biol Chem 1990; 265(29):17401–4.PubMedGoogle Scholar
  62. 62.
    Czekay RP, Orlando RA, Woodward L et al. The expression of megalin (gp330) and LRP diverges during F9 cell differentiation. J Cell Sci 1995; 108(4):1433–41.PubMedGoogle Scholar
  63. 63.
    Lorent K, Overbergh L, Delabie J. The distribution of mRNA coding for 2 alpha macroglobulin, the murino globulins, the alpha2macroglobulin receptor and the alpha 2 macroglobulin receptor associated protein during mouse embryogenesis and in adult tissues. Differentiation 1994; 55:213–223.PubMedCrossRefGoogle Scholar
  64. 64.
    Vaccaro CA, Brody JS. Ultrastructural localisation and characterisation of proteoglycans in pulmonary alveolus. Am Review Respir Disease 1979; 120:901–910.Google Scholar
  65. 65.
    Calvitti M, Baroni T, Calastrini C et al. Bronchial branching correlates with specific glycosidase activity, extracellular glycosaminoglycan accumulation, TCFβ2, and IL-1 localization during chick embryo lund development. J Histochem Cytochem 2004; 52:325–334.PubMedGoogle Scholar
  66. 66.
    Jesudason EC, Connell MG, fernig DG et al. Heparin and in vitro experimental lung hypoplasia. Ped Surg Int 2000; 16:247–251.CrossRefGoogle Scholar
  67. 67.
    Rubin JB, Choi Y, Segal RA. Cerebellar proteoglycans regulate sonic hedgehog responses during development. Development 2002; 129:223–2232.Google Scholar
  68. 68.
    Bellaiche Y, The I, Perrimon N. Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion. Nature 1998; 394:85–88.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2006

Authors and Affiliations

  1. 1.Immunobiology Group, MRC/UoE Centre for Inflammation ResearchThe Queen’s Medical Research Institute, Little France CrescentEdinburghUK

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