Skip to main content

Advertisement

SpringerLink
Log in

Fine-tuning of cell signaling by glypicans

  • Visions & Reflections (Minireview)
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Hacker U, Nybakken K, Perrimon N (2005) Heparan sulphate proteoglycans: the sweet side of development. Nat Rev Mol Cell Biol 6:530–541

    Article  PubMed  Google Scholar 

  2. Bulow HE, Hobert O (2006) The molecular diversity of glycosaminoglycans shapes animal development. Annu Rev Cell Dev Biol 22:375–407

    Article  CAS  PubMed  Google Scholar 

  3. Nybakken K, Perrimon N (2002) Heparan sulfate proteoglycan modulation of developmental signaling in Dro sophila. Biochim Biophys Acta 1573:280–291

    CAS  PubMed  Google Scholar 

  4. Lin X (2004) Functions of heparan sulfate proteoglycans in cell signaling during development. Development 131:6009–6021

    Article  CAS  PubMed  Google Scholar 

  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 72:279–286

    Article  CAS  PubMed  Google Scholar 

  6. De Cat B, David G (2001) Developmental roles of the glypicans. Semin Cell Dev Biol 12:117–125

    Article  PubMed  Google Scholar 

  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 1:251–264

    Article  CAS  PubMed  Google Scholar 

  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 121:3687–3702

    CAS  PubMed  Google Scholar 

  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 128:87–94

    Google Scholar 

  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 294:352–365

    Article  CAS  PubMed  Google Scholar 

  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 17:159–164

    Article  CAS  PubMed  Google Scholar 

  12. Maccarana M, Sakura Y, Tawada A, Yoshida K, Lindahl U (1996) Domain structure of heparan sulfates from bovine organs. J Biol Chem 271:17804–17810

    Google Scholar 

  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 279:42732–42741

    Article  CAS  PubMed  Google Scholar 

  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 144:1681–1692

    CAS  PubMed  Google Scholar 

  15. Esko JD, Selleck SB (2002) Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu Rev Biochem 71:435–471

    Article  CAS  PubMed  Google Scholar 

  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 131:1563–1575

    Google Scholar 

  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 275:9410–9417

    Article  CAS  PubMed  Google Scholar 

  18. Kreuger J, Spillmann D, Li JP, Lindahl U (2006) Interactions between heparan sulfate and proteins: the concept of specificity. J Cell Biol 174:323–327

    Article  CAS  PubMed  Google Scholar 

  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 7:503–512

    Article  CAS  PubMed  Google Scholar 

  20. Song HH, Filmus J (2002) The role of glypicans in mammalian development. Biochim Biophys Acta 1573:241–246

    CAS  PubMed  Google Scholar 

  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 163:625–635

    Article  PubMed  Google Scholar 

  22. Eugster C, Panakova D, Mahmoud A, Eaton S (2007) Lipoprotein-heparan sulfate interactions in the Hh pathway. Dev Cell 13:57–71

    Article  CAS  PubMed  Google Scholar 

  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 231:31–46

    Article  CAS  PubMed  Google Scholar 

  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 225:179–187

    Article  CAS  PubMed  Google Scholar 

  25. Song HH, Shi W, Xiang YY, Filmus J (2005) The loss of glypican-3 induces alterations in Wnt signaling. J Biol Chem 280:2116–2125

    Article  CAS  PubMed  Google Scholar 

  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 130:2129–2138

    Article  CAS  PubMed  Google Scholar 

  27. Galli A, Roure A, Zeller R, Dono R (2003) Glypican 4 modulates FGF signalling and regulates dorsoventral forebrain patterning in Xenopus embryos. Development 130:4919–4929

    Article  CAS  PubMed  Google Scholar 

  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 131:601–611

    Article  CAS  PubMed  Google Scholar 

  29. Freeman M, Gurdon JB (2002) Regulatory principles of developmental signaling. Annu Rev Cell Dev Biol 18:515–539

    Article  CAS  PubMed  Google Scholar 

  30. Kirkpatrick CA, Dimitroff BD, Rawson JM, Selleck SB (2004) Spatial regulation of Wingless morphogen distribution and signaling by Dally-like protein. Dev Cell 7:513–523

    Article  CAS  PubMed  Google Scholar 

  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 132:659–666

    Article  CAS  PubMed  Google Scholar 

  32. Giraldez AJ, Copley RR, Cohen SM (2002) HSPG modification by the secreted enzyme Notum shapes the Wingless morphogen gradient. Dev Cell 2:667–676

    Article  CAS  PubMed  Google Scholar 

  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 13:226–241

    Article  CAS  PubMed  Google Scholar 

  34. Panakova D, Sprong H, Marois E, Thiele C, Eaton S (2005) Lipoprotein particles are required for Hedgehog and Wingless signalling. Nature 435:58–65

    Article  CAS  PubMed  Google Scholar 

  35. Marois E, Mahmoud A, Eaton S (2006) The endocytic pathway and formation of the Wingless morphogen gradient. Development 133:307–317

    Article  CAS  PubMed  Google Scholar 

  36. Bandtlow CE, Zimmermann DR (2000) Proteoglycans in the developing brain: new conceptual insights for old proteins. Physiol Rev 80:1267–1290

    CAS  PubMed  Google Scholar 

  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 219:353–367

    Article  CAS  PubMed  Google Scholar 

  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 352:55–60

    Article  CAS  PubMed  Google Scholar 

  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 24:8745–8752

    Article  CAS  PubMed  Google Scholar 

  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 12:241–247

    Article  CAS  PubMed  Google Scholar 

  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 53:1–11

    Article  CAS  PubMed  Google Scholar 

  42. Filmus J (2001) Glypicans in growth control and cancer. Glycobiology 11:19R–23R

    Article  CAS  PubMed  Google Scholar 

  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 146:255–264

    CAS  PubMed  Google Scholar 

  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 122:928–938

    Article  CAS  PubMed  Google Scholar 

  45. Casero R A Jr, Marton LJ (2007) Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. Nat Rev Drug Discov 6:373–390

    Article  CAS  PubMed  Google Scholar 

  46. Fransson LA, Belting M, Cheng F, Jonsson M, Mani K, Sandgren S (2004) Novel aspects of glypican glycobiology. Cell Mol Life Sci 61:1016–1024

    Article  CAS  PubMed  Google Scholar 

  47. Belting M (2003) Heparan sulfate proteoglycan as a plasma membrane carrier. Trends Biochem Sci 28:145–151

    Article  CAS  PubMed  Google Scholar 

  48. Saikali Z, Sinnett D (2000) Expression of glypican 3 (GPC3) in embryonal tumors. Int J Cancer 89:418–422

    Article  CAS  PubMed  Google Scholar 

  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 82:184–189

    Article  CAS  PubMed  Google Scholar 

  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 13:1133–1139

    Article  CAS  PubMed  Google Scholar 

  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 103:455–465

    Article  CAS  PubMed  Google Scholar 

  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 320:1148–1155

    Article  CAS  PubMed  Google Scholar 

  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 67:57–65

    Article  CAS  PubMed  Google Scholar 

  54. Lindahl U (2007) Heparan sulfate-protein interactions–a concept for drug design? Thromb Haemost 98:109–115

    CAS  PubMed  Google Scholar 

  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 12:2689–2697

    Article  CAS  PubMed  Google Scholar 

  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 61:1785–1794

    CAS  PubMed  Google Scholar 

  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 280:15300–15306

    Article  CAS  PubMed  Google Scholar 

  58. Marty C, Schwendener RA (2005) Cytotoxic tumor targeting with scFv antibody-modified liposomes. Methods Mol Med 109:389–402

    CAS  PubMed  Google Scholar 

  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 66:2414–2422

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank K. Dudley for critically reading the manuscript and the members of the laboratory for helpful discussions. This research was supported by the ‘Fondation pour la Recherche Medicale’ (FRM), the ‘Fondation de France’ (FdF), the ‘Association Française contre les Myopathies’ (AFM) and by the Marie Curie Host Grant for Transfer of Knowledge (MTKD-CT-2004-509804).

Author information

Authors and Affiliations

  1. Developmental Biology Institute of Marseille-Luminy (IBDML), CNRS UMR 6216, Inserm, Université de la Méditerrannée, Campus de Luminy, Case 907, 13288, Marseille Cedex 09, France

    A. Fico, F. Maina & R. Dono

Authors
  1. A. Fico
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Maina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Dono
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. Dono.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fico, A., Maina, F. & Dono, R. Fine-tuning of cell signaling by glypicans. Cell. Mol. Life Sci. 68, 923–929 (2011). https://doi.org/10.1007/s00018-007-7471-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-007-7471-6

Keywords

Search

Navigation