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. 1996 Apr 1;133(1):199–209. doi: 10.1083/jcb.133.1.199

Suppression of tumorigenicity by plakoglobin: an augmenting effect of N- cadherin

PMCID: PMC2120779  PMID: 8601608

Abstract

Plakoglobin is a major component of the submembranal plaque of adherens junctions and desmosomes in mammalian cells. It is closely related to the Drosophila segment polarity gene armadillo which has a role in the transduction of transmembrane signals that regulate cell fate. Like its close homologue beta-catenin, plakoglobin can associate with the product of the tumor suppressor gene APC that is linked to human colon cancer. We have studied the effect of plakoglobin overexpression, and the cooperation between plakoglobin and N-cadherin, on the morphology and tumorigenic ability of cells either lacking, or expressing cadherin and alpha- and beta-catenin. Overexpression of plakoglobin in SV40- transformed 3T3 (SVT2) cells suppressed the tumorigenicity of the cells in syngeneic mice. Transfection with N-cadherin conferred an epithelial phenotype on the cell culture, but had no significant effect on the tumorigenicity of the cells. Cotransfection of plakoglobin and N- cadherin into SVT2 cells, however, was considerably more effective in tumor suppression than plakoglobin overexpression alone. Finally, transfection of plakoglobin into a human renal carcinoma cell line that expresses neither cadherins nor plakoglobin, or alpha-and beta-catenin, resulted in a dose-dependent suppression of tumor formation by these cells in nude mice. Plakoglobin, in these cells, did not exhibit junctional localization and was diffusely distributed in the cytoplasm, with a significant amount of the protein also localized in the nucleus. The results suggest that plakoglobin can efficiently suppress the tumorigenicity of cells in the presence of, or independently of the cadherin-catenin complex.

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Selected References

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  1. Aberle H., Bierkamp C., Torchard D., Serova O., Wagner T., Natt E., Wirsching J., Heidkämper C., Montagna M., Lynch H. T. The human plakoglobin gene localizes on chromosome 17q21 and is subjected to loss of heterozygosity in breast and ovarian cancers. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6384–6388. doi: 10.1073/pnas.92.14.6384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Behrens J., Mareel M. M., Van Roy F. M., Birchmeier W. Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion. J Cell Biol. 1989 Jun;108(6):2435–2447. doi: 10.1083/jcb.108.6.2435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bejsovec A., Wieschaus E. Segment polarity gene interactions modulate epidermal patterning in Drosophila embryos. Development. 1993 Oct;119(2):501–517. doi: 10.1242/dev.119.2.501. [DOI] [PubMed] [Google Scholar]
  4. Bradley R. S., Cowin P., Brown A. M. Expression of Wnt-1 in PC12 cells results in modulation of plakoglobin and E-cadherin and increased cellular adhesion. J Cell Biol. 1993 Dec;123(6 Pt 2):1857–1865. doi: 10.1083/jcb.123.6.1857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cowin P., Kapprell H. P., Franke W. W., Tamkun J., Hynes R. O. Plakoglobin: a protein common to different kinds of intercellular adhering junctions. Cell. 1986 Sep 26;46(7):1063–1073. doi: 10.1016/0092-8674(86)90706-3. [DOI] [PubMed] [Google Scholar]
  6. Cowin P. Unraveling the cytoplasmic interactions of the cadherin superfamily. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10759–10761. doi: 10.1073/pnas.91.23.10759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cunningham C. C., Gorlin J. B., Kwiatkowski D. J., Hartwig J. H., Janmey P. A., Byers H. R., Stossel T. P. Actin-binding protein requirement for cortical stability and efficient locomotion. Science. 1992 Jan 17;255(5042):325–327. doi: 10.1126/science.1549777. [DOI] [PubMed] [Google Scholar]
  8. Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
  9. Franke W. W., Goldschmidt M. D., Zimbelmann R., Mueller H. M., Schiller D. L., Cowin P. Molecular cloning and amino acid sequence of human plakoglobin, the common junctional plaque protein. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4027–4031. doi: 10.1073/pnas.86.11.4027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Funayama N., Fagotto F., McCrea P., Gumbiner B. M. Embryonic axis induction by the armadillo repeat domain of beta-catenin: evidence for intracellular signaling. J Cell Biol. 1995 Mar;128(5):959–968. doi: 10.1083/jcb.128.5.959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Geiger B., Ayalon O., Ginsberg D., Volberg T., Rodríguez Fernández J. L., Yarden Y., Ben-Ze'ev A. Cytoplasmic control of cell adhesion. Cold Spring Harb Symp Quant Biol. 1992;57:631–642. doi: 10.1101/sqb.1992.057.01.069. [DOI] [PubMed] [Google Scholar]
  13. Giancotti F. G., Ruoslahti E. Elevated levels of the alpha 5 beta 1 fibronectin receptor suppress the transformed phenotype of Chinese hamster ovary cells. Cell. 1990 Mar 9;60(5):849–859. doi: 10.1016/0092-8674(90)90098-y. [DOI] [PubMed] [Google Scholar]
  14. Glück U., Ben-Ze'ev A. Modulation of alpha-actinin levels affects cell motility and confers tumorigenicity on 3T3 cells. J Cell Sci. 1994 Jul;107(Pt 7):1773–1782. doi: 10.1242/jcs.107.7.1773. [DOI] [PubMed] [Google Scholar]
  15. Glück U., Kwiatkowski D. J., Ben-Ze'ev A. Suppression of tumorigenicity in simian virus 40-transformed 3T3 cells transfected with alpha-actinin cDNA. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):383–387. doi: 10.1073/pnas.90.2.383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hinck L., Nelson W. J., Papkoff J. Wnt-1 modulates cell-cell adhesion in mammalian cells by stabilizing beta-catenin binding to the cell adhesion protein cadherin. J Cell Biol. 1994 Mar;124(5):729–741. doi: 10.1083/jcb.124.5.729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hinck L., Näthke I. S., Papkoff J., Nelson W. J. Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly. J Cell Biol. 1994 Jun;125(6):1327–1340. doi: 10.1083/jcb.125.6.1327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hoschuetzky H., Aberle H., Kemler R. Beta-catenin mediates the interaction of the cadherin-catenin complex with epidermal growth factor receptor. J Cell Biol. 1994 Dec;127(5):1375–1380. doi: 10.1083/jcb.127.5.1375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hülsken J., Birchmeier W., Behrens J. E-cadherin and APC compete for the interaction with beta-catenin and the cytoskeleton. J Cell Biol. 1994 Dec;127(6 Pt 2):2061–2069. doi: 10.1083/jcb.127.6.2061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Karnovsky A., Klymkowsky M. W. Anterior axis duplication in Xenopus induced by the over-expression of the cadherin-binding protein plakoglobin. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4522–4526. doi: 10.1073/pnas.92.10.4522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Knudsen K. A., Wheelock M. J. Plakoglobin, or an 83-kD homologue distinct from beta-catenin, interacts with E-cadherin and N-cadherin. J Cell Biol. 1992 Aug;118(3):671–679. doi: 10.1083/jcb.118.3.671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  23. Navarro P., Gómez M., Pizarro A., Gamallo C., Quintanilla M., Cano A. A role for the E-cadherin cell-cell adhesion molecule during tumor progression of mouse epidermal carcinogenesis. J Cell Biol. 1991 Oct;115(2):517–533. doi: 10.1083/jcb.115.2.517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Navarro P., Lozano E., Cano A. Expression of E- or P-cadherin is not sufficient to modify the morphology and the tumorigenic behavior of murine spindle carcinoma cells. Possible involvement of plakoglobin. J Cell Sci. 1993 Aug;105(Pt 4):923–934. doi: 10.1242/jcs.105.4.923. [DOI] [PubMed] [Google Scholar]
  25. Peifer M., McCrea P. D., Green K. J., Wieschaus E., Gumbiner B. M. The vertebrate adhesive junction proteins beta-catenin and plakoglobin and the Drosophila segment polarity gene armadillo form a multigene family with similar properties. J Cell Biol. 1992 Aug;118(3):681–691. doi: 10.1083/jcb.118.3.681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Peifer M., Rauskolb C., Williams M., Riggleman B., Wieschaus E. The segment polarity gene armadillo interacts with the wingless signaling pathway in both embryonic and adult pattern formation. Development. 1991 Apr;111(4):1029–1043. doi: 10.1242/dev.111.4.1029. [DOI] [PubMed] [Google Scholar]
  27. Peifer M., Wieschaus E. The segment polarity gene armadillo encodes a functionally modular protein that is the Drosophila homolog of human plakoglobin. Cell. 1990 Dec 21;63(6):1167–1176. doi: 10.1016/0092-8674(90)90413-9. [DOI] [PubMed] [Google Scholar]
  28. Powell S. M., Zilz N., Beazer-Barclay Y., Bryan T. M., Hamilton S. R., Thibodeau S. N., Vogelstein B., Kinzler K. W. APC mutations occur early during colorectal tumorigenesis. Nature. 1992 Sep 17;359(6392):235–237. doi: 10.1038/359235a0. [DOI] [PubMed] [Google Scholar]
  29. Prasad G. L., Fuldner R. A., Cooper H. L. Expression of transduced tropomyosin 1 cDNA suppresses neoplastic growth of cells transformed by the ras oncogene. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7039–7043. doi: 10.1073/pnas.90.15.7039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rodríguez Fernández J. L., Geiger B., Salomon D., Ben-Ze'ev A. Overexpression of vinculin suppresses cell motility in BALB/c 3T3 cells. Cell Motil Cytoskeleton. 1992;22(2):127–134. doi: 10.1002/cm.970220206. [DOI] [PubMed] [Google Scholar]
  31. Rodríguez Fernández J. L., Geiger B., Salomon D., Ben-Ze'ev A. Suppression of vinculin expression by antisense transfection confers changes in cell morphology, motility, and anchorage-dependent growth of 3T3 cells. J Cell Biol. 1993 Sep;122(6):1285–1294. doi: 10.1083/jcb.122.6.1285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Rodríguez Fernández J. L., Geiger B., Salomon D., Sabanay I., Zöller M., Ben-Ze'ev A. Suppression of tumorigenicity in transformed cells after transfection with vinculin cDNA. J Cell Biol. 1992 Oct;119(2):427–438. doi: 10.1083/jcb.119.2.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. 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]
  34. Salomon D., Ayalon O., Patel-King R., Hynes R. O., Geiger B. Extrajunctional distribution of N-cadherin in cultured human endothelial cells. J Cell Sci. 1992 May;102(Pt 1):7–17. doi: 10.1242/jcs.102.1.7. [DOI] [PubMed] [Google Scholar]
  35. Shibata T., Gotoh M., Ochiai A., Hirohashi S. Association of plakoglobin with APC, a tumor suppressor gene product, and its regulation by tyrosine phosphorylation. Biochem Biophys Res Commun. 1994 Aug 30;203(1):519–522. doi: 10.1006/bbrc.1994.2213. [DOI] [PubMed] [Google Scholar]
  36. Sokol S., Christian J. L., Moon R. T., Melton D. A. Injected Wnt RNA induces a complete body axis in Xenopus embryos. Cell. 1991 Nov 15;67(4):741–752. doi: 10.1016/0092-8674(91)90069-b. [DOI] [PubMed] [Google Scholar]
  37. Sommers C. L., Gelmann E. P., Kemler R., Cowin P., Byers S. W. Alterations in beta-catenin phosphorylation and plakoglobin expression in human breast cancer cells. Cancer Res. 1994 Jul 1;54(13):3544–3552. [PubMed] [Google Scholar]
  38. 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]
  39. Tsukita S., Itoh M., Nagafuchi A., Yonemura S., Tsukita S. Submembranous junctional plaque proteins include potential tumor suppressor molecules. J Cell Biol. 1993 Dec;123(5):1049–1053. doi: 10.1083/jcb.123.5.1049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. 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]

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