SpringerLink
Log in

Soluble N-cadherin fragment promotes angiogenesis

  • Original Research Paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Endothelial cells express two dependent intercellular adhesion molecules: vascular endothelial (VE)-cadherin, specific for endothelial cells, and N-cadherin, also present in neuronal, lens, skeletal and heart muscle cells, osteoblasts, pericytes and fibroblasts. While there exists a vast amount of evidence that VE-cadherin promotes angiogenesis, the role of N-cadherin still remains to be elucidated. We found that a soluble 90-kDa fragment N-cadherin promotes angiogenesis in the rabbit cornea assay and in the chorioallantoic assay when cleaved enzymatically from the extracellular domain of N-cadherin. Soluble N-cadherin stimulates migration of endothelial cells in the wound healing assay and stimulates phosphorylation of extracellular regulated kinase. In vitro experiments with PD173074 and knock-down of N-cadherin and fibroblast growth factor (FGF)-receptor, showed that the pro-angiogenic effect of soluble N-cadherin is N-cadherin- and FGF-receptor-dependent. Our results suggest that soluble N-cadherin stimulates migration of endothelial cells through the FGF-receptor.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jain RK, Schlenger K, Höckel M, Yuan F (1997) Quantitative angiogenesis assays: progress and problems. Nat Med 3:1203–1208

    Article  PubMed  CAS  Google Scholar 

  2. Carmeliet P, Lampugnani M-G, Moons L et’al (1999) Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98:147–157

    Article  PubMed  CAS  Google Scholar 

  3. Fukumura D, Xavier R, Sugiura T et’al (1998) Tumor induction of VEGF promoter activity in stromal cells. Cell 94:715–725

    Article  PubMed  CAS  Google Scholar 

  4. Yancopoulos GD, Davis S, Gale NW et’al (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248

    Article  PubMed  CAS  Google Scholar 

  5. Chang C, Werb Z (2001) The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis. Trends Cell Biol 11:S37–S43

    PubMed  CAS  Google Scholar 

  6. Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395

    Article  PubMed  CAS  Google Scholar 

  7. Haas TL, Davis SJ, Madri JA (1998) Three-dimensional type I collagen lattices induce coordinate expression of matrix metalloproteinases MT1-MMP and MMP-2 in microvascular endothelial cells. J Biol Chem 273:3604–3610

    Article  PubMed  CAS  Google Scholar 

  8. Eliceiri BP (2001) Integrin and growth factor receptor crosstalk. Circ Res 89:1104–1110

    PubMed  CAS  Google Scholar 

  9. Friedlander M, Brooks PC, Shaffer RW et’al (1995) Definition of two angiogenic pathways by distinct αv integrins. Science 270:1500–1502

    Article  PubMed  CAS  Google Scholar 

  10. Rusnati M, Tanghetti E, Dell’Era P et’al (1997) αvβ3 integrin mediates the cell-adhesive capacity and biological activity of basic fibroblast growth factor (FGF-2) in cultured endothelial cells. Mol Biol Cell 8:2449–2461

    PubMed  CAS  Google Scholar 

  11. Presta M, Dell’Era P, Mitola S et’al (2005) Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 16:159–178

    Article  PubMed  CAS  Google Scholar 

  12. Wei Y, Waltz DA, Rao N et’al (1994) Identification of the urokinase receptor as an adhesion receptor for vitronectin. J␣Biol Chem 269:32380–32388

    PubMed  CAS  Google Scholar 

  13. Andreasen PA, Kjøller L, Christensen L, Duffy MJ (1997) The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 72:1–22

    Article  PubMed  CAS  Google Scholar 

  14. Soler AP, Knudsen KA (1994) N-cadherin involvement in cardiac myocyte interaction and myofibrillogenesis. Dev Biol 162:9–17

    Article  PubMed  CAS  Google Scholar 

  15. Derycke LDM, Bracke ME (2004) N-cadherin in the spotlight of cell–cell adhesion, differentiation, embryogenesis, invasion and signalling. Int J Dev Biol 48:463–476

    Article  PubMed  CAS  Google Scholar 

  16. Schnädelbach O, Blaschuk OW, Symonds M et’al (2000) N-cadherin influences migration of oligodendrocytes on astrocyte monolayers. Mol Cell Neurosci 15:288–302

    Article  PubMed  CAS  Google Scholar 

  17. Navarro P, Ruco L, Dejana E (1998) Differential localization of VE- and N-cadherins in human endothelial cells: VE-cadherin competes with N-cadherin for junctional localization. J Cell Biol 140:1475–1484

    Article  PubMed  CAS  Google Scholar 

  18. Gerhardt H, Wolburg H, Redies C (2000) N-cadherin mediates pericytic-endothelial interaction during brain angiogenesis in the chicken. Dev Dyn 218:472–479

    Article  PubMed  CAS  Google Scholar 

  19. Dejana E (2004) Endothelial cell–cell junctions: happy together. Nat Rev Mol Cell Biol 5:261–270

    Article  PubMed  CAS  Google Scholar 

  20. Luo Y, Radice GL (2005) N-cadherin acts upstream of VE-cadherin in controlling vascular morphogenesis. J Cell Biol 169:29–34

    Article  PubMed  CAS  Google Scholar 

  21. Noë V, Fingleton B, Jacobs K et’al (2001) Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 114:111–118

    PubMed  Google Scholar 

  22. Ryniers F, Stove C, Goethals M et’al (2002) Plasmin produces an E-cadherin fragment that stimulates cancer cell invasion. Biol Chem 383:159–165

    Article  PubMed  CAS  Google Scholar 

  23. Paradies NE, Grunwald GB (1993) Purification and characterization of NCAD90, a soluble endogenous form of N-cadherin, which is generated by proteolysis during retinal development and retains adhesive and neurite-promoting function. J Neurosci Res 36:33–45

    Article  PubMed  CAS  Google Scholar 

  24. Lassalle P, LaGrou C, Delneste Y et’al (1992) Human endothelial cells transfected by SV40 T antigens: characterization and potential use as a source of normal endothelial factors. Eur J Immunol 22:425–431

    PubMed  CAS  Google Scholar 

  25. Mège RM, Matsuzaki F, Gallin WJ et’al (1988) Construction of epithelioid sheets by transfection of mouse sarcoma cells with cDNAs for chicken cell adhesion molecules. Proc Natl Acad Sci USA 85:7274–7278

    Article  PubMed  Google Scholar 

  26. Willems J, Bruyneel E, Noë V et’al (1995) Cadherin-dependent cell aggregation is affected by decapeptide derived from rat extracellular super-oxide dismutase. FEBS Lett 363:289–292

    Article  PubMed  CAS  Google Scholar 

  27. Mohammadi M, Froum S, Hamby JM et’al (1998) Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J 17:5896–5904

    Article  PubMed  CAS  Google Scholar 

  28. Hatta K, Takeichi M (1986) Expression of N-cadherin adhesion molecules associated with early morphogenetic events in chick development. Nature 320:447–449

    Article  PubMed  CAS  Google Scholar 

  29. De Wever O, Westbroek W, Verloes A et’al (2004) Critical role of N-cadherin in myofibroblast invasion and migration in vitro stimulated by colon-cancer-cell-derived TGF-β or wounding. J Cell Sci 117:4691–4703

    Article  PubMed  CAS  Google Scholar 

  30. Ziche M, Morbidelli L, Masini E et’al (1994) Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest 94:2036–2044

    Article  PubMed  CAS  Google Scholar 

  31. Ziche M, Morbidelli L, Choudhuri R et’al (1997) Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis. J Clin Invest 99:2625–2634

    PubMed  CAS  Google Scholar 

  32. Maragoudakis ME, Panoutsacopoulou M, Sarmonika M (1988) Rate of basement biosynthesis as an index to angiogenesis. Tissue Cell 20:531–539

    Article  PubMed  CAS  Google Scholar 

  33. Harris-Hooker SA, Gajdusek CM, Wight TN, Schwartz SM (1983) Neovascular responses induced by cultured aortic endothelial cells. J Cell Physiol 114:302–310

    Article  PubMed  CAS  Google Scholar 

  34. Derycke L, De Wever O, Stove V et al (2006) Soluble N-cadherin in human biological fluids. Int J Cancer In Press.

  35. Suyama K, Shapiro I, Guttman M, Hazan RB (2002) A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer Cell 2:301–314

    Article  PubMed  CAS  Google Scholar 

  36. Erez N, Zamir E, Gour BJ, Blaschuk OW et’al (2004) Induction of apoptosis in cultured endothelial cells by a cadherin antagonist peptide: involvement of fibroblast growth factor receptor-mediated signaling. Exp Cell Res 294:366–378

    Article  PubMed  CAS  Google Scholar 

  37. Williams E, Williams G, Gour BJ et’al (2000) A novel family of cyclic peptide antagonists suggests that N-cadherin specificity is determined by amino acids that flank the HAV motif. J Biol Chem 275:4007–4012

    Article  PubMed  CAS  Google Scholar 

  38. Skaper SD, Facci L, Williams G et’al (2004) A dimeric version of the short N-cadherin binding motif HAVDI promotes neuronal cell survival by activating an N-cadherin/fibroblast growth factor receptor signalling cascade. Mol Cell Neurosci 26:17–23

    Article  PubMed  CAS  Google Scholar 

  39. Williams G, Williams E-J, Doherty P (2002) Dimeric versions of two short N-cadherin binding motifs (HAVDI and INPISG) function as N-cadherin agonists. J Biol Chem 277:4361–4367

    Article  PubMed  CAS  Google Scholar 

  40. Reiss K, Maretzky T, Ludwig A et’al (2005) ADAM10 cleavage of N-cadherin and regulation of cell–cell adhesion and β-catenin nuclear signalling. EMBO J 24:742–752

    Article  PubMed  CAS  Google Scholar 

  41. Marambaud P, Wen PH, Dutt A et’al (2003) A CBP binding␣transcriptional repressor produced by the PS1/ε-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 114:635–645

    Article  PubMed  CAS  Google Scholar 

  42. Hunter I, McGregor D, Robins SP (2001) Caspase-dependent cleavage of cadherins and catenins during osteoblast apoptosis. J Bone Miner Res 16:466–477

    Article  PubMed  CAS  Google Scholar 

  43. Islam S, Carey TE, Wolf GT et’al (1996) Expression of N-cadherin by human squamous carcinoma cells induces a scattered fibroblastic phenotype with disrupted cell–cell adhesion. J Cell Biol 135:1643–1654

    Article  PubMed  CAS  Google Scholar 

  44. Hazan RB, Kang L, Whooley BP, Borgen PI (1997) N-cadherin promotes adhesion between invasive breast cancer cells and the stroma. Cell Adhes Commun 4:399–411

    PubMed  CAS  Google Scholar 

  45. Kim J-B, Islam S, Kim YJ et’al (2000) N-cadherin extracellular repeat 4 mediates epithelial to mesenchymal transition and increased motility. J Cell Biol 151:1193–1206

    Article  PubMed  CAS  Google Scholar 

  46. Utton MA, Eickholt B, Howell FV et’al (2001) Soluble N-cadherin stimulates fibroblast growth factor receptor dependent neurite outgrowth and N-cadherin and the fibroblast growth factor receptor co-cluster in cells. J Neurochem 76:1421–1430

    Article  PubMed  CAS  Google Scholar 

  47. Doherty P, Walsh FS (1996) CAM-FGF receptor interactions: a model for axonal growth. Mol Cell Neurosci 8:99–111

    Article  CAS  Google Scholar 

  48. Williams E, Furness J, Walsh FS, Doherty P (1994) Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, NCAM and N-cadherin. Neuron 13:583–594

    Article  PubMed  CAS  Google Scholar 

  49. Cavallaro U, Niedermeyer J, Fuxa M, Christofori G (2001) N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling. Nat Cell Biol 3:650–657

    Article  PubMed  CAS  Google Scholar 

  50. Nayeem N, Silletti S, Yang X-M et’al (1999) A potential role for the plasmin(ogen) system in the posttranslational cleavage of the neural cell adhesion molecule L1. J Cell Sci 112:4739–4749

    PubMed  CAS  Google Scholar 

  51. Mechtersheimer S, Gutwein P, Agmon-Levin N et’al (2001) Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins. J Cell Biol 155:661–673

    Article  PubMed  CAS  Google Scholar 

  52. Sato Y (2001) Role of ETS family transcription factors in vascular development and angiogenesis. Cell Struct Funct 26:19–24

    Article  PubMed  CAS  Google Scholar 

  53. Hashiya N, Jo N, Aoki M et’al (2004) In vivo evidence of angiogenesis induced by transcription factor Ets-1. Ets-1 is located upstream of angiogenesis cascade. Circulation 109:3035–3041

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge G. De Bruyne for technical assistance, J. Roels for preparation of the illustrations. We thank J. Willems (Kortrijk, Belgium), P. Doherty (London, UK), C. Redies (Essen, Germany), R.M. Megè (Paris, France) and M. Wheelock (Toledo, USA) for providing reagents. This work was supported by FWO (Fonds voor Wetenschappelijk Onderzoek)-Flanders, Brussels, Belgium, by BACR (Belgian Association for Cancer Research), Belgium, by the Sixth Framework program of the European Community (METABRE, LSHC-CT-2004-503049) and by the Italian Ministry for University and Research (FIRB project no. RBNE01M9HS_002, RBNE01458S_007) (to M.Z.). L.D. is supported by a fellowship from the “Centrum voor Gezwelziekten,” University of Ghent, Belgium.

Author information

Authors and Affiliations

  1. Laboratory of Experimental Cancerology, Department of Radiotherapy and Nuclear Medicine, Ghent University Hospital, De Pintelaan 185, 9000, Gent, Belgium

    L. Derycke, O. De Wever & M. Bracke

  2. Laboratory of Angiogenesis, Section of Pharmacology, Department of Molecular Biology, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy

    L. Morbidelli & M. Ziche

  3. Department of Ophthalmology, Ghent University Hospital, De Pintelaan 185, 9000, Gent, Belgium

    E. Van Aken

Authors
  1. L. Derycke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Morbidelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Ziche
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. O. De Wever
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Bracke
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. Van Aken
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L. Derycke.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Derycke, L., Morbidelli, L., Ziche, M. et al. Soluble N-cadherin fragment promotes angiogenesis. Clin Exp Metastasis 23, 187–201 (2006). https://doi.org/10.1007/s10585-006-9029-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-006-9029-7

Keywords

Search

Navigation