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:

Fibulins: a versatile family of extracellular matrix proteins

Nature Reviews Molecular Cell Biology volume 4, pages 479–489 (2003)Cite this article

Key Points

  • The fibulin protein family consists of five isoforms (fibulin-1, -2, -3, -4 and -5), which are localized to the extracellular matrix.

  • Fibulin isoforms vary in size (50–200 kDa) and have an elongated multidomain structure that is dominated by numerous calcium-binding epidermal growth factor-like modules.

  • The fibulins show a widespread deposition in various extracellular structures such as microfibrils, basement membranes and elastic fibres.

  • The widespread distribution of fibulins correlates well with their broad binding repertoire for fibronectin, collagens, basement-membrane proteins, elastin and proteoglycans.

  • The cell-biological activities of fibulins include the binding of integrin receptors and the modulation of cell proliferation and malignant transformation.

  • New information on the biological roles of the fibulins is now becoming available from the analysis of inherited human diseases and transgenic animals.

Abstract

Fibulins are a newly recognized family of extracellular matrix proteins. The five known members of the family share an elongated structure and many calcium-binding sites, owing to the presence of tandem arrays of epidermal growth factor-like domains. They have overlapping binding sites for several basement-membrane proteins, tropoelastin, fibrillin, fibronectin and proteoglycans, and they participate in diverse supramolecular structures. New insights into their biological roles are now emerging from studies of transgenic mice and of some inherited human diseases.

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: The modular domain structure of fibulins as predicted from their sequence.
Figure 2: Potential structural models for anaphylatoxin-like modules and calcium-binding epidermal growth factor-like domain pairs in fibulins.
Figure 3: The exon–intron structure of the human fibulin genes.
Figure 4: The shapes of fibulins.

Similar content being viewed by others

References

  1. Argraves, W. S., Dickerson, K., Burgess, W. H. & Ruoslahti, E. Fibulin, a novel protein that interacts with the fibronectin receptor β subunit cytoplasmic domain. Cell 58, 623–629 (1989).

    Article  CAS  PubMed  Google Scholar 

  2. Argraves, W. S., Tran, H., Burgess, W. H. & Dickerson, K. Fibulin is an extracellular matrix and plasma glycoprotein with repeated domain structure. J. Cell Biol. 111, 3155–3164 (1990). Fibulin-1 is identified and is found to be a new class of ECM protein.

    Article  CAS  PubMed  Google Scholar 

  3. Kluge, M., Mann, K., Dziadek, M. & Timpl, R. Characterization of a novel calcium-binding 90-kDa glycoprotein (BM-90) shared by basement membranes and serum. Eur. J. Biochem. 193, 651–659 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Pan, T. -C. et al. Sequence of extracellular mouse protein BM-90/fibulin and its calcium-dependent binding to other basement membrane ligands. Eur. J. Biochem. 215, 733–740 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Pan, T. -C. et al. Structure and expression of fibulin-2, a novel extracellular matrix protein with multiple EGF-like repeats and consensus motifs for calcium-binding. J. Cell Biol. 123, 1269–1277 (1993). The first evidence that there is a fibulin protein family that contains different fibulin isoforms.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang, R. -Z. et al. Fibulin-2 (FBLN2): human cDNA sequence, mRNA expression and mapping of the gene on human and mouse chromosomes. Genomics 22, 425–430 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. Sasaki, T., Göhring, W., Pan, T. -C., Chu, M. -L. & Timpl, R. Binding of mouse and human fibulin-2 to extracellular matrix ligands. J. Mol. Biol. 254, 892–899 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Sasaki, T. et al. Dimer model for the microfibrillar protein fibulin-2 and identification of the connecting disulfide bridge. EMBO J. 16, 3035–3043 (1997). The first extensive model of the fibulin-2 structure.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tran, H., Mattei, M., Godyna, S. & Argraves, W. S. Human Fibulin-1D: molecular cloning, expression and similarity with S1-5 protein, a new member of the fibulin-1 gene family. Matrix Biol. 15, 479–493 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Giltay, R., Timpl, R. & Kostka, G. Sequence, recombinant expression and tissue localization of two novel extracellular matrix proteins, fibulin-3 and fibulin-4. Matrix Biol. 18, 469–480 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Zhang, H. -Y., Lardelli, M. & Ekblom, P. Sequence of zebrafish fibulin-1 and its expression in developing heart and other embryonic organs. Dev. Genes Evol. 207, 340–351 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Barth, J. L., Argraves, K. M., Roark, E. F., Little, C. D. & Argraves, W. S. Identification of chicken and C. elegans fibulin-1 homologs and characterization of the C. elegans fibulin-1 gene. Matrix Biol. 17, 635–646 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Huber, R., Scholze, H., Paques, E. P. & Deisenhofer, J. Crystal structure analysis and molecular model of human C3a anaphylatoxin. Hoppe-Seyler's Z. Physiol. Chem. 361, 1389–1399 (1989).

    Article  Google Scholar 

  14. Lecka-Czernik, B., Lumpkin, C. K. & Goldstein, S. An overexpressed gene transcript in senescent and quiescent human fibroblasts encoding a novel protein in the epidermal growth factor-like repeat family stimulates DNA synthesis. Mol. Cell. Biol. 15, 120–129 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gallagher, W. M. et al. Human fibulin-4: analysis of its biosynthetic processing and mRNA expression in normal and tumour tissues. FEBS Lett. 489, 59–66 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Maurer, P. & Hohenester, E. Structural and functional aspects of calcium-binding in extracellular matrix proteins. Matrix Biol. 15, 569–580 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Downing, A. K. et al. Solution structure of a pair of calcium-binding epidermal growth factor-like domains: implications for the Marfan syndrome and other genetic disorders. Cell 85, 597–605 (1996). This paper explains how the structure of cbEGF-like modules is stabilized by calcium ligation.

    Article  CAS  PubMed  Google Scholar 

  18. Sasaki, T., Mann, K., Murphy, G., Chu, M. -L. & Timpl, R. Different susceptibilities of fibulin-1 and fibulin-2 to cleavage by matrix metalloproteinases and other tissue proteases. Eur. J. Biochem. 240, 427–434 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Sasaki, T. et al. Structural characterization of two variants of fibulin-1 that differ in nidogen affinity. J. Mol. Biol. 245, 241–250 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Roark, E. F. et al. The association of human fibulin-1 with elastic fibers: an immunohistological, ultrastructural, and RNA study. J. Histochem. Cytochem. 43, 401–411 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Stone, E. M. et al. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nature Genet. 22, 199–202 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Nakamura, T. et al. Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature 415, 171–175 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Yanagisawa, H. et al. Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature 415, 168–171 (2002). This work describes, together with reference 22, the role of fibulin-5 in stabilizing elastic fibres.

    Article  PubMed  Google Scholar 

  24. Spence, S. G., Argraves, W. S., Walters, L., Hungerford, J. E. & Little, C. Fibulin is localized at sites of epithelial–mesenchymal transitions in the early avian embryo. Dev. Biol. 151, 473–484 (1992).

    Article  CAS  PubMed  Google Scholar 

  25. Zhang, H. -Y., Timpl, R., Sasaki, T., Chu, M. -L. & Ekblom, P. Fibulin-1 and fibulin-2 expression during organogenesis in the developing mouse embryo. Dev. Dyn. 205, 348–364 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Miosge, N. et al. The extracellular matrix proteins fibulin-1 and fibulin-2 in the early human embryo. Histochem. J. 28, 109–116 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Hungerford, J. E., Owens, G. K., Argraves, W. S. & Little, C. D. Development of aortic vessel wall as defined by vascular smooth muscle and extracellular matrix markers. Dev. Biol. 178, 375–392 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Bouchey, D., Argraves, W. S. & Little, C. D. Fibulin-1, vitronectin expression during avian cardiac valve and septa development. Anat. Rec. 244, 540–551 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Zhang, H. -Y., Kluge, M., Timpl, R., Chu, M. -L. & Ekblom, P. The extracellular matrix glycoproteins BM-90 and tenascin are expressed in the mesenchyme at sites of endothelial–mesenchymal conversion in the embryonic mouse heart. Differentiation 52, 211–220 (1993).

    Article  CAS  PubMed  Google Scholar 

  30. Zhang, H. -Y. et al. Extracellular matrix protein fibulin-2 is expressed in the embryonic endocardial cushion tissue and is a prominent component of valves in adult heart. Dev. Biol. 167, 18–26 (1995).

    Article  CAS  PubMed  Google Scholar 

  31. Tsuda, T., Wang, H., Timpl, R. & Chu, M. -L. Fibulin-2 expression marks transformed mesenchymal cells in developing cardiac valves, aortic arch vessels and coronary vessels. Dev. Dyn. 222, 89–100 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Miosge, N., Sasaki, T., Chu, M. -L., Herken, R. & Timpl, R. Ultrastructural localization of microfibrillar fibulin-1 and fibulin-2 during heart development indicates a switch in molecular associations. Cell. Mol. Life Sci. 54, 606–613 (1997).

    Article  Google Scholar 

  33. Gallagher, W. M. et al. MBP1: a novel mutant p53-specific protein partner with oncogenic properties. Oncogene 18, 3608–3616 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Kowal, R. C., Richardson, J. A., Miano, J. M. & Olsen, E. N. EVEC. A novel epidermal growth factor-like repeat containing protein upregulated in embryonic and injured adult vasulature. Circ. Res. 84, 1166–1176 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Ohsawa, I., Takamura, C. & Kohsaka, S. Fibulin-1 binds the amino-terminal head of β-amyloid precursor protein. J. Neurochem. 76, 1411–1420 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Reinhardt, D. P. et al. Fibrillin-1 and fibulin-2 interact and are colocalized in some tissues. J. Biol. Chem. 271, 19489–19496 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Sasaki, T. et al. Tropoelastin binding to fibulins, nidogen-2 and other extracellular matrix proteins. FEBS Lett. 460, 280–284 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Sasaki, T., Wiedemann, H., Matzner, M., Chu, M. -L. & Timpl, R. Expression of fibulin-2 by fibroblasts and deposition with fibronectin into a fibrillar matrix. J. Cell Sci. 109, 2895–2904 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Loveland, K. et al. Developmental changes in the basement membrane of the normal and hypothyroid postnatal rat testis: segmental localization of fibulin-2 and fibronectin. Biol. Reprod. 58, 1123–1130 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Raghunath, M. et al. Confocal laser scanning analysis of the association of fibulin-2 with fibrillin-1 and fibronectin define different stages of skin regeneration. J. Invest. Dermatol. 112, 97–101 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Fässler, R., Sasaki, T., Timpl, R., Chu, M. -L. & Werner, S. Differential regulation of fibulin, tenascin and nidogen expression during wound healing of normal and glucocorticoid-treated mice. Exp. Cell Res. 222, 111–116 (1996).

    Article  PubMed  Google Scholar 

  42. Hunzelmann, N., Nischt, R., Brenneisen, P., Eickert, A. & Krieg, T. Increased deposition of fibulin-2 in solar elastosis and its colocalization with elastic fibers. Brit. J. Dermatol. 145, 217–222 (2001).

    Article  CAS  Google Scholar 

  43. Kusubata, M. et al. Spatiotemporal changes of fibronectin, tenascin-C, fibulin-1, and fibulin-2 in the skin during the development of chronic contact dermatitis. J. Invest. Dermatol. 113, 906–912 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Roger, P., Pujol, P., Lucas, A., Baldet, P. & Rochefort, H. Increased immunostaining of fibulin-1, an estrogen-regulated protein in the stroma of human ovarian epithelial tumors. Am. J. Pathol. 153, 1579–1588 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Balbona, K. et al. Fibulin binds to itself and to the carboxyl-terminal heparin-binding region of fibronectin. J. Biol. Chem. 267, 20120–20125 (1992).

    Article  CAS  PubMed  Google Scholar 

  46. Tran, H., Van Dusen, W. J. & Argraves, W. S. The self-association and fibronectin-binding sites of fibulin-1 map to calcium-binding epidermal growth factor-like domains. J. Biol. Chem. 272, 22600–22606 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. Roman, J. & McDonald, J. A. Fibulin's organization into the extracellular matrix of fetal lung fibroblasts is dependent on fibronectin matrix assembly. Am. J. Respir. Cell Mol. Biol. 8, 538–545 (1993).

    Article  CAS  PubMed  Google Scholar 

  48. Godyna, S., Mann, D. M. & Argraves, W. S. A quantitative analysis of the incorporation of fibulin-1 into the extracellular matrix indicates that fibronectin assembly is required. Matrix Biol. 14, 467–477 (1994).

    Article  Google Scholar 

  49. Adam, S. et al. Binding of fibulin-1 to nidogen depends on its C-terminal globular domain and a specific array of calcium-binding epidermal growth factor-like (EG) modules. J. Mol. Biol. 272, 226–236 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Ries, A., Göhring, W., Fox, J. W., Timpl, R. & Sasaki, T. Recombinant domains of mouse nidogen-1 and their binding to basement membrane proteins and monoclonal antibodies. Eur. J. Biochem. 268, 5119–5128 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. 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 

  52. Hopf, M., Göhring, W., Mann, K. & Timpl, R. Mapping of binding sites for nidogens, fibulin-2, fibronectin and heparin to different IG modules of perlecan. J. Mol. Biol. 311, 529–541 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Timpl, R. et al. Structure and function of laminin LG modules. Matrix Biol. 19, 309–317 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. 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 

  55. Utani, A., Nomizu, M. & Yamada, Y. Fibulin-2 binds to the short arms of laminin-5 and laminin-1 via conserved amino acid sequences. J. Biol. Chem. 272, 2814–2820 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Sasaki, T. et al. Short arm region of laminin-5 γ-2 chain: structure, mechanism of processing and binding to heparin and proteins. J. Mol. Biol. 314, 751–763 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. 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 

  58. 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 

  59. Sasaki, T., Hohenester, E. & Timpl, R. Structure and function of collagen-derived endostatin inhibitors of angiogenesis. IUBMB Life 53, 77–84 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Ruoslahti, E. Brain extracellular matrix. Glycobiology 6, 489–492 (1996).

    Article  CAS  PubMed  Google Scholar 

  61. Aspberg, A., Adam, S., Kostka, G., Timpl, R. & Heinegard, D. Fibulin-1 is a ligand for the C-type lectin domains of aggrecan and versican. J. Biol. Chem. 274, 20444–20449 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Olin, A. J. et al. The proteoglycans aggrecan and versican form networks with fibulin-2 through their lectin domain binding. J. Biol. Chem. 276, 1253–1261 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Tran, H. et al. The interaction of fibulin-1 with fibrinogen. A potential role in hemostasis and thrombosis. J. Biol. Chem. 270, 19458–19464 (1995).

    Article  CAS  PubMed  Google Scholar 

  64. Godyna, S., Dias-Ricart, M. & Argraves, W. S. Fibulin-1 mediates platelet adhesion via a bridge of fibrinogen. Blood 88, 2569–2577 (1996).

    Article  CAS  PubMed  Google Scholar 

  65. Kostka, G. et al. Perinatal lethality and endothedlial cell abnormalities in several vessel compartments of fibulin-1 deficient mice. Mol. Cell. Biol. 21, 7025–7034 (2001). This paper shows that a fibulin-1 deficiency causes a haemorrhagic phenotype.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Perbal, B. et al. The C-terminal domain of the regulatory protein NOVH is sufficient to promote interaction with fibulin-1C: a clue for a role of NOVH in cell-adhesion signalling. Proc. Natl Acad. Sci. USA 96, 869–874 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Pfaff, M., Sasaki, T., Tangemann, K., Chu, M. -L. & Timpl, R. Integrin-binding and cell-adhesion studies of fibulins reveal a particular affinity for αIIbβ3. Exp. Cell Res. 219, 87–92 (1995).

    Article  CAS  PubMed  Google Scholar 

  68. Twal, W. O. et al. Fibulin-1 suppression of fibronectin-regulated cell adhesion and motility. J. Cell Sci. 114, 4587–4598 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Nakamura, T. et al. DANCE, a novel secreted RGD protein expressed in developing, atherosclerotic, and balloon-injured arteries. J. Biol. Chem. 274, 22476–22483 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Schiemann, W. P., Blobe, G. C., Kalume, D. E., Pandey, A. & Lodish, H. F. Context-specific effects of fibulin-5 (DANCE/EVEC) on cell proliferation, motility, and invasion. Fibulin-5 is induced by transforming growth factor-β and affects protein kinase cascades. J. Biol. Chem. 277, 27367–27377 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Heine, H., Delude, R. L., Monks, B. G., Esperik, T. & Golenbock, D. T. Bacterial lipopolysaccharide induces expression of the stress response genes hop and H411. J. Biol. Chem. 274, 21049–21055 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Qing, J. et al. Surpression of anchorage-independent growth and matrigel invasion and delayed tumor formation by elevated expression of fibulin-1D in human fibrosarcoma-derived cell lines. Oncogene 15, 2159–2168 (1997).

    Article  CAS  PubMed  Google Scholar 

  73. Clinton, G. M. et al. Estrogens increase the expression of fibulin-1, an extracellular matrix protein secreted by human ovarian cancer cells. Proc. Natl Acad Sci. USA 93, 316–320 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hayashido, Y. et al. Estradiol and fibulin-1 inhibit motility of human ovarian- and breast-cancer cells induced by fibronectin. Int. J. Cancer 75, 654–658 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Debeer, P. et al. The fibulin-1 gene (FLBN1) is disrupted in a t(12;22) associated with a complex type of synpolydactyly. J. Med. Genet. 39, 98–104 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tartellin, E. E. et al. Molecular genetic heterogeneity in autosomal dominant drusen. J. Med. Genet. 38, 381–384 (2001).

    Article  Google Scholar 

  77. Marmorstein, L. Y. et al. Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration. Proc. Natl Acad. Sci. USA 99, 13067–13072 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Midwood, K. S. & Schwarzbauer, J. E. Elastic fibres: building bridges between cells and their matrix. Curr. Biol. 12, R279–R281 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Loeys, B. et al. Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum. Mol. Genet. 11, 2113–2118 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Markova, D. et al. Genetic heterogeneity of cutis laxa: a heterozygous tandem duplication within the fibulin-5 (FBLN5) gene. Am. J. Hum. Genet. 72, 998–1004 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kielty, C. M., Sherrat, M. J. & Shuttleworth, C. A. Elastic fibers. J. Cell Sci. 115, 2817–2828 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Dietz, H. C. & Mecham, R. P. Mouse models of genetic diseases resulting from mutations in elastic fiber proteins. Matrix Biol. 19, 481–488 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Milewicz, D. M., Urban, Z. & Boyd, C. Genetic disorders of the elastic fiber system. Matrix Biol. 19, 471–480 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Pan, T. -C., Kostka, G., Zhang, R. -Z., Timpl, R. & Chu, M. -L. Complete exon–intron organization of the mouse fibulin-1 gene and its comparison with the human fibulin-1 gene. FEBS Lett. 444, 38–42 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Mattei, M. G., Pan, T. -C., Zhang, R. -Z., Timpl, R. & Chu, M. -L. The fibulin-1 gene (FBLN1) is located on human chromosome 22 and mouse chromosome 15. Genomics 22, 437–438 (1994).

    Article  CAS  PubMed  Google Scholar 

  86. Grässel, S., Sicot, F. -X., Gotta, S. & Chu, M. -L. Mouse fibulin-2 gene. Complete exon–intron organization and promoter characterization. Eur. J. Biochem. 263, 471–477 (1999).

    Article  PubMed  Google Scholar 

  87. Ikegawa, S., Toda, T., Okui, K. & Nakamura, Y. Structure and chromosomal assignment of the human S1-5 gene (FBNL) that is highly homologous to fibrillin. Genomics 35, 590–592 (1996).

    Article  CAS  PubMed  Google Scholar 

  88. Katsanis, N., Venable, S., Smith, J. R. & Lupski, J. R. Isolation of a paralog of the Doyne honeycombe retinal dystrophy gene from the multiple retinopathy critical region on 11q13. Hum. Genet. 106, 66–72 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Kowal, R. C., Jolsin, J. M., Olson, E. N. & Schultz, R. A. Assignment of fibulin–5 (FBLN5) to human chromosome 14q31 by in situ hybridization and radiation hybrid mapping. Cytogenet. Cell Genet. 87, 2–3 (1999).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Part of the work described here was supported by research grants from the Deutsche Forschungsgemeinschaft for T.S. and R.T., the European Community for R.T., and the National Institutes of Health for M.-L.C. The authors are grateful to S. Argraves for communicating unpublished work and to J. Uitto for critically reading the manuscript.

Author information

Authors and Affiliations

  1. Laboratory of Protein Chemistry, Max Planck Institute for Biochemistry, Martinsried, D-82152, Germany

    Rupert Timpl

  2. Department of Molecular Medicine, Max Planck Institute for Biochemistry, Martinsried, D-82152, Germany

    Takako Sasaki & Günter Kostka

  3. Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, 19107, USA

    Mon-Li Chu

Authors
  1. Rupert Timpl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takako Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Günter Kostka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mon-Li Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rupert Timpl.

Related links

Related links

DATABASES

InterPro

AT module

cbEGF-like module

C-type lectin domain

EGF-like module

LG

LocusLink

collagen IV

fibrinogen

laminin-1

Swiss-Prot

ADAMTS-1

aggrecan

brevican

fibrillin-1

fibronectin

fibulin-1

fibulin-2

fibulin-3

fibulin-4

fibulin-5

neurocan

nidogen-1

perlecan

tropoelastin

versican

FURTHER INFORMATION

GenBank database

National Center for Biotechnology Information

Glossary

EDTA

(ethylenediamine tetra-acetic acid). A strong chelator of bivalent cations.

Kd VALUE

The equilibrium dissociation constant of bimolecular reactions.

PERINEURAL TISSUE

The tissue around a nerve or group of nerves.

ELASTOTIC SKIN

Skin that shows degenerative changes of the elastic fibres. The condition can be associated with skin diseases, ageing or prolonged exposure to sunlight.

CONTACT DERMATITIS

Itching, redness or inflammation of the skin that is caused by direct exposure to irritating substances, such as chemicals, metals, clothing, cosmetics and plants.

ELASTINOPATHY

Pathological changes of the elastic fibres that lead to various degenerative diseases.

MESENCHYMAL TISSUE

The tissue that originates from mesenchymal cells, which are unspecified cells that are derived mainly from the primitive mesoderm during embryogenesis. The connective tissues of the body develop from the mesenchymal cells.

ANGIOGENESIS

A process of blood-vessel branching, in which blood vessels sprout from small capillaries.

RGD-DEPENDENT INTEGRINS

A specific group of cellular integrin receptors that bind to the arginine-glycine-aspartate (RGD) sequences of their ligands.

WERNER SYNDROME

A premature ageing disorder that is inherited in an autosomal recessive mode. The clinical symptoms can include short stature, wrinkled skin, baldness, cataracts and muscular atrophy.

SYNPOLYDACTYLY

A developmental defect that is characterized by the fusion (syndactyly) and splitting (polydactyly) of fingers or toes. It is usually an autosomal dominant disease and can result from mutations in the homeobox genes.

MACULAR DEGENERATIVE DISEASE

An incurable eye disease that is caused by the deterioration of the central portion of the retina, which is known as the macula. The disease is heterogeneous and includes the rare heritable forms, the sporadic early-onset form and the age-related form.

MARFAN SYNDROME

A heritable connective tissue disease that affects several organ systems, including the skeleton, eyes, lungs, heart and blood vessels. The disease is caused by dominant mutations in the fibrillin-1 gene.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Timpl, R., Sasaki, T., Kostka, G. et al. Fibulins: a versatile family of extracellular matrix proteins. Nat Rev Mol Cell Biol 4, 479–489 (2003). https://doi.org/10.1038/nrm1130

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1130

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