α-E-Catenin is a potential regulator of canonical Wnt and HIPPO-signallings in myocardium
Abstract
The structural integrity of the myocardium is necessary for heart function and maintains by intercalated disks. Alpha-E-catenin – is important component of adherens junction in adult myocardium. In addition, during last time the possible signalling function of a-E-catenin was described. The aim of our work was to investigate the α-E-catenin regulatory function in canonical Wnt and HIPPO signalling in adult heart. Materials and methods. Our work was done with α- E-catenin conditional knockout mice and aMHC-Cre - transgenic animals using. Expression of genes involved in the canonical Wnt- and HIPPO signalling were analysed with rtPCR using. Canonical Wnt signalling activity was investigated by Western blot analysis. Result. We have shown that both heterozygous and homozygous deletion of α-E-catenin gene in the embryonic heart leads to activation of WNT / β-catenin signalling, namely we registered the higher level of c-Fos, c-Myc and Ctnnb1 genes expression and increasing of phosphorylated GSK3β in adult heart. In addition, we observed the HIPPO-signalling pathway activation after α- E-catenin gene ablation, namely we observed increasing of Ctgf, Il1rl1, Tnfrsf1b, Aurka genes expression. Conclusions. Α-E-catenin has an important signalling function in adult heart, namely α-E-catenin regulates cytoplasmic level of main transcriptional activators of the canonical Wnt- and HIPPO - signalling cascades: β-catenin and Yap what leas to limiting their signalling activity.
Keywords: α-E-catenin, β-catenin, HIPPO, Wnt-signalling, gene expression, myocardium
References
Piven O. O. Perturbations of adhesive complexes in a myocardium tissue as one of mechanisms of heart function disorders. Ukrainian Journal of Cardiology. 2010. No. 6. P. 110-117.
Brade T., Manner J., Kuhl M. The role of Wnt signalling in cardiac development and tissue remodelling in the mature heart. Cardiovasc. Res. 2006. Vol. 72. P. 198-209. doi: 10.1016/j.cardiores.2006.06.025
Sheikh F., Chen Y.; Liang X., Hirschy A., Stenbit A. E., Gu Y., Dalton N. D., Yajima T., Lu Y., Knowlton K. U., Peterson K. L., Perriard J., Chen J. α-E-Catenin inactivation disrupts the cardiomyocyte adherens junction, resulting in cardiomyopathy and susceptibility to wall rupture. Circulation. 2006. Vol. 114(10). P. 1046-1055. doi: 10.1161/CIRCULATIONAHA.106.634469
Li J., Goossens S., Henge J., Gao E., Cheng L., Tyberghein K., Shang X., Rycke R. D., Roy F., Radice G. L. Loss of αT-catenin alters the hybrid adhering junctions in the heart and leads to dilated cardiomyopathy and ventricular arrhythmia following acute ischemia. J. Cell Sci. 2012. Vol. 125. P. 1058-1067. doi: 10.1242/jcs.098640
Silvis M. T., Kreger B. T., Lien W., Klezovitch O., Rudakova G. M., Camargo F. D., Lantz D., Seykora J. T., Vasioukhin V. α-Catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator Yap1. Sci Signal. 2012. Vol. 4(174): ra33. doi: 10.1126/scisignal.2001823
Schlegelmilch K., Mohseni M., Kirak O., Pruszak J., Rodriguez J. R, Zhou D., Kreger B. T., Vasioukhin V., Avruch J., Brummelkamp T. R., Camargo F. D. Yap1 acts downstream of a-catenin to control epidermal proliferation. Cell. 2011. Vol. 144. P. 782-795. doi: 10.1016/j.cell.2011.02.031
Neumann S. Schneider M., Daugherty R. L., Gottardi C. J., Eming S. A., Beijer A., Noegel A. A., Karakesisoglou I. Nesprin-2 Interacts with a-Catenin and Regulates Wnt Signaling at the Nuclear Envelope. J. Biol. Chem. 2010. Vol. 285(45). P. 34932–34938. doi: 10.1074/jbc.M110.119651
Choi S. H, Estaras C., Moresco J. J, Yates III J. Y., Jones K. A. a-Catenin interacts with APC to regulate b-catenin proteolysis and transcriptional repression of Wnt target genes. Genes Dev. 2013. Vol. 27(22). P. 2473-2488. doi: 10.1101/gad.229062.113
Piven O., Kostetskii I., Macewicz L., Kolomijec Y., Radice G.,Lukash L. Requirement for N-cadherin-catenin complex in heart development. Exp. Biol. Med. 2011. Vol. 236(7). P. 816-822. doi: 10.1258/ebm.2011.010362
Balatskyy V. V., Akymenko I., Matsevych L. L., Piven O. O., Lukash L. L. Alpha-E-catenin in histological reconstruction of myocardium with aging. Fakt. Eksp. Evol. Org. 2016. Vol. 18. P. 219-222.
Cokkinos D. V. Introduction to translational cardiovascular research. Springer International Publishing, 2015. 610 p. doi: 10.1007/978-3-319-08798-6
Gise A. Lin Z., Schlegelmilch K., Honor L. B., Pan G. M., J. N., O., Ishiwata T. YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy. PNAS. 2011. Vol. 109(7). P. 2394-2399. doi: 10.1073/pnas.1116136109
Nagy A., Gertsenstein M., Vintersten K., Behringer R. Manipulating the Mouse Embryo: A Laboratory Manual. 3rd ed. Cold Spring Harbor Laboratory Press. 2003. 764 p.
Archbold H. C., Yang Y. X., Chen L., Cadigan K. M. How do they do Wnt they do?: regulation of transcription by the Wnt/β-catenin pathway. ActaPhysiol. 2012. Vol. 204(1). P.74–109. doi: 10.1111/j.1748-1716.2011.02293.x
Broch K., Ueland T., Yndestad A., Aukrust P., Gullestad L. Heart failure biomarkers: focus on interleukin-1 receptor-like 1-based blood tests. Drugs Today (Barc). 2012. Vol. 48(7). P. 479-491. doi: 10.1358/dot.2012.48.7.1811719
Chen S. N., Gurha P., Lombardi R., Ruggiero A., Willerson J. T., Marian A.J. The Hippo pathway is activated and is a causal mechanism for adipogenesis in arrhythmogenic cardiomyopathy. Circulation Res. 2014. Vol. 114(3). P. 454-468. doi: 10.1161/CIRCRESAHA.114.302810
