Skip to main content
SpringerLink
Log in

The effect of plakophilin-2 gene mutations on the activity of canonical WNT signaling

  • Published:
Cell and Tissue Biology Aims and scope Submit manuscript

Abstract

Plakophilin-2 is a desmosomal protein encoded by PKP2 gene. Desmosomal proteins are usually considered as structural proteins with the main function of maintaining intercellular interactions. Genetic studies revealed that mutations in desmosomal genes could lead to arrhythmogenic right ventricular cardiomyopathy, a heart disease characterized by substitution of cardiomyocytes by adipose and fibrotic tissue predominantly in the right ventricle. Wnt signaling is a signal transduction pathway presumably involved in the development of pathology. The purpose of this study was to investigate Wnt activity in cells with wild-type and mutant PKP2 gene during adipogenic and cardiomyogenic differentiation. We used multipotent mesenchymal stromal cells and iPS cells generated from a patient carrying PKP2 gene mutation. We found that cells with mutant PKP2 exhibited lower transcriptional activity of β-catenin, a key player of Wnt signaling, as well as attenuated expression of its targets SOX2 and SOX9. These findings suggest a signaling role of plakophilin2 by regulating Wnt activity

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ARVC:

arrhythmogenic right ventricular cardiomyopathy

iPSCs:

induced pluripotent stem cells

MMSCs:

multipotent mesenchymal stromal cells

ESCs:

embryonic stem cells

GSK3b:

glycogen synthase kinase 3 beta

PPARg:

peroxisome proliferator-activated receptor gamma

References

  • Awad, M.M., Calkins, H., and Judge, D.P., Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy, Nature Clin. Pract. Cardiovasc. Med., 2008, vol. 5, pp. 258–267.

    Article  CAS  Google Scholar 

  • Basso, C., Thiene, G., Corrado, D., Angelini, A., Nava, A., and Valente, M., Arrhythmogenic right ventricular cardiomyopathy, dysplasia, dystrophy or myocarditis?, Circulation, 1996, vol. 94, pp. 983–991.

    Article  CAS  PubMed  Google Scholar 

  • Caspi, O., Huber, I., Gepstein, A., Arbel, G., Maizels, L., Boulos, M., and Gepstein, L., Modeling of arrhythmogenic right ventricular cardiomyopathy with human induced pluripotent stem cells, Circ. Cardiovasc. Genet., 2013, vol. 6, pp. 557–568.

    Article  CAS  PubMed  Google Scholar 

  • Chen, S.N., Gurha, P., Lombardi, R., Ruggiero, A., Willerson, J.T., and Marian, A.J., The hippo pathway is activated and is a causal mechanism for adipogenesis in arrhythmogenic cardiomyopathy, Circ. Res., 2014, vol. 114, pp. 454–468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corrado, D., Basso, C., Thiene, G., McKenna, W.J., Davies, M.J., Fontaliran, F., Nava, A., Silvestri, F., Blomström-Lundqvist, C., Wlodarska, E.K., Fontaine, G., and Camerini, F., Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study, J. Am. Coll. Cardiol., 1997, vol. 30, pp. 1512–1520.

    Article  CAS  PubMed  Google Scholar 

  • Delva, E., Tucker, D.K., and Kowalczyk, A.P., The Desmosome, Cold Spring Harbor Perspectives in Biology. 1. Cold Spring Harbor, 2009. doi: 10.1101/cshperspect.a002543

    Google Scholar 

  • Franke, W.W., Borrmann, C.M., Grund, C., and Pieperhoff, S., The area composita of adhering junctions connecting heart muscle cells of vertebrates. I. Molecular definition in intercalated disks of cardiomyocytes by immunoelectron microscopy of desmosomal proteins, Eur. J. Cell Biol., 2006, vol. 85, pp. 69–82.

    Article  CAS  PubMed  Google Scholar 

  • Fuerer, C. and Nusse, R., Lentiviral vectors to probe and manipulate the Wnt signaling pathway, PLoS ONE, 2010, vol. 5, pp. 1–7.

    Article  Google Scholar 

  • Garcia-gras, E., Lombardi, R., Giocondo, M.J., Willerson, J.T., Schneider, M.D., Khoury, D.S., and Marian, A.J., Suppreßsion of canonical Wnt/ß-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy, J. Clin. Invest., 2006, vol. 116, pp. 2012–2021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerull, B., Heuser, A., Wichter, T., Paul, M., Basson, C.T., McDermott, D.A., Lerman, B.B., Markowitz, S.M., Ellinor, P.T., MacRae, C.A., Peters, S., Grossmann, K.S., Drenckhahn, J., Michely, B., Sasse-Klaassen, S., Birchmeier, W., Dietz, R., Breithardt, G., Schulze-Bahr, E., and Thierfelder, L., Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy, Nat Genet., 2004, vol. 36, pp. 1162–1164.

    Article  CAS  PubMed  Google Scholar 

  • Heuberger, J. and Birchmeier, W., Interplay of cadherinmediated cell adhesion and canonical Wnt signaling, Cold Spring Harb. Perspect. Biol., 2010, vol. 2. doi: 10.1101/cshperspect.a002915

    Google Scholar 

  • Khudiakov, A.A., Kurapeev, D.I., Kostareva, A.A., and Malashicheva, A.B., Comparison of different methods for generation of functional human cardiomyocytes, Cell. Transplant. Tiss. Eng., 2013, vol. 8, 2, pp. 46–54.

    Google Scholar 

  • Kim, C., Wong, J., Wen, J., Wang, S., Wang, C., Spiering, S., Kan, N.G., Forcales, S., Puri, P.L., Leone, T.C., Marine, J.E., Calkins, H., Kelly, D.P., Judge, D.P., and Chen, H-S.V., Studying arrhythmogenic right ventricular dysplasia with patient-specific IPSCs, Nature, 2013, vol. 494, pp. 105–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leckband, D.E., le Duc, Q., Wang, N., and de Rooij, J., Mechanotransduction at cadherin-mediated adhesions, Curr. Opin. Cell Biol., 2011, vol. 23, pp. 523–530.

    Article  CAS  PubMed  Google Scholar 

  • Li, J., Swope, D., Raess, N., Cheng, L., Muller, E.J., and Radice, G.L., Cardiac tissue-restricted deletion of plakoglobin results in progressive cardiomyopathy and activation of beta-catenin signaling, Mol. Cell Biol., 2011, vol. 31, pp. 1134–1144.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lombardi, R. and Marian, A.J., Molecular genetics and pathogenesis of arrhythmogenic right ventricular cardiomyopathy: a disease of cardiac stem cells, Pediatr. Cardiol., 2011, vol. 32, pp. 360–365.

    Article  PubMed  Google Scholar 

  • Ma, D., Wei, H., Lu, J., Ho, S., Zhang, G., Sun, X., Oh, Y., Tan, S.H., Ng, M.L., Shim, W., Wong, P., and Liew, R., Generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes as a cellular model of arrhythmogenic right ventricular cardiomyopathy, Eur. Heart J., 2013, vol. 34, pp. 1122–1123.

    Article  CAS  PubMed  Google Scholar 

  • Mummery, C., Ward-van Oostwaard, D., Doevendans, P., Spijker, R., van den Brink, S., Hassink, R., van der Heyden, M., Opthof, T., Pera, M., de la Riviere, A.B., Passier, R., and Tertoolen, L., Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells, Circulation, 2003, vol. 107, pp. 2733–2740.

    Article  CAS  PubMed  Google Scholar 

  • Oxford, E.M., Danko, C.G., Fox, P.R., Kornreich, B.G., and Moïse, N.S., Change in ß-catenin localization suggests involvement of the canonical wnt pathway in boxer dogs with arrhythmogenic right ventricular cardiomyopathy, J. Vet. Intern. Med., 2014, vol. 28, pp. 92–101.

    Article  CAS  PubMed  Google Scholar 

  • Thiene, G., Nava A., Corrado, D., Rossi, L., and Pennelli, N., Right ventricular cardiomyopathy and sudden death in young people, N. Engl. J. Med., 1988, vol. 318, pp. 129–133.

    Article  CAS  PubMed  Google Scholar 

  • Zhurinsky, J., Shtutman, M., and Ben-Ze’ev, A., Differential mechanisms of LEF/TCF family-dependent transcriptional activation by beta-catenin and plakoglobin, Mol. Cell Biol., 2000, vol. 20, pp. 4238–4252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zuk, P.A., Zhu, M., Mizuno, H., Huang, J., Futrell, J.W., Katz, A.J., Benhaim, P., Lorenz, H.P., and Hedrick, M.H., Multilineage cells from human adipose tissue: implications for cell-based therapies, Tis. Eng., 2001, vol. 7, pp. 211–226.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia

    A. A. Khudiakov & A. N. Tomilin

  2. Federal Almazov Northwest Medical Research Center, St. Petersburg, 197341, Russia

    A. A. Khudiakov, D. A. Kostina, A. A. Kostareva & A. B. Malashicheva

  3. St. Petersburg State University, St. Petersburg, 199034, Russia

    A. B. Malashicheva

Authors
  1. A. A. Khudiakov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. A. Kostina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. A. Kostareva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. N. Tomilin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. B. Malashicheva
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. B. Malashicheva.

Additional information

Original Russian Text © A.A. Khudiakov, D.A. Kostina, A.A. Kostareva, A.N. Tomilin, A.B. Malashicheva, 2015, published in Tsitologiya, 2015, Vol. 57, No. 12, pp. 868–875.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khudiakov, A.A., Kostina, D.A., Kostareva, A.A. et al. The effect of plakophilin-2 gene mutations on the activity of canonical WNT signaling. Cell Tiss. Biol. 10, 106–113 (2016). https://doi.org/10.1134/S1990519X16020061

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1990519X16020061

Keywords

Search

Navigation