Cellular and Molecular Life Sciences

, Volume 68, Issue 6, pp 923–929

Fine-tuning of cell signaling by glypicans

Visions & Reflections (Minireview)

Abstract

Signaling peptides of the extracellular environment regulate cell biological processes underlying embryonic development, tissue homeostasis, and pathophysiology. The heparan sulphate proteoglycans, glypicans, have evolved as essential modulators of key regulatory proteins such as Wnt, Bmp, Fgf, and Shh. By acting on signal spreading and receptor activation, glypicans can control signal read-out and fate in targeted cells. Genetic and embryological studies have highlighted that glypicans act in a temporal and spatially regulated manner to modulate distinct cellular events. However, alterations of glypican function underlie human congenital malformations and cancer. Recent reports are starting to reveal their mechanism of action and how they can ensure tight modulation of cell signaling.

Keywords

Glypican HSPG Cell signaling Signaling cell-based therapy modulator Morphogen Human disorder Cancer Stem cells 

References

  1. 1.
    Hacker U, Nybakken K, Perrimon N (2005) Heparan sulphate proteoglycans: the sweet side of development. Nat Rev Mol Cell Biol 6:530–541CrossRefPubMedGoogle Scholar
  2. 2.
    Bulow HE, Hobert O (2006) The molecular diversity of glycosaminoglycans shapes animal development. Annu Rev Cell Dev Biol 22:375–407CrossRefPubMedGoogle Scholar
  3. 3.
    Nybakken K, Perrimon N (2002) Heparan sulfate proteoglycan modulation of developmental signaling in Dro sophila. Biochim Biophys Acta 1573:280–291PubMedGoogle Scholar
  4. 4.
    Lin X (2004) Functions of heparan sulfate proteoglycans in cell signaling during development. Development 131:6009–6021CrossRefPubMedGoogle Scholar
  5. 5.
    DeBaun MR, Ess J, Saunders S (2001) Simpson Golabi Behmel syndrome: progress toward understanding the molecular basis for overgrowth, malformation, and cancer predisposition. Mol Genet Metab 72:279–286CrossRefPubMedGoogle Scholar
  6. 6.
    De Cat B, David G (2001) Developmental roles of the glypicans. Semin Cell Dev Biol 12:117–125CrossRefPubMedGoogle Scholar
  7. 7.
    Topczewski J, Sepich DS, Myers DC, Walker C, Amores A, Lele Z, Hammerschmidt M, Postlethwait J, Solnica-Krezel L (2001) The zebrafish glypican knypek controls cell polarity during gastrulation movements of convergent extension. Dev Cell 1:251–264CrossRefPubMedGoogle Scholar
  8. 8.
    Nakato H, Futch TA, Selleck SB (1995) The division abnormally delayed (dally) gene: a putative integral membrane proteoglycan required for cell division patterning during postembryonic development of the nervous system in Drosophila. Development 121:3687–3702PubMedGoogle Scholar
  9. 9.
    Baeg GH, Lin X, Khare N, Baumgartner S, Perrimon N (2001) Heparan sulfate proteoglycans are critical for the organization of the extracellular distribution of Wingless. Development 128:87–94Google Scholar
  10. 10.
    Hudson ML, Kinnunen T, Cinar HN, Chisholm AD (2006) C. elegans Kallmann syndrome protein KAL-1 interacts with syndecan and glypican to regulate neuronal cell migrations. Dev Biol 294:352–365CrossRefPubMedGoogle Scholar
  11. 11.
    Gumienny TL, MacNeil LT, Wang H, de Bono M, Wrana JL, Padgett RW (2007) Glypican LON-2 is a conserved negative regulator of BMP-like signaling in Caenorhabditis elegans. Curr Biol 17:159–164CrossRefPubMedGoogle Scholar
  12. 12.
    Maccarana M, Sakura Y, Tawada A, Yoshida K, Lindahl U (1996) Domain structure of heparan sulfates from bovine organs. J Biol Chem 271:17804–17810Google Scholar
  13. 13.
    Ledin J, Staatz W, Li JP, Gotte M, Selleck S, Kjellen L, Spillmann D (2004) Heparan sulfate structure in mice with genetically modified heparan sulfate production. J Biol Chem 279:42732–42741CrossRefPubMedGoogle Scholar
  14. 14.
    Perrimon N, Lanjuin A, Arnold C, Noll E (1996) Zygotic lethal mutations with maternal effect phenotypes in Drosophila melanogaster. II. Loci on the second and third chromosomes identified by P-element-induced mutations. Genetics 144:1681–1692PubMedGoogle Scholar
  15. 15.
    Esko JD, Selleck SB (2002) Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu Rev Biochem 71:435–471CrossRefPubMedGoogle Scholar
  16. 16.
    Han C, Belenkaya TY, Wang B, Lin X (2004) Distinct and collaborative roles of Drosophila EXT family proteins in morphogen signalling and gradient formation. Development 131:1563–1575Google Scholar
  17. 17.
    Tumova S, Woods A, Couchman JR (2000) Heparan sulfate chains from glypican and syndecans bind the Hep II domain of fibronectin similarly despite minor structural differences. J Biol Chem 275:9410–9417CrossRefPubMedGoogle Scholar
  18. 18.
    Kreuger J, Spillmann D, Li JP, Lindahl U (2006) Interactions between heparan sulfate and proteins: the concept of specificity. J Cell Biol 174:323–327CrossRefPubMedGoogle Scholar
  19. 19.
    Kreuger J, Perez L, Giraldez AJ, Cohen SM (2004) Opposing activities of Dally-like glypican at high and low levels of Wingless morphogen activity. Dev Cell 7:503–512CrossRefPubMedGoogle Scholar
  20. 20.
    Song HH, Filmus J (2002) The role of glypicans in mammalian development. Biochim Biophys Acta 1573:241–246PubMedGoogle Scholar
  21. 21.
    De Cat B, Muyldermans SY, Coomans C, Degeest G, Vanderschueren B, Creemers J, Biemar F, Peers B, David G (2003) Processing by proprotein convertases is required for glypican-3 modulation of cell survival, Wnt signaling, and gastrulation movements. J Cell Biol 163:625–635CrossRefPubMedGoogle Scholar
  22. 22.
    Eugster C, Panakova D, Mahmoud A, Eaton S (2007) Lipoprotein-heparan sulfate interactions in the Hh pathway. Dev Cell 13:57–71CrossRefPubMedGoogle Scholar
  23. 23.
    Grisaru S, Cano-Gauci D, Tee J, Filmus J, Rosenblum ND (2001) Glypican-3 modulates BMP- and FGF-mediated effects during renal branching morphogenesis. Dev Biol 231:31–46CrossRefPubMedGoogle Scholar
  24. 24.
    Paine-Saunders S, Viviano BL, Zupicich J, Skarnes WC, Saunders S (2000) Glypican-3 controls cellular responses to Bmp4 in limb patterning and skeletal development. Dev Biol 225:179–187CrossRefPubMedGoogle Scholar
  25. 25.
    Song HH, Shi W, Xiang YY, Filmus J (2005) The loss of glypican-3 induces alterations in Wnt signaling. J Biol Chem 280:2116–2125CrossRefPubMedGoogle Scholar
  26. 26.
    Ohkawara B, Yamamoto TS, Tada M, Ueno N (2003) Role of glypican 4 in the regulation of convergent extension movements during gastrulation in Xenopus laevis. Development 130:2129–2138CrossRefPubMedGoogle Scholar
  27. 27.
    Galli A, Roure A, Zeller R, Dono R (2003) Glypican 4 modulates FGF signalling and regulates dorsoventral forebrain patterning in Xenopus embryos. Development 130:4919–4929CrossRefPubMedGoogle Scholar
  28. 28.
    Han C, Belenkaya TY, Khodoun M, Tauchi M, Lin X (2004) Drosophila glypicans control the cell-to-cell movement of Hedgehog by a dynamin-independent process. Development 131:601–611CrossRefPubMedGoogle Scholar
  29. 29.
    Freeman M, Gurdon JB (2002) Regulatory principles of developmental signaling. Annu Rev Cell Dev Biol 18:515–539CrossRefPubMedGoogle Scholar
  30. 30.
    Kirkpatrick CA, Dimitroff BD, Rawson JM, Selleck SB (2004) Spatial regulation of Wingless morphogen distribution and signaling by Dally-like protein. Dev Cell 7:513–523CrossRefPubMedGoogle Scholar
  31. 31.
    Franch-Marro X, Marchand O, Piddini E, Ricardo S, Alexandre C, Vincent JP (2005) Glypicans shunt the Wingless signal between local signalling and further transport. Development 132:659–666CrossRefPubMedGoogle Scholar
  32. 32.
    Giraldez AJ, Copley RR, Cohen SM (2002) HSPG modification by the secreted enzyme Notum shapes the Wingless morphogen gradient. Dev Cell 2:667–676CrossRefPubMedGoogle Scholar
  33. 33.
    Hou S, Maccarana M, Min TH, Strate I, Pera EM (2007) The secreted serine protease xHtrA1 stimulates long-range FGF signaling in the early Xenopus embryo. Dev Cell 13:226–241CrossRefPubMedGoogle Scholar
  34. 34.
    Panakova D, Sprong H, Marois E, Thiele C, Eaton S (2005) Lipoprotein particles are required for Hedgehog and Wingless signalling. Nature 435:58–65CrossRefPubMedGoogle Scholar
  35. 35.
    Marois E, Mahmoud A, Eaton S (2006) The endocytic pathway and formation of the Wingless morphogen gradient. Development 133:307–317CrossRefPubMedGoogle Scholar
  36. 36.
    Bandtlow CE, Zimmermann DR (2000) Proteoglycans in the developing brain: new conceptual insights for old proteins. Physiol Rev 80:1267–1290PubMedGoogle Scholar
  37. 37.
    Hagihara K, Watanabe K, Chun J, Yamaguchi Y (2000) Glypican-4 is an FGF2-binding heparan sulfate proteoglycan expressed in neural precursor cells. Dev Dyn 219:353–367CrossRefPubMedGoogle Scholar
  38. 38.
    Luxardi G, Galli A, Forlani S, Lawson K, Maina F, Dono R (2007) Glypicans are differentially expressed during patterning and neurogenesis of early mouse brain. Biochem Biophys Res Commun 352:55–60CrossRefPubMedGoogle Scholar
  39. 39.
    Karihaloo A, Kale S, Rosenblum ND, Cantley LG (2004) Hepatocyte growth factor-mediated renal epithelial branching morphogenesis is regulated by glypican-4 expression. Mol Cell Biol 24:8745–8752CrossRefPubMedGoogle Scholar
  40. 40.
    Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen EY, Huber R, Neri G, Cao A, Forabosco A, Schlessinger D (1996) Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat Genet 12:241–247CrossRefPubMedGoogle Scholar
  41. 41.
    Veugelers M, Vermeesch J, Watanabe K, Yamaguchi Y, Marynen P, David G (1998) GPC4, the gene for human K-glypican, flanks GPC3 on xq26: deletion of the GPC3-GPC4 gene cluster in one family with Simpson-Golabi-Behmel syndrome. Genomics 53:1–11CrossRefPubMedGoogle Scholar
  42. 42.
    Filmus J (2001) Glypicans in growth control and cancer. Glycobiology 11:19R–23RCrossRefPubMedGoogle Scholar
  43. 43.
    Cano-Gauci DF, Song HH, Yang H, McKerlie C, Choo B, Shi W, Pullano R, Piscione TD, Grisaru S, Soon S, Sedlackova L, Tanswell AK, Mak TW, Yeger H, Lockwood GA, Rosenblum ND, Filmus J (1999) Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome. J Cell Biol 146:255–264PubMedGoogle Scholar
  44. 44.
    Hartwig S, Hu MC, Cella C, Piscione T, Filmus J, Rosenblum ND (2005) Glypican-3 modulates inhibitory Bmp2-Smad signaling to control renal development in vivo. Mech Dev 122:928–938CrossRefPubMedGoogle Scholar
  45. 45.
    Casero R A Jr, Marton LJ (2007) Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. Nat Rev Drug Discov 6:373–390CrossRefPubMedGoogle Scholar
  46. 46.
    Fransson LA, Belting M, Cheng F, Jonsson M, Mani K, Sandgren S (2004) Novel aspects of glypican glycobiology. Cell Mol Life Sci 61:1016–1024CrossRefPubMedGoogle Scholar
  47. 47.
    Belting M (2003) Heparan sulfate proteoglycan as a plasma membrane carrier. Trends Biochem Sci 28:145–151CrossRefPubMedGoogle Scholar
  48. 48.
    Saikali Z, Sinnett D (2000) Expression of glypican 3 (GPC3) in embryonal tumors. Int J Cancer 89:418–422CrossRefPubMedGoogle Scholar
  49. 49.
    Jakubovic BD, Jothy S (2007) Glypican-3: from the mutations of Simpson-Golabi-Behmel genetic syndrome to a tumor marker for hepatocellular carcinoma. Exp Mol Pathol 82:184–189CrossRefPubMedGoogle Scholar
  50. 50.
    Jia HL, Ye QH, Qin LX, Budhu A, Forgues M, Chen Y, Liu YK, Sun HC, Wang L, Lu HZ, Shen F, Tang ZY, Wang XW (2007) Gene expression profiling reveals potential biomarkers of human hepatocellular carcinoma. Clin Cancer Res 13:1133–1139CrossRefPubMedGoogle Scholar
  51. 51.
    Midorikawa Y, Ishikawa S, Iwanari H, Imamura T, Sakamoto H, Miyazono K, Kodama T, Makuuchi M, Aburatani H (2003) Glypican-3, overexpressed in hepatocellular carcinoma, modulates FGF2 and BMP-7 signaling. Int J Cancer 103:455–465CrossRefPubMedGoogle Scholar
  52. 52.
    Li J, Kleeff J, Kayed H, Felix K, Penzel R, Buchler MW, Korc M, Friess H (2004) Glypican-1 antisense transfection modulates TGF-beta-dependent signaling in Colo-357 pancreatic cancer cells. Biochem Biophys Res Commun 320:1148–1155CrossRefPubMedGoogle Scholar
  53. 53.
    Williamson D, Selfe J, Gordon T, Lu YJ, Pritchard-Jones K, Murai K, Jones P, Workman P, Shipley J (2007) Role for amplification and expression of glypican-5 in rhabdo-myosarcoma. Cancer Res 67:57–65CrossRefPubMedGoogle Scholar
  54. 54.
    Lindahl U (2007) Heparan sulfate-protein interactions–a concept for drug design? Thromb Haemost 98:109–115PubMedGoogle Scholar
  55. 55.
    Komori H, Fukuma D, Baba H, Nishimura Y (2006) Identification of HLA-A2- or HLA-A24-restricted CTL epitopes possibly useful for glypican-3-specific immunotherapy of hepatocellular carcinoma. Clin Cancer Res 12:2689–2697CrossRefPubMedGoogle Scholar
  56. 56.
    Marty C, Meylan C, Schott H, Ballmer-Hofer K, Schwendener RA (2004) Enhanced heparan sulfate proteo-glycan-mediated uptake of cell-penetrating peptide-modified liposomes. Cell Mol Life Sci 61:1785–1794PubMedGoogle Scholar
  57. 57.
    Richard JP, Melikov K, Brooks H, Prevot P, Lebleu B, Chernomordik LV (2005) Cellular uptake of unconjugated TAT peptide involves clathrin-dependent endocytosis and heparan sulfate receptors. J Biol Chem 280:15300–15306CrossRefPubMedGoogle Scholar
  58. 58.
    Marty C, Schwendener RA (2005) Cytotoxic tumor targeting with scFv antibody-modified liposomes. Methods Mol Med 109:389–402PubMedGoogle Scholar
  59. 59.
    Motomura Y, Senju S, Nakatsura T, Matsuyoshi H, Hirata S, Monji M, Komori H, Fukuma D, Baba H, Nishimura Y (2006) Embryonic stem cell-derived dendritic cells expressing glypican-3, a recently identified oncofetal antigen, induce protective immunity against highly metastatic mouse melanoma, B16-F10. Cancer Res 66:2414–2422CrossRefPubMedGoogle Scholar

Copyright information

© Springer Basel AG 2007

Authors and Affiliations

  1. 1.Developmental Biology Institute of Marseille-Luminy (IBDML)CNRS UMR 6216, Inserm, Université de la MéditerrannéeMarseille Cedex 09France

Personalised recommendations