Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Beyond β-catenin: prospects for a larger catenin network in the nucleus

Abstract

β-catenin is widely regarded as the primary transducer of canonical WNT signals to the nucleus. In most vertebrates, there are eight additional catenins that are structurally related to β-catenin, and three α-catenin genes encoding actin-binding proteins that are structurally related to vinculin. Although these catenins were initially identified in association with cadherins at cell–cell junctions, more recent evidence suggests that the majority of catenins also localize to the nucleus and regulate gene expression. Moreover, the number of catenins reported to be responsive to canonical WNT signals is increasing. Here, we posit that multiple catenins form a functional network in the nucleus, possibly engaging in conserved protein–protein interactions that are currently better characterized in the context of actin-based cell junctions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: An overview of vertebrate catenins.
Figure 2: Conditions that promote catenin nuclear signalling.
Figure 3: p120 catenin isoform 1 is responsive to canonical WNT signals.
Figure 4: p120 catenin modulates gene transcription via various zinc-finger domain transcriptional repressors.
Figure 5: Models for transcription inhibition by αE-catenin.

Similar content being viewed by others

References

  1. Carnahan, R. H., Rokas, A., Gaucher, E. A. & Reynolds, A. B. The molecular evolution of the p120-catenin subfamily and its functional associations. PLoS ONE 5, e15747 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. McCrea, P. D., Maher, M. T. & Gottardi, C. J. Nuclear signaling from cadherin adhesion complexes. Curr. Top. Dev. Biol. 112, 129–196 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hatzfeld, M., Wolf, A. & Keil, R. Plakophilins in desmosomal adhesion and signaling. Cell Commun. Adhes. 21, 25–42 (2014).

    Article  CAS  PubMed  Google Scholar 

  4. Johnson, J. L., Najor, N. A. & Green, K. J. Desmosomes: regulators of cellular signaling and adhesion in epidermal health and disease. Cold Spring Harb. Perspect. Med. 4, a015297 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hulpiau, P., Gul, I. S. & van Roy, F. New insights into the evolution of metazoan cadherins and catenins. Prog. Mol. Biol. Transl. Sci. 116, 71–94 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. Kowalczyk, A. P. & Nanes, B. A. Adherens junction turnover: regulating adhesion through cadherin endocytosis, degradation, and recycling. Subcell. Biochem. 60, 197–222 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kourtidis, A., Ngok, S. P. & Anastasiadis, P. Z. p120 catenin: an essential regulator of cadherin stability, adhesion-induced signaling, and cancer progression. Prog. Mol. Biol. Transl. Sci. 116, 409–432 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Takeichi, M. Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling. Nat. Rev. Mol. Cell Biol. 15, 397–410 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Meng, W., Mushika, Y., Ichii, T. & Takeichi, M. Anchorage of microtubule minus ends to adherens junctions regulates epithelial cell–cell contacts. Cell 135, 948–959 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Kurita, S., Yamada, T., Rikitsu, E., Ikeda, W. & Takai, Y. Binding between the junctional proteins afadin and PLEKHA7 and implication in the formation of adherens junction in epithelial cells. J. Biol. Chem. 288, 29356–29368 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Maiden, S. L. & Hardin, J. The secret life of α-catenin: moonlighting in morphogenesis. J. Cell Biol. 195, 543–552 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. McCrea, P. D. & Park, J. I. Developmental functions of the p120-catenin sub-family. Biochim. Biophys. Acta 1773, 17–33 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Vite, A., Li, J. & Radice, G. L. New functions for alpha-catenins in health and disease: from cancer to heart regeneration. Cell Tissue Res. 360, 773–783 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Coates, J. C. Armadillo repeat proteins: beyond the animal kingdom. Trends Cell Biol. 13, 463–471 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Hulpiau, P. & van Roy, F. New insights into the evolution of metazoan cadherins. Mol. Biol. Evol. 28, 647–657 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Oda, H. & Takeichi, M. Evolution: structural and functional diversity of cadherin at the adherens junction. J. Cell Biol. 193, 1137–1146 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Han, S. P. & Yap, A. S. An α-catenin déjà vu. Nat. Cell Biol. 15, 238–239 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Daniel, J. M. & Reynolds, A. B. The tyrosine kinase substrate p120cas binds directly to E-cadherin but not to the adenomatous polyposis coli protein or α-catenin. Mol. Cell. Biol. 15, 4819–4824 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yap, A. S., Niessen, C. M. & Gumbiner, B. M. The juxtamembrane region of the cadherin cytoplasmic tail supports lateral clustering, adhesive strengthening, and interaction with p120ctn. J. Cell Biol. 141, 779–789 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Reynolds, A. B. & Carnahan, R. H. Regulation of cadherin stability and turnover by p120ctn: implications in disease and cancer. Semin. Cell Dev. Biol. 15, 657–663 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Wildenberg, G. A. et al. p120-catenin and p190RhoGAP regulate cell–cell adhesion by coordinating antagonism between Rac and Rho. Cell 127, 1027–1039 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Klompstra, D., Anderson, D. C., Yeh, J. Y., Zilberman, Y. & Nance, J. An instructive role for C. elegans E-cadherin in translating cell contact cues into cortical polarity. Nat. Cell Biol. 17, 726–735 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kourtidis, A. et al. Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity. Nat. Cell Biol. 17, 1145–1157 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schackmann, R. C. et al. Cytosolic p120-catenin regulates growth of metastatic lobular carcinoma through Rock1-mediated anoikis resistance. J. Clin. Invest. 121, 3176–3188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bellovin, D. I., Bates, R. C., Muzikansky, A., Rimm, D. L. & Mercurio, A. M. Altered localization of p120 catenin during epithelial to mesenchymal transition of colon carcinoma is prognostic for aggressive disease. Cancer Res. 65, 10938–10945 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Perez-Moreno, M. et al. p120-catenin mediates inflammatory responses in the skin. Cell 124, 631–644 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Anastasiadis, P. Z. p120-ctn: a nexus for contextual signaling via Rho GTPases. Biochim. Biophys. Acta 1773, 34–46 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Pieters, T., van Hengel, J. & van Roy, F. Functions of p120ctn in development and disease. Front. Biosci. (Landmark Ed) 17, 760–783 (2012).

    Article  CAS  Google Scholar 

  29. Alema, S. & Salvatore, A. M. p120 catenin and phosphorylation: mechanisms and traits of an unresolved issue. Biochim. Biophys. Acta 1773, 47–58 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Kowalczyk, A. P. & Green, K. J. Structure, function, and regulation of desmosomes. Prog. Mol. Biol. Transl. Sci. 116, 95–118 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Berika, M. & Garrod, D. Desmosomal adhesion in vivo. Cell Commun. Adhes. 21, 65–75 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Keil, R. & Hatzfeld, M. The armadillo protein p0071 is involved in Rab11-dependent recycling. J. Cell Sci. 127, 60–71 (2014).

    CAS  PubMed  Google Scholar 

  33. Miller, R. K., Hong, J. Y., Munoz, W. A. & McCrea, P. D. Beta-catenin versus the other armadillo catenins: assessing our current view of canonical Wnt signaling. Prog. Mol. Biol. Transl. Sci. 116, 387–407 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hatzfeld, M. The p120 family of cell adhesion molecules. Eur. J. Cell Biol. 84, 205–214 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Hatzfeld, M. Plakophilins: multifunctional proteins or just regulators of desmosomal adhesion? Biochim. Biophys. Acta 1773, 69–77 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Roczniak-Ferguson, A. & Reynolds, A. B. Regulation of p120-catenin nucleocytoplasmic shuttling activity. J. Cell Sci. 116, 4201–4212 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Morgan, R. G., Ridsdale, J., Tonks, A. & Darley, R. L. Factors affecting the nuclear localization of β-catenin in normal and malignant tissue. J. Cell. Biochem. 115, 1351–1361 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Andrade, M. A., Petosa, C., O'Donoghue, S. I., Muller, C. W. & Bork, P. Comparison of ARM and HEAT protein repeats. J. Mol. Biol. 309, 1–18 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Chook, Y. M. & Blobel, G. Karyopherins and nuclear import. Curr. Opin. Struct. Biol. 11, 703–715 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Fagotto, F. Looking beyond the Wnt pathway for the deep nature of β-catenin. EMBO Rep. 14, 422–433 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Giannini, A. et al. Nuclear export of α-catenin: overlap between nuclear export signal sequences and the β-catenin binding site. Exp. Cell Res. 295, 150–160 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Daniel, J. M. & Reynolds, A. B. The catenin p120ctn interacts with Kaiso, a novel BTB/POZ domain zinc finger transcription factor. Mol. Cell. Biol. 19, 3614–3623 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. van Hengel, J., Vanhoenacker, P., Staes, K. & van Roy, F. Nuclear localization of the p120ctn Armadillo-like catenin is counteracted by a nuclear export signal and by E-cadherin expression. Proc. Natl Acad. Sci. USA 96, 7980–7985 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang, P. X. et al. p120-catenin isoform 3 regulates subcellular localization of Kaiso and promotes invasion in lung cancer cells via a phosphorylation-dependent mechanism. Int. J. Oncol. 38, 1625–1635 (2011).

    CAS  PubMed  Google Scholar 

  45. Park, J. I. et al. Kaiso/p120-catenin and TCF/β-catenin complexes coordinately regulate canonical Wnt gene targets. Dev. Cell 8, 843–854 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Lee, M., Ji, H., Furuta, Y., Park, J. I. & McCrea, P. D. p120-catenin regulates REST and CoREST, and modulates mouse embryonic stem cell differentiation. J. Cell Sci. 127, 4037–4051 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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. USA 92, 4522–4526 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Klymkowsky, M. W., Williams, B. O., Barish, G. D., Varmus, H. E. & Vourgourakis, Y. E. Membrane-anchored plakoglobins have multiple mechanisms of action in Wnt signaling. Mol. Biol. Cell 10, 3151–3169 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Simcha, I. et al. Differential nuclear translocation and transactivation potential of β-catenin and plakoglobin. J. Cell Biol. 141, 1433–1448 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Williams, B. O., Barish, G. D., Klymkowsky, M. W. & Varmus, H. E. A comparative evaluation of β-catenin and plakoglobin signaling activity. Oncogene 19, 5720–5728 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Zhurinsky, J., Shtutman, M. & Ben-Ze'ev, A. Differential mechanisms of LEF/TCF family-dependent transcriptional activation by β-catenin and plakoglobin. Mol. Cell. Biol. 20, 4238–4252 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Miravet, S. et al. The transcriptional factor Tcf-4 contains different binding sites for β-catenin and plakoglobin. J. Biol. Chem. 277, 1884–1891 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Solanas, G. et al. β-catenin and plakoglobin N- and C-tails determine ligand specificity. J. Biol. Chem. 279, 49849–49856 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Lien, W. H. & Fuchs, E. Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling. Genes Dev. 28, 1517–1532 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Valenta, T., Hausmann, G. & Basler, K. The many faces and functions of β-catenin. EMBO J. 31, 2714–2736 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Nusse, R. Wnt signaling. Cold Spring Harb. Perspect. Biol. 4, a011163 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Clevers, H. & Nusse, R. Wnt/β-catenin signaling and disease. Cell 149, 1192–1205 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Holland, J. D., Klaus, A., Garratt, A. N. & Birchmeier, W. Wnt signaling in stem and cancer stem cells. Curr. Opin. Cell Biol. 25, 254–264 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Ireton, R. C. et al. A novel role for p120 catenin in E-cadherin function. J. Cell Biol. 159, 465–476 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Anastasiadis, P. Z. et al. Inhibition of RhoA by p120 catenin. Nat. Cell Biol. 2, 637–644 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Fang, X. et al. Vertebrate development requires ARVCF and p120 catenins and their interplay with RhoA and Rac. J. Cell Biol. 165, 87–98 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bonne, S., van Hengel, J., Nollet, F., Kools, P. & van Roy, F. Plakophilin-3, a novel Armadillo-like protein present in nuclei and desmosomes of epithelial cells. J. Cell Sci. 112, 2265–2276 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Chen, X., Bonne, S., Hatzfeld, M., van Roy, F. & Green, K. J. Protein binding and functional characterization of plakophilin 2. Evidence for its diverse roles in desmosomes and β-catenin signaling. J. Biol. Chem. 277, 10512–10522 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Mertens, C., Kuhn, C. & Franke, W. W. Plakophilins 2a and 2b: constitutive proteins of dual location in the karyoplasm and the desmosomal plaque. J. Cell Biol. 135, 1009–1025 (1996).

    Article  CAS  PubMed  Google Scholar 

  65. Mariner, D. J., Wang, J. & Reynolds, A. B. ARVCF localizes to the nucleus and adherens junction and is mutually exclusive with p120(ctn) in E-cadherin complexes. J. Cell Sci. 113, 1481–1490 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Koutras, C., Lessard, C. B. & Levesque, G. A nuclear function for the presenilin 1 neuronal partner NPRAP/δ-catenin. J. Alzheimers Dis. 27, 307–316 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Hatzfeld, M. & Nachtsheim, C. Cloning and characterization of a new armadillo family member, 0071, associated with the junctional plaque: evidence for a subfamily of closely related proteins. J. Cell Sci. 109, 2767–2778 (1996).

    Article  CAS  PubMed  Google Scholar 

  68. Schmidt, A. et al. Plakophilins 1a and 1b: widespread nuclear proteins recruited in specific epithelial cells as desmosomal plaque components. Cell Tissue Res. 290, 481–499 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Klymkowsky, M. W. Plakophilin, armadillo repeats, and nuclear localization. Microsc. Res. Tech. 45, 43–54 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Bogaerts, S., Vanlandschoot, A., van Hengel, J. & van Roy, F. Nuclear translocation of αN-catenin by the novel zinc finger transcriptional repressor ZASC1. Exp. Cell Res. 311, 1–13 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Kausalya, P. J., Phua, D. C. & Hunziker, W. Association of ARVCF with zonula occludens (ZO)-1 and ZO-2: binding to PDZ-domain proteins and cell–cell adhesion regulate plasma membrane and nuclear localization of ARVCF. Mol. Biol. Cell 15, 5503–5515 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Daniel, J. M., Spring, C. M., Crawford, H. C., Reynolds, A. B. & Baig, A. The p120ctn-binding partner Kaiso is a bi-modal DNA-binding protein that recognizes both a sequence-specific consensus and methylated CpG dinucleotides. Nucleic Acids Res. 30, 2911–2919 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ruzov, A. et al. The interaction of xKaiso with xTcf3: a revised model for integration of epigenetic and Wnt signalling pathways. Development 136, 723–727 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Prokhortchouk, A. et al. The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor. Genes Dev. 15, 1613–1618 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ruzov, A. et al. Kaiso is a genome-wide repressor of transcription that is essential for amphibian development. Development 131, 6185–6194 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Blattler, A. et al. ZBTB33 binds unmethylated regions of the genome associated with actively expressed genes. Epigenetics Chromatin 6, 13 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Defossez, P. A. et al. The human enhancer blocker CTC-binding factor interacts with the transcription factor Kaiso. J. Biol. Chem. 280, 43017–43023 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Koh, D. I. et al. KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes. Proc. Natl Acad. Sci. USA 111, 15078–15083 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kim, S. W. et al. Non-canonical Wnt signals are modulated by the Kaiso transcriptional repressor and p120-catenin. Nat. Cell Biol. 6, 1212–1220 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Spring, C. M. et al. The catenin p120ctn inhibits Kaiso-mediated transcriptional repression of the β-catenin/TCF target gene matrilysin. Exp. Cell Res. 305, 253–265 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Donaldson, N. S. et al. Kaiso represses the cell cycle gene cyclin D1 via sequence-specific and methyl-CpG-dependent mechanisms. PLoS ONE 7, e50398 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. van de Ven, R. A. et al. Nuclear p120-catenin regulates the anoikis resistance of mouse lobular breast cancer cells through Kaiso-dependent Wnt11 expression. Dis. Model. Mech. 8, 373–384 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Hong, J. Y. et al. Down's-syndrome-related kinase Dyrk1A modulates the p120-catenin–Kaiso trajectory of the Wnt signaling pathway. J. Cell Sci. 125, 561–569 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Liu, X. et al. MUC1 regulates cyclin D1 gene expression through p120 catenin and β-catenin. Oncogenesis 3, e107 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Jiang, G. et al. p120-catenin isoforms 1 and 3 regulate proliferation and cell cycle of lung cancer cells via β-catenin and Kaiso respectively. PLoS ONE 7, e30303 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Brannon, M., Gomperts, M., Sumoy, L., Moon, R. T. & Kimelman, D. A β-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus. Genes Dev. 11, 2359–2370 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tetsu, O. & McCormick, F. β-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422–426 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Gustavson, M. D., Crawford, H. C., Fingleton, B. & Matrisian, L. M. Tcf binding sequence and position determines β-catenin and Lef-1 responsiveness of MMP-7 promoters. Mol. Carcinog. 41, 125–139 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Pieters, T., van Roy, F. & van Hengel, J. Functions of p120ctn isoforms in cell–cell adhesion and intracellular signaling. Front. Biosci. (Landmark Ed) 17, 1669–1694 (2012).

    Article  CAS  Google Scholar 

  90. Bass-Zubek, A. E., Godsel, L. M., Delmar, M. & Green, K. J. Plakophilins: multifunctional scaffolds for adhesion and signaling. Curr. Opin. Cell Biol. 21, 708–716 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Keirsebilck, A. et al. Molecular cloning of the human p120ctn catenin gene (CTNND1): expression of multiple alternatively spliced isoforms. Genomics 50, 129–146 (1998).

    Article  CAS  PubMed  Google Scholar 

  92. Yanagisawa, M. et al. A p120 catenin isoform switch affects Rho activity, induces tumor cell invasion, and predicts metastatic disease. J. Biol. Chem. 283, 18344–18354 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Markham, N. O. et al. DIPA-family coiled-coils bind conserved isoform-specific head domain of p120-catenin family: potential roles in hydrocephalus and heterotopia. Mol. Biol. Cell 25, 2592–2603 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Hong, J. Y. et al. Shared molecular mechanisms regulate multiple catenin proteins: canonical Wnt signals and components modulate p120-catenin isoform-1 and additional p120 subfamily members. J. Cell Sci. 123, 4351–4365 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kim, H. et al. δ-catenin promotes E-cadherin processing and activates β-catenin-mediated signaling: implications on human prostate cancer progression. Biochim. Biophys. Acta 1822, 509–521 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Oh, M. et al. GSK-3 phosphorylates δ-catenin and negatively regulates its stability via ubiquitination/proteosome-mediated proteolysis. J. Biol. Chem. 284, 28579–28589 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Hosking, C. R. et al. The transcriptional repressor Glis2 is a novel binding partner for p120 catenin. Mol. Biol. Cell 18, 1918–1927 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Negrini, S., Prada, I., D'Alessandro, R. & Meldolesi, J. REST: an oncogene or a tumor suppressor? Trends Cell Biol. 23, 289–295 (2013).

    Article  CAS  PubMed  Google Scholar 

  99. Qureshi, I. A., Gokhan, S. & Mehler, M. F. REST and CoREST are transcriptional and epigenetic regulators of seminal neural fate decisions. Cell Cycle 9, 4477–4486 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Nelson, R. W. & Gumbiner, B. M. A cell-free assay system for β-catenin signaling that recapitulates direct inductive events in the early Xenopus laevis embryo. J. Cell Biol. 147, 367–374 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kam, Y. & Quaranta, V. Cadherin-bound β-catenin feeds into the Wnt pathway upon adherens junctions dissociation: evidence for an intersection between β-catenin pools. PLoS ONE 4, e4580 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Howard, S., Deroo, T., Fujita, Y. & Itasaki, N. A positive role of cadherin in Wnt/β-catenin signalling during epithelial–mesenchymal transition. PLoS ONE 6, e23899 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gavard, J. & Mege, R. M. Once upon a time there was β-catenin in cadherin-mediated signalling. Biol. Cell 97, 921–926 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Nelson, W. J. & Nusse, R. Convergence of Wnt, β-catenin, and cadherin pathways. Science 303, 1483–1487 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. McEwen, A. E., Escobar, D. E. & Gottardi, C. J. Signaling from the adherens junction. Subcell. Biochem. 60, 171–196 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Xiao, K., Oas, R. G., Chiasson, C. M. & Kowalczyk, A. P. Role of p120-catenin in cadherin trafficking. Biochim. Biophys. Acta 1773, 8–16 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. He, Y., Ki, H., Kim, H. & Kim, K. δ-catenin interacts with LEF-1 and negatively regulates its transcriptional activity. Cell Biol. Int. 39, 954–961 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Rodova, M., Kelly, K. F., VanSaun, M., Daniel, J. M. & Werle, M. J. Regulation of the rapsyn promoter by Kaiso and δ-catenin. Mol. Cell. Biol. 24, 7188–7196 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gu, D. et al. Caspase-3 cleavage links δ-catenin to the novel nuclear protein ZIFCAT. J. Biol. Chem. 286, 23178–23188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Harmon, R. M. & Green, K. J. Structural and functional diversity of desmosomes. Cell Commun. Adhes. 20, 171–187 (2013).

    Article  CAS  PubMed  Google Scholar 

  111. Munoz, W. A. et al. Plakophilin-3 catenin associates with the ETV1/ER81 transcription factor to positively modulate gene activity. PLoS ONE 9, e86784 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Oh, S., Shin, S. & Janknecht, R. ETV1, 4 and 5: an oncogenic subfamily of ETS transcription factors. Biochim. Biophys. Acta 1826, 1–12 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Hollenhorst, P. C., McIntosh, L. P. & Graves, B. J. Genomic and biochemical insights into the specificity of ETS transcription factors. Annu. Rev. Biochem. 80, 437–471 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Goossens, S. et al. A unique and specific interaction between αT-catenin and plakophilin-2 in the area composita, the mixed-type junctional structure of cardiac intercalated discs. J. Cell Sci. 120, 2126–2136 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Mertens, C. et al. Nuclear particles containing RNA polymerase III complexes associated with the junctional plaque protein plakophilin 2. Proc. Natl Acad. Sci. USA 98, 7795–7800 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Sobolik-Delmaire, T., Reddy, R., Pashaj, A., Roberts, B. J. & Wahl, J. K. 3rd Plakophilin-1 localizes to the nucleus and interacts with single-stranded DNA. J. Invest. Dermatol. 130, 2638–2646 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Hofmann, I. et al. Identification of the junctional plaque protein plakophilin 3 in cytoplasmic particles containing RNA-binding proteins and the recruitment of plakophilins 1 and 3 to stress granules. Mol. Biol. Cell 17, 1388–1398 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Wolf, A. et al. Plakophilin 1 stimulates translation by promoting eIF4A1 activity. J. Cell Biol. 188, 463–471 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Buckley, C. D. et al. The minimal cadherin–catenin complex binds to actin filaments under force. Science 346, 1254211 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Priya, R. & Yap, A. S. Active tension: the role of cadherin adhesion and signaling in generating junctional contractility. Curr. Top. Dev. Biol. 112, 65–102 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. Schneider, S., Herrenknecht, K., Butz, S., Kemler, R. & Hausen, P. Catenins in Xenopus embryogenesis and their relation to the cadherin-mediated cell–cell adhesion system. Development 118, 629–640 (1993).

    Article  CAS  PubMed  Google Scholar 

  122. Benjamin, J. M. et al. αE-catenin regulates actin dynamics independently of cadherin-mediated cell–cell adhesion. J. Cell Biol. 189, 339–352 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Gottardi, C. J. & Gumbiner, B. M. Distinct molecular forms of β-catenin are targeted to adhesive or transcriptional complexes. J. Cell Biol. 167, 339–349 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Takahashi, N., Ishihara, S., Takada, S., Tsukita, S. & Nagafuchi, A. Posttranscriptional regulation of α-catenin expression is required for Wnt signaling in L cells. Biochem. Biophys. Res. Commun. 277, 691–698 (2000).

    Article  CAS  PubMed  Google Scholar 

  125. Giannini, A. L., Vivanco, M. & Kypta, R. M. α-catenin inhibits β-catenin signaling by preventing formation of a β-catenin·T-cell factor·DNA complex. J. Biol. Chem. 275, 21883–21888 (2000).

    Article  CAS  PubMed  Google Scholar 

  126. Hwang, S. G. et al. Regulation of β-catenin signaling and maintenance of chondrocyte differentiation by ubiquitin-independent proteasomal degradation of α-catenin. J. Biol. Chem. 280, 12758–12765 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Merdek, K. D., Nguyen, N. T. & Toksoz, D. Distinct activities of the α-catenin family, α-catulin and α-catenin, on β-catenin-mediated signaling. Mol. Cell. Biol. 24, 2410–2422 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Sehgal, R. N., Gumbiner, B. M. & Reichardt, L. F. Antagonism of cell adhesion by an α-catenin mutant, and of the Wnt-signaling pathway by α-catenin in Xenopus embryos. J. Cell Biol. 139, 1033–1046 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Choi, S. H. et al. α-catenin interacts with APC to regulate β-catenin proteolysis and transcriptional repression of Wnt target genes. Genes Dev. 27, 2473–2488 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Daugherty, R. L. et al. α-catenin is an inhibitor of transcription. Proc. Natl Acad. Sci. USA 111, 5260–5265 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. El-Bahrawy, M., Talbot, I., Poulsom, R. & Alison, M. Variable nuclear localization of α-catenin in colorectal carcinoma. Lab. Invest. 82, 1167–1174 (2002).

    Article  CAS  PubMed  Google Scholar 

  132. Hofmann, W. A. et al. Actin is part of pre-initiation complexes and is necessary for transcription by RNA polymerase II. Nat. Cell Biol. 6, 1094–1101 (2004).

    Article  CAS  PubMed  Google Scholar 

  133. Hu, P., Wu, S. & Hernandez, N. A role for β-actin in RNA polymerase III transcription. Genes Dev. 18, 3010–3015 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Kukalev, A., Nord, Y., Palmberg, C., Bergman, T. & Percipalle, P. Actin and hnRNP U cooperate for productive transcription by RNA polymerase II. Nat. Struct. Mol. Biol. 12, 238–244 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Philimonenko, V. V. et al. Nuclear actin and myosin I are required for RNA polymerase I transcription. Nat. Cell Biol. 6, 1165–1172 (2004).

    Article  CAS  PubMed  Google Scholar 

  136. Vasioukhin, V., Bauer, C., Degenstein, L., Wise, B. & Fuchs, E. Hyperproliferation and defects in epithelial polarity upon conditional ablation of α-catenin in skin. Cell 104, 605–617 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. Kobielak, A. & Fuchs, E. Links between α-catenin, NF-κB, and squamous cell carcinoma in skin. Proc. Natl Acad. Sci. USA 103, 2322–2327 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Piao, H. L. et al. α-catenin acts as a tumour suppressor in E-cadherin-negative basal-like breast cancer by inhibiting NF-κB signalling. Nat. Cell Biol. 16, 245–254 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Lien, W. H., Klezovitch, O., Fernandez, T. E., Delrow, J. & Vasioukhin, V. αE-catenin controls cerebral cortical size by regulating the Hedgehog signaling pathway. Science 311, 1609–1612 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Rhee, J., Ryu, J. H., Kim, J. H., Chun, C. H. & Chun, J. S. α-catenin inhibits β-catenin-T-cell factor/lymphoid enhancing factor transcriptional activity and collagen type II expression in articular chondrocytes through formation of Gli3R·α-catenin·β-catenin ternary complex. J. Biol. Chem. 287, 11751–11760 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Schlegelmilch, K. et al. Yap1 acts downstream of α-catenin to control epidermal proliferation. Cell 144, 782–795 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Silvis, M. R. et al. α-catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator Yap1. Sci. Signal. 4, ra33 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Drees, F., Pokutta, S., Yamada, S., Nelson, W. J. & Weis, W. I. α-catenin is a molecular switch that binds E-cadherin–β-catenin and regulates actin-filament assembly. Cell 123, 903–915 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Hansen, S. D. et al. αE-catenin actin-binding domain alters actin filament conformation and regulates binding of nucleation and disassembly factors. Mol. Biol. Cell 24, 3710–3720 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. de Lanerolle, P. & Serebryannyy, L. Nuclear actin and myosins: life without filaments. Nat. Cell Biol. 13, 1282–1288 (2011).

    Article  CAS  PubMed  Google Scholar 

  146. Huveneers, S. & de Rooij, J. Mechanosensitive systems at the cadherin–F-actin interface. J. Cell Sci. 126, 403–413 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. Battaglia, S., Maguire, O. & Campbell, M. J. Transcription factor co-repressors in cancer biology: roles and targeting. Int. J. Cancer 126, 2511–2519 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Barrett, C. W. et al. Kaiso directs the transcriptional corepressor MTG16 to the Kaiso binding site in target promoters. PLoS ONE 7, e51205 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Filion, G. J. et al. A family of human zinc finger proteins that bind methylated DNA and repress transcription. Mol. Cell. Biol. 26, 169–181 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Fournier, A., Sasai, N., Nakao, M. & Defossez, P. A. The role of methyl-binding proteins in chromatin organization and epigenome maintenance. Brief. Funct. Genomics 11, 251–264 (2012).

    Article  CAS  PubMed  Google Scholar 

  151. Yoon, H. G., Chan, D. W., Reynolds, A. B., Qin, J. & Wong, J. N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso. Mol. Cell 12, 723–734 (2003).

    Article  CAS  PubMed  Google Scholar 

  152. Turner, T. N. et al. Loss of δ-catenin function in severe autism. Nature 520, 51–56 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank their colleagues in the field, and the reviewers for their helpful comments, and apologize to those whose work was not cited owing to space considerations. P.D.M. was supported by U.S. National Institutes of Health (NIH) grant GM107079 and C.J.G. by GM076561.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Pierre D. McCrea or Cara J. Gottardi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Related links

Related links

FURTHER INFORMATION

WNT homepage

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McCrea, P., Gottardi, C. Beyond β-catenin: prospects for a larger catenin network in the nucleus. Nat Rev Mol Cell Biol 17, 55–64 (2016). https://doi.org/10.1038/nrm.2015.3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm.2015.3

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing