Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Basement membrane proteoglycans: from cellar to ceiling

Nature Reviews Molecular Cell Biology volume 6, pages 646–656 (2005)Cite this article

Key Points

  • Basement membrane (BM) proteoglycans are more than charged filtering agents. These complex macromolecules can direct cell responses by a wide range of sophisticated mechanisms. BM proteoglycans are directly involved in regulating angiogenesis and, consequently, tumour progression, and their partial or total absence causes several congenital diseases that affect the cardiovascular, musculoskeletal and nervous systems.

  • Whereas the two heparan sulphate proteoglycans collagen XVIII and perlecan dictate BM stability and integrity in a variety of tissues, C-terminal-derived fragments of both collagen XVIII (endostatin) and perlecan (endorepellin) inhibit the growth of blood vessels by targeting tumour-associated endothelial cells. BM proteoglycans can have a bipolar activity — through the heparan sulphate chains they function as pro-angiogenic factors by modulating growth factor activity, whereas through their C-terminal angiostatic fragments they have the opposite function.

  • The mechanism of action of endostatin and endorepellin involves their specific interaction with two cell surface receptors, the α5β1 and the α2β1 integrins, respectively, through a process that ultimately disrupts the endothelial cell cytoskeleton and focal adhesions, thereby blocking cell migration and capillary morphogenesis. This seems to be the primary angiostatic function of these processed forms of BM proteoglycans.

  • The presence of these fragments in the urine and blood of normal and diseased patients indicate that they might exert a physiological role in vivo, and that, in the future, they could become biomolecular markers for certain diseases.

  • A number of future challenges include the precise delineation of their signalling networks and an improved understanding of their in vivo activities and interacting partners. By increasing our knowledge we will optimize the use of these endogenous angiogenesis inhibitors in the battle against cancer and other diseases where angiogenesis is dominant.

Abstract

The biology of basement membrane proteoglycans extends far beyond the original notion of anionic filters. These complex molecules have dual roles as structural constituents of basement membranes and functional regulators of several growth-factor signalling pathways. As such, they are involved in angiogenesis and, consequently, in tumour progression and their partial or total absence causes several congenital defects that affect the musculoskeletal, cardiovascular and nervous systems. New findings indicate a potential functional coupling between the intricate make-up of basement membrane proteoglycans and their ability to control important biological processes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structural domains of human collagen XVIII and of its NC1/endostatin domain.
Figure 2: Structural domains of human perlecan.
Figure 3: Endostatin specifically targets growing tumours.
Figure 4: Structure and biological activity of LG3.
Figure 5: Diverse signalling events evoked by endostatin, endorepellin and collagen I.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Yurchenco, P. D., Amenta, P. S. & Patton, B. L. Basement membrane assembly, stability and activities observed through a developmental lens. Matrix Biol. 22, 521–538 (2004). An excellent and comprehensive review on basement membrane constituents.

    Article  CAS  PubMed  Google Scholar 

  2. Kanwar, Y. S. & Farquhar, M. G. Presence of heparan sulfate in the glomerular basement membrane. Proc. Natl Acad. Sci. USA 76, 1303–1307 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Oh, S. P. et al. Isolation and sequencing of cDNAs for proteins with multiple domains of Gly-Xaa-Yaa repeats identify a distinct family of collagenous proteins. Proc. Natl Acad. Sci. USA 91, 4229–4233 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rehn, M. & Pihlajaniemi, T. α1(XVIII), a collagen chain with frequent interruptions in the collagenous sequence, a distinct tissue distribution, and homology with type XV collagen. Proc. Natl Acad. Sci. USA 91, 4234–4238 (1994). References 3 and 4 provide the first reports on collagen XVIII.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Iozzo, R. V. Matrix proteoglycans: from molecular design to cellular function. Annu. Rev. Biochem. 67, 609–652 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Bezakova, G. & Ruegg, M. A. New insights into the roles of agrin. Nature Rev. Mol. Cell Biol. 4, 295–308 (2003).

    Article  CAS  Google Scholar 

  7. Iozzo, R. V. & San Antonio, J. D. Heparan sulfate proteoglycans: heavy hitters in the angiogenesis arena. J. Clin. Invest. 108, 349–355 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li, D., Clark, C. C. & Myers, J. C. Basement membrane zone type XV collagen is a disulfide-bonded chondroitin sulfate proteoglycan in human tissues and cultured cells. J. Biol. Chem. 275, 22339–22347 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Marneros, A. G. & Olsen, B. R. The role of collagen-derived proteolytic fragments in angiogenesis. Matrix Biol. 20, 337–345 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Saarela, J., Rehn, M., Oikarinen, A., Autio-Harmainen, H. & Pihlajaniemi, T. The short and long forms of type XVIII collagen show clear tissue specificities in their expression and location in basement membrane zones in humans. Am. J. Pathol. 153, 611–626 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Muragaki, Y. et al. Mouse Col18a1 is expressed in a tissue-specific manner as three alternative variants and is localized in basement membrane zones. Proc. Natl Acad. Sci. USA 92, 8763–8767 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rehn, M. & Pihlajaniemi, T. Identification of three N-terminal ends of type XVIII collagen chains and tissue-specific differences in the expression of the corresponding transcripts. The longest form contains a novel motif homologous to rat and Drosophila frizzled proteins. J. Biol. Chem. 270, 4705–4711 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Halfter, W., Dong, S., Schurer, B. & Cole, G. J. Collagen XVIII is a basement membrane heparan sulfate proteoglycan. J. Biol. Chem. 273, 25404–25412 (1998). These authors discovered that collagen XVIII is a heparan sulphate proteoglycan.

    Article  CAS  PubMed  Google Scholar 

  14. Dong, G, Cole, G. J. & Halfter, W. Expression of collagen XVIII and localization of its glycosaminoglycan attachment sites. J. Biol. Chem. 278, 1700–1707 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Pufe, T. et al. Endostatin/collagen XVIII — an inhibitor of angiogenesis — is expressed in cartilage and fibrocartilage. Matrix Biol. 23, 267–276 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Amenta, P. S. et al. Proteoglycan-collagen XV in human tissues is seen linking banded collagen fibers subjacent to the basement membrane. J. Histochem. Cytochem. 53, 165–176 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Fukai, N. et al. Lack of collagen XVIII/endostatin results in eye abnormalities. EMBO J. 21, 1535–1544 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ylikärppä, R. et al. Lack of type XVIII collagen results in anterior ocular defects. FASEB J. 17, 2257–2259 (2003). By generating collagen-XVIII-null animals, these authors (references 17 and 18) provide compelling evidence for a principal role of collagen XVIII in eye development.

    Article  PubMed  CAS  Google Scholar 

  19. Marneros, A. G. et al. Collagen XVIII/endostatin is essential for vision and retinal pigment epithelial function. EMBO J. 23, 89–99 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Sertie, A. L. et al. 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). Human Mol. Gen. 9, 2051–2058 (2000).

    Article  CAS  Google Scholar 

  21. Suzuki, O. T. et al. Molecular analysis of collagen XVIII reveals novel mutations, presence of a third isoform, and possible genetic heterogeneity in Knobloch syndrome. Am. J. Hum. Genet. 71, 1320–1329 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Utriainen, A. et al. Structurally altered basement membranes and hydrocephalus in a type XVIII collagen deficient mouse line. Human Mol. Gen. 13, 2089–2099 (2004).

    Article  CAS  Google Scholar 

  23. Moulton, K. S. et al. Loss of collagen XVIII enhances neovascularization and vascular permeability in atherosclerosis. Circulation 110, 1330–1336 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Elamaa, H., Sormunen, R., Rehn, M., Soininen, R. & Pihlajaniemi, T. Endostatin overexpression specifically in the lens and skin leads to cataract and ultrastructural alterations in basement membranes. Am. J. Pathol. 166, 221–229 (2004).

    Article  Google Scholar 

  25. Ackley, B. D. et al. The NC1/endostatin domain of Caenorhabditis elegans type XVIII collagen affects cell migration and axon guidance. J. Cell Biol. 152, 1219–1232 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kliemann, S. E., Waetge, R. T., Suzuki, O. T., Passos-Bueno, M. R. & Rosemberg, S. Evidence of neuronal migration disorders in Knobloch syndrome: clinical and molecular analysis of two novel families. Am. J. Med. Genet. 119, 15–19 (2003).

    Article  Google Scholar 

  27. Ackley, B. D. et al. The basement membrane components nidogen and type XVIII collagen regulate organization of neuromuscular junctions in Caenorhabditis elegans. J. Neurosci. 23, 3577–3587 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Eklund, L. et al. Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice. Proc. Natl Acad. Sci. USA 98, 1194–1199 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ylikärppä, R. et al. Double knockout mice reveal a lack of major functional compensation between collagens XV and XVIII. Matrix Biol. 22, 443–448 (2003).

    Article  PubMed  CAS  Google Scholar 

  30. Noonan, D. M. et al. The complete sequence of perlecan, a basement membrane heparan sulfate proteoglycan, reveals extensive similarity with laminin A chain, low density lipoprotein-receptor, and the neural cell adhesion molecule. J. Biol. Chem. 266, 22939–22947 (1991). The first complete characterization of the modular nature of perlecan protein core.

    Article  CAS  PubMed  Google Scholar 

  31. Iozzo, R. V. Perlecan: a gem of a proteoglycan. Matrix Biol. 14, 203–208 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. Iozzo, R. V., Cohen, I. R., Grä ssel, S. & Murdoch, A. D. The biology of perlecan: the multifaceted heparan sulphate proteoglycan of basement membranes and pericellular matrices. Biochem. J. 302, 625–639 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dolan, M., Horchar, T., Rigatti, B. & Hassell, J. R. Identification of sites in domain I of perlecan that regulate heparan sulfate synthesis. J. Biol. Chem. 272, 4316–4322 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Friedrich, M. V. K. et al. Structural basis of glycosaminoglycan modification and of heterotypic interactions of perlecan domain V. J. Mol. Biol. 294, 259–270 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Rogalski, T. M., Williams, B. D., Mullen, G. P. & Moerman, D. G. Products of the unc-52 gene in Caenorhabditis elegans are homologous to the core protein of the mammalian basement membrane heparan sulfate proteoglycan. Genes Dev. 7, 1471–1484 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Cohen, I. R., Grä ssel, S., Murdoch, A. D. & Iozzo, R. V. Structural characterization of the complete human perlecan gene and its promoter. Proc. Natl Acad. Sci. USA 90, 10404–10408 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Friedrich, M. V. K., Schneider, M., Timpl, R. & Baumgartner, S. Perlecan domain V of Drosophila melanogaster – sequence, recombinant analysis and tissue expression. Eur. J. Biochem. 267, 3149–3159 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Iozzo, R. V. Biosynthesis of heparan sulfate proteoglycan by human colon carcinoma cells and its localization at the cell surface. J. Cell Biol. 99, 403–417 (1984).

    Article  CAS  PubMed  Google Scholar 

  39. Bix, G. & Iozzo, R. V. Matrix revolutions: 'tails' of basement-membrane components with angiostatic functions. Trends Cell Biol. 15, 52–60 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. SundarRaj, N., Fite, D., Ledbetter, S., Chakravarti, S. & Hassell, J. R. Perlecan is a component of cartilage matrix and promotes chondrocyte attachment. J. Cell Sci. 108, 2663–2672 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Handler, M., Yurchenco, P. D. & Iozzo, R. V. Developmental expression of perlecan during murine embryogenesis. Dev. Dyn. 210, 130–145 (1997). Comprehensive analysis of perlecan expression in murine development.

    Article  CAS  PubMed  Google Scholar 

  42. French, M. M. et al. Expression of the heparan sulfate proteoglycan, perlecan, during mouse embryogenesis and perlecan chondrogenic activity in vitro. J. Cell Biol. 145, 1103–1115 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Melrose, J., Smith, S. & Whitelock, J. Perlecan immunolocalizes to perichondrial vessels and canals in human fetal cartilaginous primordia in early vascular and matrix remodeling events associated with diarthrodial joint development. J. Histochem. Cytochem. 52, 1405–1413 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Govindraj, P. et al. Isolation and identification of the major heparan sulfate proteoglycans in the developing bovine rib growth plate. J. Biol. Chem. 277, 19461–19469 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Iozzo, R. V. & Murdoch, A. D. Proteoglycans of the extracellular environment: clues from the gene and protein side offer novel perspectives in molecular diversity and function. FASEB J. 10, 598–614 (1996).

    Article  CAS  PubMed  Google Scholar 

  46. Nugent, M. A., Nugent, H. M., Iozzo, R. V., Sanchack, K. & Edelman, E. R. Perlecan is required to inhibit thrombosis after deep vascular injury and contributes to endothelial cell-mediated inhibition of intimal hyperplasia. Proc. Natl Acad. Sci. USA 97, 6722–6727 (2000). Presents compelling evidence for a role of perlecan in vascular injury.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tapanadechopone, P., Tumova, S., Jiang, X. & Couchman, J. R. Epidermal transformation leads to increased perlecan synthesis with heparin-binding-growth-factor affinity. Biochem. J. 355, 517–527 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jiang, J. et al. Essential contribution of tumor-derived perlecan to epidermal tumor growth and angiogenesis. J. Histochem. Cytochem. 52, 1575–1590 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Hassell, J. R., Yamada, Y. & Arikawa-Hirasawa, E. Role of perlecan in skeletal development and diseases. Glycoconj. J. 19, 263–267 (2003).

    Article  Google Scholar 

  50. Olsen, B. R. Life without perlecan has its problems. J. Cell Biol. 147, 909–911 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Costell, M. et al. Perlecan maintains the integrity of cartilage and some basement membranes. J. Cell Biol. 147, 1109–1122 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Arikawa-Hirasawa, E., Watanabe, E., Takami, H., Hassell, J. R. & Yamada, Y. Perlecan is essential for cartilage and cephalic development. Nature Genet. 23, 354–358 (1999). References 51 and 52 report the first characterization of perlecan-deficient mice and describe multiple vascular and cartilage abnormalities.

    Article  CAS  PubMed  Google Scholar 

  53. Costell, M. et al. Hyperplastic conotruncal endocardial cushions and transposition of great arteries in perlecan-null mice. Circ. Res. 91, 158–164 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. González-Iriarte, M. et al. Development of the coronary arteries in a murine model of transposition of great arteries. J. Mol. Cell. Cardio. 35, 795–802 (2003).

    Article  CAS  Google Scholar 

  55. Rossi, M. et al. Heparan sulfate chains of perlecan are indispensable in the lens capsule but not in the kidney. EMBO J. 22, 236–245 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tran, P. -K. et al. Increased intimal hyperplasia and smooth muscle cell proliferation in transgenic mice with heparan sulfate-deficient perlecan. Circ. Res. 94, 550–558 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Zhou, Z. et al. Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice. Cancer Res. 64, 4699–4702 (2004). The phenotype of perlecan-null mice is indeed complex, as shown by additional characterization of perlecan-deficient animals (references 53 and 54), or transgenic animals in which the heparan sulphate chains of perlecan were specifically targeted (references 55–57).

    Article  CAS  PubMed  Google Scholar 

  58. Arikawa-Hirasawa, E. et al. Dyssegmental dysplasia, Silverman–Handmaker type, is caused by functional null mutations of the perlecan gene. Nature Genet. 27, 431–434 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Arikawa-Hirasawa, E., Wilcox, W. R. & Yamada, Y. Dyssegmental dysplasia, Silverman–Handmaker type: unexpected role of perlecan in cartilage development. Am. J. Med. Genet. 106, 254–257 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Nicole, S. et al. Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz–Jampel syndrome (chondrodystrophic myotonia). Nature Genet. 26, 480–483 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Arikawa-Hirasawa, E. et al. Structural and functional mutations of the perlecan gene cause Schwartz–Jampel syndrome, with myotonic myopathy and chondrodysplasia. Am. J. Hum. Genet. 70, 1368–1375 (2002). References 58–61 show a direct involvement of perlecan gene mutations in causing two distinct human genetic syndromes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Cartaud, A. et al. MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction. J. Cell Biol. 165, 505–515 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Arikawa-Hirasawa, E., Rossi, S. G., Rotundo, R. L. & Yamada, Y. Absence of acetylcholinesterase at the neuromuscular junctions of perlecan-null mice. Nature Neurosci. 5, 119–123 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Voigt, A., Pflanz, R., Schafer, U. & Jackle, H. Perlecan participates in proliferation activation of quiescent Drosophila neuroblasts. Dev. Dyn. 224, 403–412 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Park, Y. et al. Drosophila perlecan modulates FGF and hedgehog signals to activate neural stem cell division. Dev. Biol. 253, 247–257 (2003). Shows that perlecan is directly involved in modulating growth factors and morphogens during development.

    Article  CAS  PubMed  Google Scholar 

  66. Rogalski, T. M., Gilchrist, E. J., Mullen, G. P. & Moerman, D. G. Mutations in the unc-52 gene responsible for body wall muscle defects in adult Caenorhabditis elegans are located in alternatively spliced exons. Genetics 139, 159–169 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mullen, G. P., Rogalski, T. M., Bush, J. A., Gorji, P. R. & Moerman, D. G. Complex patterns of alternative splicing mediate the spatial and temporal distribution of perlecan/UNC-52 in Caenorhabditis elegans. Mol. Biol. Cell 10, 3205–3221 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Merz, D. C., Alves, G., Kawano, T., Zheng, H. & Culotti, J. G. UNC-52/perlecan affects gonadal leader cell migrations in C. elegans hermaphrodites through alterations in growth factor signaling. Dev. Biol. 256, 173–186 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. O'Reilly, M. S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Hohenester, E., Sasaki, T., Olsen, B. R. & Timpl, R. Crystal structure of the angiogenesis inhibitor endostatin at 1.5 Å resolution. EMBO J. 17, 1656–1664 (1998). An important paper that reports the solution structure of the C-terminal end of collagen XVIII, endostatin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sasaki, T. et al. Structural basis and potential role of heparin/heparan sulfate binding to the angiogenesis inhibitor endostatin. EMBO J. 18, 6240–6248 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kreuger, J. et al. Role of heparan sulfate domain organization in endostatin inhibition of endothelial cell function. EMBO J. 21, 6303–6311 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Boehm, T., Folkman, J., Browder, T. & O'Reilly, M. S. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390, 404–407 (1997).

    Article  CAS  PubMed  Google Scholar 

  74. Sasaki, T. et al. Structure, function and tissue forms of the C-terminal globular domain of collagen XVIII containing the angiogenesis inhibitor endostatin. EMBO J. 17, 4249–4256 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yamaguchi, N. et al. Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding. EMBO J. 18, 4414–4423 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Citrin, D. et al. In vivo tumor imaging in mice with near-infrared labeled endostatin. Mol. Can. Ther. 3, 481–488 (2004). Reports clear evidence that endostatin targets the tumour vasculature.

    CAS  Google Scholar 

  77. Ramchandran, R. et al. Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin. Biochem. Biophys. Res. Commun. 255, 735–739 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Sasaki, T. et al. Endostatins derived from collagens XV and XVIII differ in structural and binding properties, tissue distribution and anti-angiogenic activity. J. Mol. Biol. 301, 1179–1190 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Bilbe, G. et al. Restin: a novel intermediate filament-associated protein highly expressed in the Reed–Sternberg cells of Hodgkin's disease. EMBO J. 11, 2103–2113 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Gaetzner, S. et al. Endostatin's heparan sulfate-binding site is essential for inhibition of angiogenesis and enhances in situ binding to capillary-like structures in bone explants. Matrix Biol. 23, 557–561 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Mongiat, M., Sweeney, S., San Antonio, J. D., Fu, J. & Iozzo, R. V. Endorepellin, a novel inhibitor of angiogenesis derived from the C terminus of perlecan. J. Biol. Chem. 278, 4238–4249 (2003). The first report of endorepellin as an angiostatic factor.

    Article  CAS  PubMed  Google Scholar 

  82. Bix, G. et al. Endoprepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through the α2β1 integrin. J. Cell Biol. 166, 97–109 (2004). This paper addresses the mechanism of action of endorepellin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Miosge, N., Simniok, T., Sprysch, P. & Herken, R. The collagen type XVIII endostatin domain is co-localized with perlecan in basement membranes in vivo. J. Histochem. Cytochem. 51, 285–296 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Gonzalez, E. M. et al. BMP-1/Tolloid-like metalloproteases process endorepellin, the angiostatic C-terminal fragment of perlecan. J. Biol. Chem. 280, 7080–7087 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Hohenester, E., Tisi, D., Talts, J. F. & Timpl, R. The crystal structure of a laminin G-like module reveals the molecular basis of α-dystroglycan binding to laminins, perlecan, and agrin. Mol. Cell 4, 783–792 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Tisi, D., Talts, J. F., Timpl, R. & Hohenester, E. Structure of the C-terminal laminin G-like domain pair of the laminin α2 chain harbouring binding sites for α-dystroglycan and heparin. EMBO J. 19, 1432–1440 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wizemann, H. et al. Distinct requirements for heparin and α-dystroglycan binding revealed by structure-based mutagenesis of the laminin α2 LG4–LG5 domain pair. J. Mol. Biol. 332, 635–642 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Rudenko, G., Hohenester, E. & Muller, Y. A. LG/LNS domains: multiple functions — one business end? Trends Biochem. Sci. 26, 363–368 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Oda, O. et al. Purification and characterization of perlecan fragment in urine of end-stage renal failure patients. Clin. Chim. Acta 255, 119–132 (1996).

    Article  CAS  PubMed  Google Scholar 

  90. Vuadens, F. et al. Identification of biologic markers of the premature rupture of fetal membranes: proteomic approach. Proteomics 3, 1521–1525 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Adkins, J. N. et al. Toward a human blood serum proteome: analysis by multidimensional separation coupled with mass spectrometry. Mol. Cell. Proteom. 1, 947–955 (2002).

    Article  CAS  Google Scholar 

  92. Karumanchi, S. A. et al. Cell surface glypicans are low-affinity endostatin receptors. Mol. Cell 7, 811–822 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. Ortega, N. & Werb, Z. New functional roles for non-collagenous domains of basement membrane collagens. J. Cell Sci. 115, 4201–4214 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Sottile, J. Regulation of angiogenesis by extracellular matrix. Biochim. Biophys. Acta 1654, 13–22 (2004).

    CAS  PubMed  Google Scholar 

  95. Rehn, M. et al. Interaction of endostatin with integrins implicated in angiogenesis. Proc. Natl Acad. Sci. USA 98, 1024–1029 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Wickström, S. A., Alitalo, K. & Keski-Oja, J. Endostatin associates with integrin α5β1 and caveolin-1, and activates Src via a tyrosyl phosphatase-dependent pathway in human endothelial cells. Cancer Res. 62, 5580–5589 (2002).

    PubMed  Google Scholar 

  97. Wickström, S. A., Alitalo, K. & Keski-Oja, J. Endostatin associates with lipid rafts and induces reorganization of the actin cytoskeleton via down-regulation of RhoA activity. J. Biol. Chem. 278, 37895–37901 (2003). References 96 and 97 provide convincing evidence for the binding of endostatin to α 5 β 1 integrin and elucidate its mechanism of action.

    Article  PubMed  Google Scholar 

  98. Sudhakar, A. et al. Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by αvβ3 and α5β1 integrins. Proc. Natl Acad. Sci. USA 100, 4766–4771 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Guo, W. & Giancotti, F. G. Integrin signalling during tumour progression. Nature Rev. Mol. Cell Biol. 5, 816–826 (2004). Excellent review on integrin signalling and cancer.

    Article  CAS  Google Scholar 

  100. Abdollahi, A. H. P. et al. Endostatin's antioangiogenic signaling network. Mol. Cell 13, 649–663 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Emsley, J., Knight, C. G., Farndale, R. W., Barnes, M. J. & Liddington, R. C. Structural basis of collagen recognition by integrin α2β1 . Cell 101, 47–56 (2000).

    Article  CAS  PubMed  Google Scholar 

  102. Whelan, M. C. & Senger, D. R. Collagen I initiates endothelial cell morphogenesis by inducing actin polymerization through suppression of cyclic AMP and protein kinase A. J. Biol. Chem. 278, 327–334 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Sweeney, S. M. et al. Angiogenesis in collagen I requires α2β1 ligation of a GFP*GER sequence and possible p38 MAPK activation and focal adhesion disassembly. J. Biol. Chem. 278, 30516–30524 (2003). References 102 and 103 investigate the role of collagen in inducing vascular morphogenesis.

    Article  CAS  PubMed  Google Scholar 

  104. Keezer, S. M. et al. Angiogenesis inhibitors target the endothelial cell cytoskeleton through altered regulation of heat shock protein 27 and cofilin. Cancer Res. 63, 6405–6412 (2003).

    CAS  PubMed  Google Scholar 

  105. Guex, N. & Peitsch, M. C. SWISS-MODEL and Swiss-Pdb Viewer: An environment for comparative protein modeling. Electrophoresis 18, 2714–2723 (1997).

    Article  CAS  PubMed  Google Scholar 

  106. Aricescu, A. R., McKinnell, I. W., Halfter, W. & Stoker, A. W. Heparan sulfate proteoglycans are ligands for receptor protein tyrosine phosphatase σ. Mol. Cell Biol. 22, 1881–1892 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. van Horssen, J. et al. Collagen XVIII: a novel heparan sulfate proteoglycan associated with vascular amyloid depositions and senile plaques in Alzheimer's disease brains. Brain Pathol. 12, 456–462 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Bengtsson, E. et al. The leucine-rich repeat protein PRELP binds perlecan and collagens and may function as a basement membrane anchor. J. Biol. Chem. 277, 15061–15068 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Knox, S., Merry, C., Stringer, S., Melrose, J. & Whitelock, J. Not all perlecans are created equal. Interactions with fibroblast growth factor (FGF) 2 and FGF receptors. J. Biol. Chem. 277, 14657–14665 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Xu, Y., Liu, Y. J. & Yu, Q. Angiopoietin-3 is tethered on the cell surface via heparan sulfate proteoglycans. J. Biol. Chem. 279, 41179–41188 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Tiedemann, K. et al. Microfibrils at basement membrane zones interact with perlecan via fibrillin-1. J. Biol. Chem. 280, 11404–11412 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Hummel, S. et al. Extracellular matrices of the avian ovarian follicle. Molecular characterization of chicken perlecan. J. Biol. Chem. 279, 23486–23494 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Mongiat, M. et al. The protein core of the proteoglycan perlecan binds specifically to fibroblast growth factor-7. J. Biol. Chem. 275, 7095–7100 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. Göhring, W., Sasaki, T., Heldin, C. H. & Timpl, R. Mapping of the binding of platelet-derived growth factor to distinct domains of the basement membrane proteins BM-40 and perlecan and distinction from the BM-40 collagen-binding epitope. Eur. J. Biochem. 255, 60–66 (1998).

    Article  PubMed  Google Scholar 

  115. Hopf, M., Göhring, W., Kohfeldt, E., Yamada, Y. & Timpl, R. Recombinant domain IV of perlecan binds to nidogens, laminin–nidogen complex, fibronectin, fibulin-2 and heparin. Eur. J. Biochem. 259, 917–925 (1999).

    Article  CAS  PubMed  Google Scholar 

  116. Brown, J. C., Sasaki, T., Göhring, W., Yamada, E. & Timpl, R. The C-terminal domain V of perlecan promotes β1 integrin-mediated cell adhesion, binds heparin, nidogen and fibulin-2 and can be modified by glycosaminoglycans. Eur. J. Biochem. 250, 39–46 (1997).

    Article  CAS  PubMed  Google Scholar 

  117. Talts, J. F., Andac, Z., Göhring, W., Brancaccio, A. & Timpl, R. Binding of the G domains of laminin α1 and α2 chains and perlecan to heparin, sulfatides, α-dystroglycan and several extracellular matrix proteins. EMBO J. 18, 863–870 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Mongiat, M. et al. Perlecan protein core interacts with extracellular matrix protein 1 (ECM1), a glycoprotein involved in bone formation and angiogenesis. J. Biol. Chem. 278, 17491–17499 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Gonzalez, E. M., Mongiat, M., Slater, S. J., Baffa, R. & Iozzo, R. V. A novel interaction between perlecan protein core and progranulin: Potential effects on tumor growth. J. Biol. Chem. 278, 38113–38116 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I thank C. C. Clark and J. Hassell for critical reading of this manuscript, G. Bix and C. C. Reed for help with the illustrations and valuable comments, K. Camphausen for generously providing Fig. 3 and ART (Advanced Research Technologies) Inc. for the help with computer imaging. I apologize for failing to cite all relevant studies in the field because of space constraints. The original research was supported in part by the National Institutes of Health, and by the Commonwealth of Pennsylvania.

Author information

Authors and Affiliations

  1. Department of Pathology, Anatomy and Cell Biology, and the Cellular Biology and Signalling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, 19107, Pennsylvania, USA

    Renato V. Iozzo

Authors
  1. Renato V. Iozzo
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Supplementary information

Related links

Related links

DATABASES

OMIM

Knobloch syndrome

Swiss-Prot

agrin

cle-1

Collagen XVIII

hspg2

Perlecan

unc-52

Flybase

trol

FURTHER INFORMATION

DeepView/Swiss PDB Viewer

Persistence of Vision Raytracer

Glossary

BASEMENT MEMBRANE

A thin, complex extracellular matrix that separates endothelial and epithelial cells from their subjacent connective tissues. It is composed of various collagens, proteoglycans and adhesive glycoproteins.

HEPARAN SULPHATE PROTEOGLYCAN

A specialized protein that has the glycosaminoglycan heparan sulphate covalently attached to a serine residue within a region often enriched in acidic amino acid residues.

MULTIPLEXINS

(Multiple triple helix domains and interruptions.) This collagen subfamily comprises types XV and XVIII, which contain several interruptions in the central triple-helical (Gly–X–Y motif) domain and a unique Cterminal (NC1) domain. The interruptions generate flexible regions that enable the formation of polymers different to those generated by the fibrillar collagen types I, II, III, V and XI.

NEUROMUSCULAR JUNCTION

The site of contact between the terminal of a motor neuron and the membrane of a muscle fibre. Nerve impulses are transmitted across the gap by diffusion of a transmitter.

BASEMENT MEMBRANE ZONE

A region contiguous with the basement membrane where various proteins function as the anchoring structures to the subjacent connective tissue.

FIBROCARTILAGE

A specialized form of cartilage composed of bundles of thick, clearly-defined collagen fibres, which is found in symphyseal joints (such as vertebrae) and in intervertebral and articular discs. It withstands tension and pressure, and absorbs shocks.

CHOROID PLEXI

Collections of villous-like processes at select sites in the ventricular system of the brain. These processes contain a special secretory epithelium that secretes cerebrospinal fluid.

INTEGRINS

A large family of heterodimeric transmembrane proteins that function as receptors for cell-adhesion molecules.

GROWTH PLATE

An area of developing cartilaginous tissue near the ends of long bones, between the widened part of the shaft (the metaphysis) and the end (epiphysis) of the bone. The growth plate regulates and helps determine the length and shape of the mature bone.

WNT PROTEINS

A family of highly conserved, secreted signalling molecules that regulate cell–cell interactions during embryogenesis.

MATRIX METALLOPROTEINASES (MMPs).

A large family of secreted or transmembrane metal-dependent enzymes that collectively can digest all extracellular matrix and basement membrane constituents. They are active during tissue remodelling and angiogenesis.

XENOGRAFT

Tissue or organ graft between species. These grafts are usually rejected unless immunocompromised animals are used.

LG

(Laminin-like globular domain). LG modules are present in a number of basement membrane constituent proteins including laminin, perlecan and agrin. They fold into individual units and often possess important biological activity, as in the case of perlecan LG3.

STRESS FIBRES

Bundles of parallel filaments that contain F-actin and other contractile molecules. They often stretch between cell attachments as if under stress.

COLLAGEN SANDWICH

A widely used in vitro angiogenic assay in which endothelial cells are cultured between two layers of collagen type I. Within hours, visible capillary-like structures are formed.

MATRIGEL

The extracellular matrix secreted by the Engelbrecht–Holm–Swarm mouse sarcoma cell line. It contains laminin, collagen IV, nidogen/entactin and proteoglycans, and therefore resembles the basement membrane.

LIPID RAFTS

Rich in cholesterol, glycosphingolipids, glycosylphosphatidylinositol-anchored proteins and signalling molecules, these membrane microdomains function as signalling platforms.

FOCAL ADHESION

An integrin-mediated cell–substrate adhesion structure that anchors the ends of actin filaments (stress fibres) and mediates strong attachments to substrates. It also functions as an integrin signalling platform.

I DOMAIN

A ∼200 amino-acid inserted domain in the N-terminal region of the α2 and α1 integrin subunits that specifically binds various collagens. The binding is concentration-dependent and requires manganese and magnesium ions. The I domain is also known as MIDAS, for metal ion-dependent adhesion site.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Iozzo, R. Basement membrane proteoglycans: from cellar to ceiling. Nat Rev Mol Cell Biol 6, 646–656 (2005). https://doi.org/10.1038/nrm1702

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1702

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing