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. 1996 Aug 15;98(4):886–893. doi: 10.1172/JCI118870

Inhibition of cultured cell growth by vascular endothelial cadherin (cadherin-5/VE-cadherin).

L Caveda 1, I Martin-Padura 1, P Navarro 1, F Breviario 1, M Corada 1, D Gulino 1, M G Lampugnani 1, E Dejana 1
PMCID: PMC507501  PMID: 8770858

Abstract

Endothelial cell proliferation is inhibited by the establishment of cell to cell contacts. Adhesive molecules at junctions could therefore play a role in transferring negative growth signals. The transmembrane protein VE-cadherin (vascular endothelial cadherin/cadherin-S) is selectively expressed at intercellular clefts in the endothelium. The intracellular domain interacts with cytoplasmic proteins called catenins that transmit the adhesion signal and contribute to the anchorage of the protein to the actin cytoskeleton. Transfection of VE-cadherin in both Chinese hamster ovary (CHO) and L929 cells confers inhibition of cell growth. Truncation of VE-cadherin cytoplasmic region, responsible for linking catenins, does not affect VE-cadherin adhesive properties but abolishes its effect on cell growth. Seeding human umbilical vein endothelial cells or VE-cadherin transfectants on a recombinant VE-cadherin amino-terminal fragment inhibited their proliferation. These data show that VE-cadherin homotypic engagement at junctions participates in density dependent inhibition of cell growth. This effect requires both the extracellular adhesive domain and the intracellular catenin binding region of the molecule.

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Selected References

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  1. Arsura M., Introna M., Passerini F., Mantovani A., Golay J. B-myb antisense oligonucleotides inhibit proliferation of human hematopoietic cell lines. Blood. 1992 May 15;79(10):2708–2716. [PubMed] [Google Scholar]
  2. Ausio J. Structure and dynamics of transcriptionally active chromatin. J Cell Sci. 1992 May;102(Pt 1):1–5. doi: 10.1242/jcs.102.1.1. [DOI] [PubMed] [Google Scholar]
  3. Balzac F., Belkin A. M., Koteliansky V. E., Balabanov Y. V., Altruda F., Silengo L., Tarone G. Expression and functional analysis of a cytoplasmic domain variant of the beta 1 integrin subunit. J Cell Biol. 1993 Apr;121(1):171–178. doi: 10.1083/jcb.121.1.171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Breier G., Breviario F., Caveda L., Berthier R., Schnürch H., Gotsch U., Vestweber D., Risau W., Dejana E. Molecular cloning and expression of murine vascular endothelial-cadherin in early stage development of cardiovascular system. Blood. 1996 Jan 15;87(2):630–641. [PubMed] [Google Scholar]
  5. Breviario F., Caveda L., Corada M., Martin-Padura I., Navarro P., Golay J., Introna M., Gulino D., Lampugnani M. G., Dejana E. Functional properties of human vascular endothelial cadherin (7B4/cadherin-5), an endothelium-specific cadherin. Arterioscler Thromb Vasc Biol. 1995 Aug;15(8):1229–1239. doi: 10.1161/01.atv.15.8.1229. [DOI] [PubMed] [Google Scholar]
  6. DeLisser H. M., Yan H. C., Newman P. J., Muller W. A., Buck C. A., Albelda S. M. Platelet/endothelial cell adhesion molecule-1 (CD31)-mediated cellular aggregation involves cell surface glycosaminoglycans. J Biol Chem. 1993 Jul 25;268(21):16037–16046. [PubMed] [Google Scholar]
  7. Dejana E., Corada M., Lampugnani M. G. Endothelial cell-to-cell junctions. FASEB J. 1995 Jul;9(10):910–918. [PubMed] [Google Scholar]
  8. Dejana E., Lampugnani M. G., Giorgi M., Gaboli M., Marchisio P. C. Fibrinogen induces endothelial cell adhesion and spreading via the release of endogenous matrix proteins and the recruitment of more than one integrin receptor. Blood. 1990 Apr 1;75(7):1509–1517. [PubMed] [Google Scholar]
  9. Del Sal G., Ruaro M. E., Philipson L., Schneider C. The growth arrest-specific gene, gas1, is involved in growth suppression. Cell. 1992 Aug 21;70(4):595–607. doi: 10.1016/0092-8674(92)90429-g. [DOI] [PubMed] [Google Scholar]
  10. Fawcett J., Buckley C., Holness C. L., Bird I. N., Spragg J. H., Saunders J., Harris A., Simmons D. L. Mapping the homotypic binding sites in CD31 and the role of CD31 adhesion in the formation of interendothelial cell contacts. J Cell Biol. 1995 Mar;128(6):1229–1241. doi: 10.1083/jcb.128.6.1229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Folkman J., Shing Y. Angiogenesis. J Biol Chem. 1992 Jun 5;267(16):10931–10934. [PubMed] [Google Scholar]
  12. Frixen U. H., Behrens J., Sachs M., Eberle G., Voss B., Warda A., Löchner D., Birchmeier W. E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol. 1991 Apr;113(1):173–185. doi: 10.1083/jcb.113.1.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Geiger B., Ayalon O. Cadherins. Annu Rev Cell Biol. 1992;8:307–332. doi: 10.1146/annurev.cb.08.110192.001515. [DOI] [PubMed] [Google Scholar]
  14. Golay J., Capucci A., Arsura M., Castellano M., Rizzo V., Introna M. Expression of c-myb and B-myb, but not A-myb, correlates with proliferation in human hematopoietic cells. Blood. 1991 Jan 1;77(1):149–158. [PubMed] [Google Scholar]
  15. Grunwald G. B. The structural and functional analysis of cadherin calcium-dependent cell adhesion molecules. Curr Opin Cell Biol. 1993 Oct;5(5):797–805. doi: 10.1016/0955-0674(93)90028-o. [DOI] [PubMed] [Google Scholar]
  16. Gulino D., Boudignon C., Zhang L. Y., Concord E., Rabiet M. J., Marguerie G. Ca(2+)-binding properties of the platelet glycoprotein IIb ligand-interacting domain. J Biol Chem. 1992 Jan 15;267(2):1001–1007. [PubMed] [Google Scholar]
  17. Heasman J., Crawford A., Goldstone K., Garner-Hamrick P., Gumbiner B., McCrea P., Kintner C., Noro C. Y., Wylie C. Overexpression of cadherins and underexpression of beta-catenin inhibit dorsal mesoderm induction in early Xenopus embryos. Cell. 1994 Dec 2;79(5):791–803. doi: 10.1016/0092-8674(94)90069-8. [DOI] [PubMed] [Google Scholar]
  18. Heimark R. L., Degner M., Schwartz S. M. Identification of a Ca2(+)-dependent cell-cell adhesion molecule in endothelial cells. J Cell Biol. 1990 May;110(5):1745–1756. doi: 10.1083/jcb.110.5.1745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Heimark R. L., Schwartz S. M. The role of membrane-membrane interactions in the regulation of endothelial cell growth. J Cell Biol. 1985 Jun;100(6):1934–1940. doi: 10.1083/jcb.100.6.1934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hinck L., Näthke I. S., Papkoff J., Nelson W. J. Beta-catenin: a common target for the regulation of cell adhesion by Wnt-1 and Src signaling pathways. Trends Biochem Sci. 1994 Dec;19(12):538–542. doi: 10.1016/0968-0004(94)90057-4. [DOI] [PubMed] [Google Scholar]
  21. Hülsken J., Behrens J., Birchmeier W. Tumor-suppressor gene products in cell contacts: the cadherin-APC-armadillo connection. Curr Opin Cell Biol. 1994 Oct;6(5):711–716. doi: 10.1016/0955-0674(94)90098-1. [DOI] [PubMed] [Google Scholar]
  22. Kemler R. Classical cadherins. Semin Cell Biol. 1992 Jun;3(3):149–155. doi: 10.1016/s1043-4682(10)80011-x. [DOI] [PubMed] [Google Scholar]
  23. Kemler R. From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet. 1993 Sep;9(9):317–321. doi: 10.1016/0168-9525(93)90250-l. [DOI] [PubMed] [Google Scholar]
  24. Klymkowsky M. W., Parr B. The body language of cells: the intimate connection between cell adhesion and behavior. Cell. 1995 Oct 6;83(1):5–8. doi: 10.1016/0092-8674(95)90226-0. [DOI] [PubMed] [Google Scholar]
  25. Lampugnani M. G., Corada M., Caveda L., Breviario F., Ayalon O., Geiger B., Dejana E. The molecular organization of endothelial cell to cell junctions: differential association of plakoglobin, beta-catenin, and alpha-catenin with vascular endothelial cadherin (VE-cadherin). J Cell Biol. 1995 Apr;129(1):203–217. doi: 10.1083/jcb.129.1.203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lampugnani M. G., Resnati M., Dejana E., Marchisio P. C. The role of integrins in the maintenance of endothelial monolayer integrity. J Cell Biol. 1991 Feb;112(3):479–490. doi: 10.1083/jcb.112.3.479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lampugnani M. G., Resnati M., Raiteri M., Pigott R., Pisacane A., Houen G., Ruco L. P., Dejana E. A novel endothelial-specific membrane protein is a marker of cell-cell contacts. J Cell Biol. 1992 Sep;118(6):1511–1522. doi: 10.1083/jcb.118.6.1511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Martìn-Padura I., De Castellarnau C., Uccini S., Pilozzi E., Natali P. G., Nicotra M. R., Ughi F., Azzolini C., Dejana E., Ruco L. Expression of VE (vascular endothelial)-cadherin and other endothelial-specific markers in haemangiomas. J Pathol. 1995 Jan;175(1):51–57. doi: 10.1002/path.1711750109. [DOI] [PubMed] [Google Scholar]
  29. Muller W. A., Ratti C. M., McDonnell S. L., Cohn Z. A. A human endothelial cell-restricted, externally disposed plasmalemmal protein enriched in intercellular junctions. J Exp Med. 1989 Aug 1;170(2):399–414. doi: 10.1084/jem.170.2.399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nagafuchi A., Takeichi M. Cell binding function of E-cadherin is regulated by the cytoplasmic domain. EMBO J. 1988 Dec 1;7(12):3679–3684. doi: 10.1002/j.1460-2075.1988.tb03249.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Navarro P., Caveda L., Breviario F., Mândoteanu I., Lampugnani M. G., Dejana E. Catenin-dependent and -independent functions of vascular endothelial cadherin. J Biol Chem. 1995 Dec 29;270(52):30965–30972. doi: 10.1074/jbc.270.52.30965. [DOI] [PubMed] [Google Scholar]
  32. Ozawa M., Ringwald M., Kemler R. Uvomorulin-catenin complex formation is regulated by a specific domain in the cytoplasmic region of the cell adhesion molecule. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4246–4250. doi: 10.1073/pnas.87.11.4246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ranscht B. Cadherins and catenins: interactions and functions in embryonic development. Curr Opin Cell Biol. 1994 Oct;6(5):740–746. doi: 10.1016/0955-0674(94)90102-3. [DOI] [PubMed] [Google Scholar]
  34. Ross R. The pathogenesis of atherosclerosis--an update. N Engl J Med. 1986 Feb 20;314(8):488–500. doi: 10.1056/NEJM198602203140806. [DOI] [PubMed] [Google Scholar]
  35. Rubinfeld B., Souza B., Albert I., Müller O., Chamberlain S. H., Masiarz F. R., Munemitsu S., Polakis P. Association of the APC gene product with beta-catenin. Science. 1993 Dec 10;262(5140):1731–1734. doi: 10.1126/science.8259518. [DOI] [PubMed] [Google Scholar]
  36. Schwartz S. M., Gajdusek C. M., Selden S. C., 3rd Vascular wall growth control: the role of the endothelium. Arteriosclerosis. 1981 Mar-Apr;1(2):107–126. doi: 10.1161/01.atv.1.2.107. [DOI] [PubMed] [Google Scholar]
  37. Su L. K., Vogelstein B., Kinzler K. W. Association of the APC tumor suppressor protein with catenins. Science. 1993 Dec 10;262(5140):1734–1737. doi: 10.1126/science.8259519. [DOI] [PubMed] [Google Scholar]
  38. Suzuki S., Sano K., Tanihara H. Diversity of the cadherin family: evidence for eight new cadherins in nervous tissue. Cell Regul. 1991 Apr;2(4):261–270. doi: 10.1091/mbc.2.4.261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Takeichi M. Cadherin cell adhesion receptors as a morphogenetic regulator. Science. 1991 Mar 22;251(5000):1451–1455. doi: 10.1126/science.2006419. [DOI] [PubMed] [Google Scholar]
  40. Takeichi M. Cadherins in cancer: implications for invasion and metastasis. Curr Opin Cell Biol. 1993 Oct;5(5):806–811. doi: 10.1016/0955-0674(93)90029-p. [DOI] [PubMed] [Google Scholar]
  41. Tsukita S., Tsukita S., Nagafuchi A., Yonemura S. Molecular linkage between cadherins and actin filaments in cell-cell adherens junctions. Curr Opin Cell Biol. 1992 Oct;4(5):834–839. doi: 10.1016/0955-0674(92)90108-o. [DOI] [PubMed] [Google Scholar]
  42. Vestal D. J., Ranscht B. Glycosyl phosphatidylinositol--anchored T-cadherin mediates calcium-dependent, homophilic cell adhesion. J Cell Biol. 1992 Oct;119(2):451–461. doi: 10.1083/jcb.119.2.451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Vleminckx K., Vakaet L., Jr, Mareel M., Fiers W., van Roy F. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell. 1991 Jul 12;66(1):107–119. doi: 10.1016/0092-8674(91)90143-m. [DOI] [PubMed] [Google Scholar]
  44. Watabe M., Nagafuchi A., Tsukita S., Takeichi M. Induction of polarized cell-cell association and retardation of growth by activation of the E-cadherin-catenin adhesion system in a dispersed carcinoma line. J Cell Biol. 1994 Oct;127(1):247–256. doi: 10.1083/jcb.127.1.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zanetti A., Conforti G., Hess S., Martìn-Padura I., Ghibaudi E., Preissner K. T., Dejana E. Clustering of vitronectin and RGD peptides on microspheres leads to engagement of integrins on the luminal aspect of endothelial cell membrane. Blood. 1994 Aug 15;84(4):1116–1123. [PubMed] [Google Scholar]

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