Cellular and Molecular Life Sciences

, Volume 66, Issue 21, pp 3421–3434 | Cite as

Multifunctionality of extracellular and cell surface heparan sulfate proteoglycans

  • Catherine Kirn-Safran
  • Mary C. Farach-Carson
  • Daniel D. Carson
Review

Abstract

Heparan sulfate proteoglycans are a remarkably diverse family of glycosaminoglycan-bearing protein cores that include the syndecans, the glypicans, perlecan, agrin, and collagen XVIII. Members of this protein class play key roles during normal processes that occur during development, tissue morphogenesis, and wound healing. As key components of basement membranes in organs and tissues, they also participate in selective filtration of biological fluids, in establishing cellular barriers, and in modulation of angiogenesis. The ability to perform these functions is provided both by the features of the protein cores as well as by the unique properties of heparan sulfate, which is assembled as a polymer of N-acetylglucosamine and glucuronic acid and modified by specific enzymes to generate specialized biologically active structures. This article discusses the structures and functions of this amazing family of proteoglycans and provides a platform for further study of the individual members.

Keywords

Heparan sulfate Proteoglycan Glycosaminoglycan Perlecan Syndecan Glypican Agrin Collagen XVIII 

References

  1. 1.
    Farach-Carson MC, Carson DD (2007) Perlecan—a multifunctional extracellular proteoglycan scaffold. Glycobiology 17:897–905PubMedGoogle Scholar
  2. 2.
    Farach-Carson MC, Hecht JT, Carson DD (2005) Heparan sulfate proteoglycans: key players in cartilage biology. Crit Rev Eukaryot Gene Expr 15:29–48PubMedGoogle Scholar
  3. 3.
    Bix G, Iozzo RV (2008) Novel interactions of perlecan: unraveling perlecan’s role in angiogenesis. Microsc Res Tech 71:339–348PubMedGoogle Scholar
  4. 4.
    Harvey SJ, Miner JH (2008) Revisiting the glomerular charge barrier in the molecular era. Curr Opin Nephrol Hypertens 17:393–398PubMedGoogle Scholar
  5. 5.
    Morita H, Yoshimura A, Inui K, Ideura T, Watanabe H, Wang L, Soininen R, Tryggvason K (2005) Heparan sulfate of perlecan is involved in glomerular filtration. J Am Soc Nephrol 16:1703–1710PubMedGoogle Scholar
  6. 6.
    Whitelock JM, Melrose J, Iozzo RV (2008) Diverse cell signaling events modulated by perlecan. Biochemistry 47:11174–11183PubMedGoogle Scholar
  7. 7.
    Farach-Carson MC, Brown AJ, Lynam M, Safran JB, Carson DD (2008) A novel peptide sequence in perlecan domain IV supports cell adhesion, spreading and FAK activation. Matrix Biol 27:150–160PubMedGoogle Scholar
  8. 8.
    Kwiatkowska D, Kwiatkowska-Korczak J (1999) Adhesive glycoproteins of the extracellular matrix. Postepy Hig Med Dosw 53:55–74PubMedGoogle Scholar
  9. 9.
    Castillo GM, Ngo C, Cummings J, Wight TN, Snow AD (1997) Perlecan binds to the beta-amyloid proteins (A beta) of Alzheimer’s disease, accelerates A beta fibril formation, and maintains A beta fibril stability. J Neurochem 69:2452–2465PubMedGoogle Scholar
  10. 10.
    Gonzalez EM, Reed CC, Bix G, Fu J, Zhang Y, Gopalakrishnan B, Greenspan DS, Iozzo RV (2005) BMP-1/tolloid-like metalloproteases process endorepellin, the angiostatic C-terminal fragment of perlecan. J Biol Chem 280:7080–7087PubMedGoogle Scholar
  11. 11.
    Bix G, Castello R, Burrows M, Zoeller JJ, Weech M, Iozzo RA, Cardi C, Thakur ML, Barker CA, Camphausen K, Iozzo RV (2006) Endorepellin in vivo: targeting the tumor vasculature and retarding cancer growth and metabolism. J Natl Cancer Inst 98:1634–1646PubMedCrossRefGoogle Scholar
  12. 12.
    Kummer TT, Misgeld T, Sanes JR (2006) Assembly of the postsynaptic membrane at the neuromuscular junction: paradigm lost. Curr Opin Neurobiol 16:74–82PubMedGoogle Scholar
  13. 13.
    Phillips WD (1995) Acetylcholine receptors and the cytoskeletal connection. Clin Exp Pharmacol Physiol 22:961–965PubMedGoogle Scholar
  14. 14.
    Winzen U, Cole GJ, Halfter W (2003) Agrin is a chimeric proteoglycan with the attachment sites for heparan sulfate/chondroitin sulfate located in two multiple serine-glycine clusters. J Biol Chem 278:30106–30114PubMedGoogle Scholar
  15. 15.
    Williams S, Ryan C, Jacobson C (2008) Agrin and neuregulin, expanding roles and implications for therapeutics. Biotechnol Adv 26:187–201PubMedGoogle Scholar
  16. 16.
    Oh SP, Warman ML, Seldin MF, Cheng SD, Knoll JH, Timmons S, Olsen BR (1994) Cloning of cDNA and genomic DNA encoding human type XVIII collagen and localization of the alpha 1 (XVIII) collagen gene to mouse chromosome 10 and human chromosome 21. Genomics 19:494–499PubMedGoogle Scholar
  17. 17.
    Bix G, Iozzo RV (2005) Matrix revolutions: “tails” of basement-membrane components with angiostatic functions. Trends Cell Biol 15:52–60PubMedGoogle Scholar
  18. 18.
    Xu YK, Nusse R (1998) The Frizzled CRD domain is conserved in diverse proteins including several receptor tyrosine kinases. Curr Biol 8:R405–R406PubMedGoogle Scholar
  19. 19.
    Wu J, Mlodzik M (2008) The frizzled extracellular domain is a ligand for Van Gogh/Stbm during nonautonomous planar cell polarity signaling. Dev Cell 15:462–469PubMedGoogle Scholar
  20. 20.
    Beckmann G, Hanke J, Bork P, Reich JG (1998) Merging extracellular domains: fold prediction for laminin G-like and amino-terminal thrombospondin-like modules based on homology to pentraxins. J Mol Biol 275:725–730PubMedGoogle Scholar
  21. 21.
    David G (1993) Integral membrane heparan sulfate proteoglycans. Faseb J 7:1023–1030PubMedGoogle Scholar
  22. 22.
    Shimizu H, Ghazizadeh M, Sato S, Oguro T, Kawanami O (2009) Interaction between beta-amyloid protein and heparan sulfate proteoglycans from the cerebral capillary basement membrane in Alzheimer’s disease. J Clin Neurosci 16:277–282PubMedGoogle Scholar
  23. 23.
    Ohashi K (2001) Pathogenesis of beta2-microglobulin amyloidosis. Pathol Int 51:1–10PubMedGoogle Scholar
  24. 24.
    Leung EW, Rife L, Smith RE, Kay EP (2000) Extracellular matrix components in retrocorneal fibrous membrane in comparison to corneal endothelium and Descemet’s membrane. Mol Vis 6:15–23PubMedGoogle Scholar
  25. 25.
    Davis TH, Chen C, Isom LL (2004) Sodium channel beta1 subunits promote neurite outgrowth in cerebellar granule neurons. J Biol Chem 279:51424–51432PubMedGoogle Scholar
  26. 26.
    Kuma K, Iwabe N, Miyata T (1993) Motifs of cadherin- and fibronectin type III-related sequences and evolution of the receptor-type-protein tyrosine kinases: sequence similarity between proto-oncogene ret and cadherin family. Mol Biol Evol 10:539–551PubMedGoogle Scholar
  27. 27.
    Hirata K, Ishida T, Penta K, Rezaee M, Yang E, Wohlgemuth J, Quertermous T (2001) Cloning of an immunoglobulin family adhesion molecule selectively expressed by endothelial cells. J Biol Chem 276:16223–16231Google Scholar
  28. 28.
    Smith SM, West LA, Hassell JR (2007) The core protein of growth plate perlecan binds FGF-18 and alters its mitogenic effect on chondrocytes. Arch Biochem Biophys 468:244–251PubMedGoogle Scholar
  29. 29.
    Allen JM, Bateman JF, Hansen U, Wilson R, Bruckner P, Owens RT, Sasaki T, Timpl R, Fitzgerald J (2006) WARP is a novel multimeric component of the chondrocyte pericellular matrix that interacts with perlecan. J Biol Chem 281:7341–7349PubMedGoogle Scholar
  30. 30.
    Tiedemann K, Sasaki T, Gustafsson E, Gohring W, Batge B, Notbohm H, Timpl R, Wedel T, Schlotzer-Schrehardt U, Reinhardt DP (2005) Microfibrils at basement membrane zones interact with perlecan via fibrillin-1. J Biol Chem 280:11404–11412PubMedGoogle Scholar
  31. 31.
    Bezakova G, Ruegg MA (2003) New insights into the roles of agrin. Nat Rev Mol Cell Biol 4:295–308PubMedGoogle Scholar
  32. 32.
    Meinen S, Barzaghi P, Lin S, Lochmuller H, Ruegg MA (2007) Linker molecules between laminins and dystroglycan ameliorate laminin-alpha2-deficient muscular dystrophy at all disease stages. J Cell Biol 176:979–993PubMedGoogle Scholar
  33. 33.
    Mascarenhas JB, Ruegg MA, Sasaki T, Eble JA, Engel J, Stetefeld J (2005) Structure and laminin-binding specificity of the NtA domain expressed in eukaryotic cells. Matrix Biol 23:507–513PubMedGoogle Scholar
  34. 34.
    Muntoni F, Torelli S, Brockington M (2008) Muscular dystrophies due to glycosylation defects. Neurotherapeutics 5:627–632PubMedGoogle Scholar
  35. 35.
    Timmer NM, van Horssen J, Otte-Holler I, Wilhelmus MM, David G, van Beers J, de Waal RM, Verbeek MM (2009) Amyloid beta induces cellular relocalization and production of agrin and glypican-1. Brain Res 1260:38–46PubMedGoogle Scholar
  36. 36.
    Liu IH, Uversky VN, Munishkina LA, Fink AL, Halfter W, Cole GJ (2005) Agrin binds alpha-synuclein and modulates alpha-synuclein fibrillation. Glycobiology 15:1320–1331PubMedGoogle Scholar
  37. 37.
    Marneros AG, Keene DR, Hansen U, Fukai N, Moulton K, Goletz PL, Moiseyev G, Pawlyk BS, Halfter W, Dong S, Shibata M, Li T, Crouch RK, Bruckner P, Olsen BR (2004) Collagen XVIII/endostatin is essential for vision and retinal pigment epithelial function. EMBO J 23:89–99PubMedGoogle Scholar
  38. 38.
    Wickstrom SA, Alitalo K, Keski-Oja J (2005) Endostatin signaling and regulation of endothelial cell–matrix interactions. Adv Cancer Res 94:197–229PubMedGoogle Scholar
  39. 39.
    Marneros AG, Olsen BR (2005) Physiological role of collagen XVIII and endostatin. FASEB J 19:716–728PubMedGoogle Scholar
  40. 40.
    Tang H, Fu Y, Lei Q, Han Q, Ploplis VA, Castellino FJ, Li L, Luo Y (2009) Fibrinogen facilitates the anti-tumor effect of nonnative endostatin. Biochem Biophys Res Commun 380:249–253PubMedGoogle Scholar
  41. 41.
    Delehedde M, Lyon M, Sergeant N, Rahmoune H, Fernig DG (2001) Proteoglycans: pericellular and cell surface multireceptors that integrate external stimuli in the mammary gland. J Mammary Gland Biol Neoplasia 6:253–273PubMedGoogle Scholar
  42. 42.
    Pakula R, Melchior A, Denys A, Vanpouille C, Mazurier J, Allain F (2007) Syndecan-1/CD147 association is essential for cyclophilin B-induced activation of p44/42 mitogen-activated protein kinases and promotion of cell adhesion and chemotaxis. Glycobiology 17:492–503PubMedGoogle Scholar
  43. 43.
    Wang Z, Gotte M, Bernfield M, Reizes O (2005) Constitutive and accelerated shedding of murine syndecan-1 is mediated by cleavage of its core protein at a specific juxtamembrane site. Biochemistry 44:12355–12361PubMedGoogle Scholar
  44. 44.
    Muramatsu T, Muramatsu H, Kojima T (2006) Identification of proteoglycan-binding proteins. Methods Enzymol 416:263–278PubMedGoogle Scholar
  45. 45.
    Sulka B, Lortat-Jacob H, Terreux R, Letourneur F, Rousselle P (2009) Tyrosine dephosphorylation of the syndecan-1 PDZ binding domain regulates syntenin-1 recruitment. J Biol Chem 284:10659–10671PubMedGoogle Scholar
  46. 46.
    Capurro MI, Shi W, Sandal S, Filmus J (2005) Processing by convertases is not required for glypican-3-induced stimulation of hepatocellular carcinoma growth. J Biol Chem 280:41201–41206PubMedGoogle Scholar
  47. 47.
    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 163:625–635PubMedGoogle Scholar
  48. 48.
    Filmus J, Capurro M, Rast J (2008) Glypicans. Genome Biol 9:224PubMedGoogle Scholar
  49. 49.
    Ronca F, Andersen JS, Paech V, Margolis RU (2001) Characterization of slit protein interactions with glypican-1. J Biol Chem 276:29141–29147PubMedGoogle Scholar
  50. 50.
    Watanabe N, Araki W, Chui DH, Makifuchi T, Ihara Y, Tabira T (2004) Glypican-1 as an A beta binding HSPG in the human brain: its localization in DIG domains and possible roles in the pathogenesis of Alzheimer’s disease. FASEB J 18:1013–1015PubMedGoogle Scholar
  51. 51.
    Esko JD, Selleck SB (2002) Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu Rev Biochem 71:435–471PubMedGoogle Scholar
  52. 52.
    Vives RR, Pye DA, Salmivirta M, Hopwood JJ, Lindahl U, Gallagher JT (1999) Sequence analysis of heparan sulphate and heparin oligosaccharides. Biochem J 339(Pt 3):767–773PubMedGoogle Scholar
  53. 53.
    Vlodavsky I, Elkin M, Abboud-Jarrous G, Levi-Adam F, Fuks L, Shafat I, Ilan N (2008) Heparanase: one molecule with multiple functions in cancer progression. Connect Tissue Res 49:207–210PubMedGoogle Scholar
  54. 54.
    Lamanna WC, Kalus I, Padva M, Baldwin RJ, Merry CL, Dierks T (2007) The heparanome—the enigma of encoding and decoding heparan sulfate sulfation. J Biotechnol 129:290–307PubMedGoogle Scholar
  55. 55.
    Gong F, Jemth P, Escobar Galvis ML, Vlodavsky I, Horner A, Lindahl U, Li JP (2003) Processing of macromolecular heparin by heparanase. J Biol Chem 278:35152–35158PubMedGoogle Scholar
  56. 56.
    Okada Y, Yamada S, Toyoshima M, Dong J, Nakajima M, Sugahara K (2002) Structural recognition by recombinant human heparanase that plays critical roles in tumor metastasis. Hierarchical sulfate groups with different effects and the essential target disulfated trisaccharide sequence. J Biol Chem 277:42488–42495PubMedGoogle Scholar
  57. 57.
    Luo Y, Ye S, Kan M, McKeehan WL (2006) Structural specificity in a FGF7-affinity purified heparin octasaccharide required for formation of a complex with FGF7 and FGFR2IIIb. J Cell Biochem 97:1241–1258PubMedGoogle Scholar
  58. 58.
    Kemp LE, Mulloy B, Gherardi E (2006) Signalling by HGF/SF and Met: the role of heparan sulphate co-receptors. Biochem Soc Trans 34:414–417PubMedGoogle Scholar
  59. 59.
    Robinson CJ, Stringer SE (2001) The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 114:853–865PubMedGoogle Scholar
  60. 60.
    Miao HQ, Navarro E, Patel S, Sargent D, Koo H, Wan H, Plata A, Zhou Q, Ludwig D, Bohlen P, Kussie P (2002) Cloning, expression, and purification of mouse heparanase. Protein Expr Purif 26:425–431PubMedGoogle Scholar
  61. 61.
    Podyma-Inoue KA, Yokote H, Sakaguchi K, Ikuta M, Yanagishita M (2002) Characterization of heparanase from a rat parathyroid cell line. J Biol Chem 277:32459–32465PubMedGoogle Scholar
  62. 62.
    Gilat D, Hershkoviz R, Goldkorn I, Cahalon L, Korner G, Vlodavsky I, Lider O (1995) Molecular behavior adapts to context: heparanase functions as an extracellular matrix-degrading enzyme or as a T cell adhesion molecule, depending on the local pH. J Exp Med 181:1929–1934PubMedGoogle Scholar
  63. 63.
    Goldshmidt O, Zcharia E, Cohen M, Aingorn H, Cohen I, Nadav L, Katz BZ, Geiger B, Vlodavsky I (2003) Heparanase mediates cell adhesion independent of its enzymatic activity. FASEB J 17:1015–1025PubMedGoogle Scholar
  64. 64.
    Elkin M, Ilan N, Ishai-Michaeli R, Friedmann Y, Papo O, Pecker I, Vlodavsky I (2001) Heparanase as mediator of angiogenesis: mode of action. FASEB J 15:1661–1663PubMedGoogle Scholar
  65. 65.
    Vlodavsky I, Friedmann Y (2001) Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. J Clin Invest 108:341–347PubMedGoogle Scholar
  66. 66.
    Goshen R, Hochberg AA, Korner G, Levy E, Ishai-Michaeli R, Elkin M, de Groot N, Vlodavsky I (1996) Purification and characterization of placental heparanase and its expression by cultured cytotrophoblasts. Mol Hum Reprod 2:679–684PubMedGoogle Scholar
  67. 67.
    D’Souza SS, Daikoku T, Farach-Carson MC, Carson DD (2007) Heparanase expression and function during early pregnancy in mice. Biol Reprod 77:433–441PubMedGoogle Scholar
  68. 68.
    Temkin V, Aingorn H, Puxeddu I, Goldshmidt O, Zcharia E, Gleich GJ, Vlodavsky I, Levi-Schaffer F (2004) Eosinophil major basic protein: first identified natural heparanase-inhibiting protein. J Allergy Clin Immunol 113:703–709PubMedGoogle Scholar
  69. 69.
    D’Souza S, Yang W, Marchetti D, Muir C, Farach-Carson MC, Carson DD (2008) HIP/RPL29 antagonizes VEGF and FGF2 stimulated angiogenesis by interfering with HS-dependent responses. J Cell Biochem 105:1183–1193PubMedGoogle Scholar
  70. 70.
    Ferro V, Dredge K, Liu L, Hammond E, Bytheway I, Li C, Johnstone K, Karoli T, Davis K, Copeman E, Gautam A (2007) PI-88 and novel heparan sulfate mimetics inhibit angiogenesis. Semin Thromb Hemost 33:557–568PubMedGoogle Scholar
  71. 71.
    Kudchadkar R, Gonzalez R, Lewis KD (2008) PI-88: a novel inhibitor of angiogenesis. Expert Opin Investig Drugs 17:1769–1776PubMedGoogle Scholar
  72. 72.
    Morimoto-Tomita M, Uchimura K, Werb Z, Hemmerich S, Rosen SD (2002) Cloning and characterization of two extracellular heparin-degrading endosulfatases in mice and humans. J Biol Chem 277:49175–49185PubMedGoogle Scholar
  73. 73.
    Zhao W, Sala-Newby GB, Dhoot GK (2006) Sulf1 expression pattern and its role in cartilage and joint development. Dev Dyn 235:3327–3335PubMedGoogle Scholar
  74. 74.
    Lum DH, Tan J, Rosen SD, Werb Z (2007) Gene trap disruption of the mouse heparan sulfate 6-O-endosulfatase gene, Sulf2. Mol Cell Biol 27:678–688PubMedGoogle Scholar
  75. 75.
    Narita K, Chien J, Mullany SA, Staub J, Qian X, Lingle WL, Shridhar V (2007) Loss of HSulf-1 expression enhances autocrine signaling mediated by amphiregulin in breast cancer. J Biol Chem 282:14413–14420PubMedGoogle Scholar
  76. 76.
    Lai JP, Sandhu DS, Yu C, Han T, Moser CD, Jackson KK, Guerrero RB, Aderca I, Isomoto H, Garrity-Park MM, Zou H, Shire AM, Nagorney DM, Sanderson SO, Adjei AA, Lee JS, Thorgeirsson SS, Roberts LR (2008) Sulfatase 2 up-regulates glypican 3, promotes fibroblast growth factor signaling, and decreases survival in hepatocellular carcinoma. Hepatology 47:1211–1222PubMedGoogle Scholar
  77. 77.
    Backen AC, Cole CL, Lau SC, Clamp AR, McVey R, Gallagher JT, Jayson GC (2007) Heparan sulphate synthetic and editing enzymes in ovarian cancer. Br J Cancer 96:1544–1548PubMedGoogle Scholar
  78. 78.
    Costell M, Gustafsson E, Aszodi A, Morgelin M, Bloch W, Hunziker E, Addicks K, Timpl R, Fassler R (1999) Perlecan maintains the integrity of cartilage and some basement membranes. J Cell Biol 147:1109–1122PubMedGoogle Scholar
  79. 79.
    Arikawa-Hirasawa E, Watanabe H, Takami H, Hassell JR, Yamada Y (1999) Perlecan is essential for cartilage and cephalic development. Nat Genet 23:354–358PubMedGoogle Scholar
  80. 80.
    Sasse P, Malan D, Fleischmann M, Roell W, Gustafsson E, Bostani T, Fan Y, Kolbe T, Breitbach M, Addicks K, Welz A, Brem G, Hescheler J, Aszodi A, Costell M, Bloch W, Fleischmann BK (2008) Perlecan is critical for heart stability. Cardiovasc Res 80:435–444PubMedGoogle Scholar
  81. 81.
    Hart M, Li L, Tokunaga T, Lindsey JR, Hassell JR, Snow AD, Fukuchi K (2001) Overproduction of perlecan core protein in cultured cells and transgenic mice. J Pathol 194:262–269PubMedGoogle Scholar
  82. 82.
    Rodgers KD, Sasaki T, Aszodi A, Jacenko O (2007) Reduced perlecan in mice results in chondrodysplasia resembling Schwartz–Jampel syndrome. Hum Mol Genet 16:515–528PubMedGoogle Scholar
  83. 83.
    Stum M, Girard E, Bangratz M, Bernard V, Herbin M, Vignaud A, Ferry A, Davoine CS, Echaniz-Laguna A, Rene F, Marcel C, Molgo J, Fontaine B, Krejci E, Nicole S (2008) Evidence of a dosage effect and a physiological endplate acetylcholinesterase deficiency in the first mouse models mimicking Schwartz–Jampel syndrome neuromyotonia. Hum Mol Genet 17:3166–3179PubMedGoogle Scholar
  84. 84.
    Nicole S, Davoine CS, Topaloglu H, Cattolico L, Barral D, Beighton P, Hamida CB, Hammouda H, Cruaud C, White PS, Samson D, Urtizberea JA, Lehmann-Horn F, Weissenbach J, Hentati F, Fontaine B (2000) Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz–Jampel syndrome (chondrodystrophic myotonia). Nat Genet 26:480–483PubMedGoogle Scholar
  85. 85.
    Stum M, Davoine CS, Vicart S, Guillot-Noel L, Topaloglu H, Carod-Artal FJ, Kayserili H, Hentati F, Merlini L, Urtizberea JA, Hammouda el H, Quan PC, Fontaine B, Nicole S (2006) Spectrum of HSPG2 (Perlecan) mutations in patients with Schwartz–Jampel syndrome. Hum Mutat 27:1082–1091PubMedGoogle Scholar
  86. 86.
    Rossi M, Morita H, Sormunen R, Airenne S, Kreivi M, Wang L, Fukai N, Olsen BR, Tryggvason K, Soininen R (2003) Heparan sulfate chains of perlecan are indispensable in the lens capsule but not in the kidney. EMBO J 22:236–245PubMedGoogle Scholar
  87. 87.
    Tran PK, Tran-Lundmark K, Soininen R, Tryggvason K, Thyberg J, Hedin U (2004) Increased intimal hyperplasia and smooth muscle cell proliferation in transgenic mice with heparan sulfate-deficient perlecan. Circ Res 94:550–558PubMedGoogle Scholar
  88. 88.
    Tran-Lundmark K, Tran PK, Paulsson-Berne G, Friden V, Soininen R, Tryggvason K, Wight TN, Kinsella MG, Boren J, Hedin U (2008) Heparan sulfate in perlecan promotes mouse atherosclerosis: roles in lipid permeability, lipid retention, and smooth muscle cell proliferation. Circ Res 103:43–52PubMedGoogle Scholar
  89. 89.
    Tran PK, Agardh HE, Tran-Lundmark K, Ekstrand J, Roy J, Henderson B, Gabrielsen A, Hansson GK, Swedenborg J, Paulsson-Berne G, Hedin U (2007) Reduced perlecan expression and accumulation in human carotid atherosclerotic lesions. Atherosclerosis 190:264–270PubMedGoogle Scholar
  90. 90.
    Gautam M, Noakes PG, Moscoso L, Rupp F, Scheller RH, Merlie JP, Sanes JR (1996) Defective neuromuscular synaptogenesis in agrin-deficient mutant mice. Cell 85:525–535PubMedGoogle Scholar
  91. 91.
    Burgess RW, Nguyen QT, Son YJ, Lichtman JW, Sanes JR (1999) Alternatively spliced isoforms of nerve- and muscle-derived agrin: their roles at the neuromuscular junction. Neuron 23:33–44PubMedGoogle Scholar
  92. 92.
    Hausser HJ, Ruegg MA, Brenner RE, Ksiazek I (2007) Agrin is highly expressed by chondrocytes and is required for normal growth. Histochem Cell Biol 127:363–374PubMedGoogle Scholar
  93. 93.
    Harvey SJ, Jarad G, Cunningham J, Rops AL, van der Vlag J, Berden JH, Moeller MJ, Holzman LB, Burgess RW, Miner JH (2007) Disruption of glomerular basement membrane charge through podocyte-specific mutation of agrin does not alter glomerular permselectivity. Am J Pathol 171:139–152PubMedGoogle Scholar
  94. 94.
    Fukai N, Eklund L, Marneros AG, Oh SP, Keene DR, Tamarkin L, Niemela M, Ilves M, Li E, Pihlajaniemi T, Olsen BR (2002) Lack of collagen XVIII/endostatin results in eye abnormalities. EMBO J 21:1535–1544PubMedGoogle Scholar
  95. 95.
    Ylikarppa R, Eklund L, Sormunen R, Kontiola AI, Utriainen A, Maatta M, Fukai N, Olsen BR, Pihlajaniemi T (2003) Lack of type XVIII collagen results in anterior ocular defects. FASEB J 17:2257–2259PubMedGoogle Scholar
  96. 96.
    Utriainen A, Sormunen R, Kettunen M, Carvalhaes LS, Sajanti E, Eklund L, Kauppinen R, Kitten GT, Pihlajaniemi T (2004) Structurally altered basement membranes and hydrocephalus in a type XVIII collagen deficient mouse line. Hum Mol Genet 13:2089–2099PubMedGoogle Scholar
  97. 97.
    Kliemann SE, Waetge RT, Suzuki OT, Passos-Bueno MR, Rosemberg S (2003) Evidence of neuronal migration disorders in Knobloch syndrome: clinical and molecular analysis of two novel families. Am J Med Genet A 119A:15–19PubMedGoogle Scholar
  98. 98.
    Sertie AL, Sossi V, Camargo AA, Zatz M, Brahe C, Passos-Bueno MR (2000) Collagen XVIII, containing an endogenous inhibitor of angiogenesis and tumor growth, plays a critical role in the maintenance of retinal structure and in neural tube closure (Knobloch syndrome). Hum Mol Genet 9:2051–2058PubMedGoogle Scholar
  99. 99.
    Iughetti P, Suzuki O, Godoi PH, Alves VA, Sertie AL, Zorick T, Soares F, Camargo A, Moreira ES, di Loreto C, Moreira-Filho CA, Simpson A, Oliva G, Passos-Bueno MR (2001) A polymorphism in endostatin, an angiogenesis inhibitor, predisposes for the development of prostatic adenocarcinoma. Cancer Res 61:7375–7378PubMedGoogle Scholar
  100. 100.
    Zorick TS, Mustacchi Z, Bando SY, Zatz M, Moreira-Filho CA, Olsen B, Passos-Bueno MR (2001) High serum endostatin levels in Down syndrome: implications for improved treatment and prevention of solid tumours. Eur J Hum Genet 9:811–814PubMedGoogle Scholar
  101. 101.
    Zambon L, Honma HN, Lourenco GJ, Saad IA, Mussi RK, Lima CS (2008) A polymorphism in the angiogenesis inhibitor, endostatin, in lung cancer susceptibility. Lung Cancer 59:276–278PubMedGoogle Scholar
  102. 102.
    Ylikarppa R, Eklund L, Sormunen R, Muona A, Fukai N, Olsen BR, Pihlajaniemi T (2003) Double knockout mice reveal a lack of major functional compensation between collagens XV and XVIII. Matrix Biol 22:443–448PubMedGoogle Scholar
  103. 103.
    Alexander CM, Reichsman F, Hinkes MT, Lincecum J, Becker KA, Cumberledge S, Bernfield M (2000) Syndecan-1 is required for Wnt-1-induced mammary tumorigenesis in mice. Nat Genet 25:329–332PubMedGoogle Scholar
  104. 104.
    McDermott SP, Ranheim EA, Leatherberry VS, Khwaja SS, Klos KS, Alexander CM (2007) Juvenile syndecan-1 null mice are protected from carcinogen-induced tumor development. Oncogene 26:1407–1416PubMedGoogle Scholar
  105. 105.
    Park PW, Pier GB, Hinkes MT, Bernfield M (2001) Exploitation of syndecan-1 shedding by Pseudomonas aeruginosa enhances virulence. Nature 411:98–102PubMedGoogle Scholar
  106. 106.
    Elenius V, Gotte M, Reizes O, Elenius K, Bernfield M (2004) Inhibition by the soluble syndecan-1 ectodomains delays wound repair in mice overexpressing syndecan-1. J Biol Chem 279:41928–41935PubMedGoogle Scholar
  107. 107.
    Stepp MA, Gibson HE, Gala PH, Iglesia DD, Pajoohesh-Ganji A, Pal-Ghosh S, Brown M, Aquino C, Schwartz AM, Goldberger O, Hinkes MT, Bernfield M (2002) Defects in keratinocyte activation during wound healing in the syndecan-1-deficient mouse. J Cell Sci 115:4517–4531PubMedGoogle Scholar
  108. 108.
    Fears CY, Gladson CL, Woods A (2006) Syndecan-2 is expressed in the microvasculature of gliomas and regulates angiogenic processes in microvascular endothelial cells. J Biol Chem 281:14533–14536PubMedGoogle Scholar
  109. 109.
    Kaksonen M, Pavlov I, Voikar V, Lauri SE, Hienola A, Riekki R, Lakso M, Taira T, Rauvala H (2002) Syndecan-3-deficient mice exhibit enhanced LTP and impaired hippocampus-dependent memory. Mol Cell Neurosci 21:158–172PubMedGoogle Scholar
  110. 110.
    Cornelison DD, Wilcox-Adelman SA, Goetinck PF, Rauvala H, Rapraeger AC, Olwin BB (2004) Essential and separable roles for Syndecan-3 and Syndecan-4 in skeletal muscle development and regeneration. Genes Dev 18:2231–2236PubMedGoogle Scholar
  111. 111.
    Strader AD, Reizes O, Woods SC, Benoit SC, Seeley RJ (2004) Mice lacking the syndecan-3 gene are resistant to diet-induced obesity. J Clin Invest 114:1354–1360PubMedGoogle Scholar
  112. 112.
    Ishiguro K, Kadomatsu K, Kojima T, Muramatsu H, Nakamura E, Ito M, Nagasaka T, Kobayashi H, Kusugami K, Saito H, Muramatsu T (2000) Syndecan-4 deficiency impairs the fetal vessels in the placental labyrinth. Dev Dyn 219:539–544PubMedGoogle Scholar
  113. 113.
    Echtermeyer F, Streit M, Wilcox-Adelman S, Saoncella S, Denhez F, Detmar M, Goetinck P (2001) Delayed wound repair and impaired angiogenesis in mice lacking syndecan-4. J Clin Invest 107:R9–R14PubMedGoogle Scholar
  114. 114.
    Alexopoulou AN, Multhaupt HA, Couchman JR (2007) Syndecans in wound healing, inflammation and vascular biology. Int J Biochem Cell Biol 39:505–528PubMedGoogle Scholar
  115. 115.
    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 12:241–247PubMedGoogle Scholar
  116. 116.
    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
  117. 117.
    Viviano BL, Silverstein L, Pflederer C, Paine-Saunders S, Mills K, Saunders S (2005) Altered hematopoiesis in glypican-3-deficient mice results in decreased osteoclast differentiation and a delay in endochondral ossification. Dev Biol 282:152–162PubMedGoogle Scholar
  118. 118.
    Lander AD, Selleck SB (2000) The elusive functions of proteoglycans: in vivo veritas. J Cell Biol 148:227–232PubMedGoogle Scholar
  119. 119.
    Lin X, Wei G, Shi Z, Dryer L, Esko JD, Wells DE, Matzuk MM (2000) Disruption of gastrulation and heparan sulfate biosynthesis in EXT1-deficient mice. Dev Biol 224:299–311PubMedGoogle Scholar
  120. 120.
    Inatani M, Irie F, Plump AS, Tessier-Lavigne M, Yamaguchi Y (2003) Mammalian brain morphogenesis and midline axon guidance require heparan sulfate. Science 302:1044–1046PubMedGoogle Scholar
  121. 121.
    Stickens D, Zak BM, Rougier N, Esko JD, Werb Z (2005) Mice deficient in Ext2 lack heparan sulfate and develop exostoses. Development 132:5055–5068PubMedGoogle Scholar
  122. 122.
    Morimoto K, Shimizu T, Furukawa K, Morio H, Kurosawa H, Shirasawa T (2002) Transgenic expression of the EXT2 gene in developing chondrocytes enhances the synthesis of heparan sulfate and bone formation in mice. Biochem Biophys Res Commun 292:999–1009PubMedGoogle Scholar
  123. 123.
    McCormick C, Duncan G, Goutsos KT, Tufaro F (2000) The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. Proc Natl Acad Sci USA 97:668–673PubMedGoogle Scholar
  124. 124.
    Presto J, Thuveson M, Carlsson P, Busse M, Wilen M, Eriksson I, Kusche-Gullberg M, Kjellen L (2008) Heparan sulfate biosynthesis enzymes EXT1 and EXT2 affect NDST1 expression and heparan sulfate sulfation. Proc Natl Acad Sci USA 105:4751–4756PubMedGoogle Scholar
  125. 125.
    Ringvall M, Ledin J, Holmborn K, van Kuppevelt T, Ellin F, Eriksson I, Olofsson AM, Kjellen L, Forsberg E (2000) Defective heparan sulfate biosynthesis and neonatal lethality in mice lacking N-deacetylase/N-sulfotransferase-1. J Biol Chem 275:25926–25930PubMedGoogle Scholar
  126. 126.
    Grobe K, Inatani M, Pallerla SR, Castagnola J, Yamaguchi Y, Esko JD (2005) Cerebral hypoplasia and craniofacial defects in mice lacking heparan sulfate Ndst1 gene function. Development 132:3777–3786PubMedGoogle Scholar
  127. 127.
    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 279:42732–42741PubMedGoogle Scholar
  128. 128.
    Li JP, Gong F, Hagner-McWhirter A, Forsberg E, Abrink M, Kisilevsky R, Zhang X, Lindahl U (2003) Targeted disruption of a murine glucuronyl C5-epimerase gene results in heparan sulfate lacking l-iduronic acid and in neonatal lethality. J Biol Chem 278:28363–28366PubMedGoogle Scholar
  129. 129.
    Forsberg E, Pejler G, Ringvall M, Lunderius C, Tomasini-Johansson B, Kusche-Gullberg M, Eriksson I, Ledin J, Hellman L, Kjellen L (1999) Abnormal mast cells in mice deficient in a heparin-synthesizing enzyme. Nature 400:773–776PubMedGoogle Scholar
  130. 130.
    Pallerla SR, Lawrence R, Lewejohann L, Pan Y, Fischer T, Schlomann U, Zhang X, Esko JD, Grobe K (2008) Altered heparan sulfate structure in mice with deleted NDST3 gene function. J Biol Chem 283:16885–16894PubMedGoogle Scholar
  131. 131.
    Forsberg E, Kjellen L (2001) Heparan sulfate: lessons from knockout mice. J Clin Invest 108:175–180PubMedGoogle Scholar
  132. 132.
    Holmborn K, Ledin J, Smeds E, Eriksson I, Kusche-Gullberg M, Kjellen L (2004) Heparan sulfate synthesized by mouse embryonic stem cells deficient in NDST1 and NDST2 is 6-O-sulfated but contains no N-sulfate groups. J Biol Chem 279:42355–42358PubMedGoogle Scholar
  133. 133.
    Grobe K, Ledin J, Ringvall M, Holmborn K, Forsberg E, Esko JD, Kjellen L (2002) Heparan sulfate and development: differential roles of the N-acetylglucosamine N-deacetylase/N-sulfotransferase isozymes. Biochim Biophys Acta 1573:209–215PubMedGoogle Scholar
  134. 134.
    Pallerla SR, Pan Y, Zhang X, Esko JD, Grobe K (2007) Heparan sulfate Ndst1 gene function variably regulates multiple signaling pathways during mouse development. Dev Dyn 236:556–563PubMedGoogle Scholar
  135. 135.
    Pan Y, Woodbury A, Esko JD, Grobe K, Zhang X (2006) Heparan sulfate biosynthetic gene Ndst1 is required for FGF signaling in early lens development. Development 133:4933–4944PubMedGoogle Scholar
  136. 136.
    Bullock SL, Fletcher JM, Beddington RS, Wilson VA (1998) Renal agenesis in mice homozygous for a gene trap mutation in the gene encoding heparan sulfate 2-sulfotransferase. Genes Dev 12:1894–1906PubMedGoogle Scholar
  137. 137.
    Merry CL, Bullock SL, Swan DC, Backen AC, Lyon M, Beddington RS, Wilson VA, Gallagher JT (2001) The molecular phenotype of heparan sulfate in the Hs2st−/− mutant mouse. J Biol Chem 276:35429–35434PubMedGoogle Scholar
  138. 138.
    Pratt T, Conway CD, Tian NM, Price DJ, Mason JO (2006) Heparan sulphation patterns generated by specific heparan sulfotransferase enzymes direct distinct aspects of retinal axon guidance at the optic chiasm. J Neurosci 26:6911–6923PubMedGoogle Scholar
  139. 139.
    Habuchi H, Nagai N, Sugaya N, Atsumi F, Stevens RL, Kimata K (2007) Mice deficient in heparan sulfate 6-O-sulfotransferase-1 exhibit defective heparan sulfate biosynthesis, abnormal placentation, and late embryonic lethality. J Biol Chem 282:15578–15588PubMedGoogle Scholar
  140. 140.
    Sugaya N, Habuchi H, Nagai N, Ashikari-Hada S, Kimata K (2008) 6-O-sulfation of heparan sulfate differentially regulates various fibroblast growth factor-dependent signalings in culture. J Biol Chem 283:10366–10376PubMedGoogle Scholar
  141. 141.
    Shworak NW, HajMohammadi S, de Agostini AI, Rosenberg RD (2002) Mice deficient in heparan sulfate 3-O-sulfotransferase-1: normal hemostasis with unexpected perinatal phenotypes. Glycoconj J 19:355–361PubMedGoogle Scholar
  142. 142.
    Holst CR, Bou-Reslan H, Gore BB, Wong K, Grant D, Chalasani S, Carano RA, Frantz GD, Tessier-Lavigne M, Bolon B, French DM, Ashkenazi A (2007) Secreted sulfatases Sulf1 and Sulf2 have overlapping yet essential roles in mouse neonatal survival. PLoS ONE 2:e575PubMedGoogle Scholar
  143. 143.
    Lamanna WC, Baldwin RJ, Padva M, Kalus I, Ten Dam G, van Kuppevelt TH, Gallagher JT, von Figura K, Dierks T, Merry CL (2006) Heparan sulfate 6-O-endosulfatases: discrete in vivo activities and functional co-operativity. Biochem J 400:63–73PubMedGoogle Scholar
  144. 144.
    Wang S, Ai X, Freeman SD, Pownall ME, Lu Q, Kessler DS, Emerson CP Jr (2004) QSulf1, a heparan sulfate 6-O-endosulfatase, inhibits fibroblast growth factor signaling in mesoderm induction and angiogenesis. Proc Natl Acad Sci USA 101:4833–4838PubMedGoogle Scholar
  145. 145.
    Ai X, Do AT, Lozynska O, Kusche-Gullberg M, Lindahl U, Emerson CP Jr (2003) QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling. J Cell Biol 162:341–351PubMedGoogle Scholar
  146. 146.
    Zcharia E, Metzger S, Chajek-Shaul T, Aingorn H, Elkin M, Friedmann Y, Weinstein T, Li JP, Lindahl U, Vlodavsky I (2004) Transgenic expression of mammalian heparanase uncovers physiological functions of heparan sulfate in tissue morphogenesis, vascularization, and feeding behavior. FASEB J 18:252–263PubMedGoogle Scholar
  147. 147.
    Kram V, Zcharia E, Yacoby-Zeevi O, Metzger S, Chajek-Shaul T, Gabet Y, Muller R, Vlodavsky I, Bab I (2006) Heparanase is expressed in osteoblastic cells and stimulates bone formation and bone mass. J Cell Physiol 207:784–792PubMedGoogle Scholar
  148. 148.
    Escobar Galvis ML, Jia J, Zhang X, Jastrebova N, Spillmann D, Gottfridsson E, van Kuppevelt TH, Zcharia E, Vlodavsky I, Lindahl U, Li JP (2007) Transgenic or tumor-induced expression of heparanase upregulates sulfation of heparan sulfate. Nat Chem Biol 3:773–778PubMedGoogle Scholar
  149. 149.
    Habuchi H, Suzuki S, Saito T, Tamura T, Harada T, Yoshida K, Kimata K (1992) Structure of a heparan sulphate oligosaccharide that binds to basic fibroblast growth factor. Biochem J 285(Pt 3):805–813PubMedGoogle Scholar
  150. 150.
    Ashikari-Hada S, Habuchi H, Kariya Y, Itoh N, Reddi AH, Kimata K (2004) Characterization of growth factor-binding structures in heparin/heparan sulfate using an octasaccharide library. J Biol Chem 279:12346–12354PubMedGoogle Scholar
  151. 151.
    Noti C, de Paz JL, Polito L, Seeberger PH (2006) Preparation and use of microarrays containing synthetic heparin oligosaccharides for the rapid analysis of heparin–protein interactions. Chemistry 12:8664–8686PubMedGoogle Scholar
  152. 152.
    Deakin JA, Lyon M (1999) Differential regulation of hepatocyte growth factor/scatter factor by cell surface proteoglycans and free glycosaminoglycan chains. J Cell Sci 112(Pt 12):1999–2009PubMedGoogle Scholar
  153. 153.
    Lyon M, Deakin JA, Mizuno K, Nakamura T, Gallagher JT (1994) Interaction of hepatocyte growth factor with heparan sulfate. Elucidation of the major heparan sulfate structural determinants. J Biol Chem 269:11216–11223PubMedGoogle Scholar
  154. 154.
    Ashikari S, Habuchi H, Kimata K (1995) Characterization of heparan sulfate oligosaccharides that bind to hepatocyte growth factor. J Biol Chem 270:29586–29593PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag, Basel/Switzerland 2009

Authors and Affiliations

  • Catherine Kirn-Safran
    • 1
  • Mary C. Farach-Carson
    • 1
    • 2
  • Daniel D. Carson
    • 2
  1. 1.Department of Biological SciencesUniversity of DelawareNewarkUSA
  2. 2.Department of Biochemistry and Cell Biology, Weiss School of Natural SciencesRice UniversityHoustonUSA

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