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A bigger picture: classical cadherins and the dynamic actin cytoskeleton

Abstract

Classical cadherin adhesion receptors influence tissue integrity in health and disease. Their biological function is intimately linked to the actin cytoskeleton. To date, research has largely focused on identifying the molecular mechanisms that physically couple cadherin to cortical actin filaments. However, the junctional cytoskeleton is dynamic. Recent developments in understanding how filament dynamics and organization in the junctional cytoskeleton are controlled provide new insights into how the actin cytoskeleton regulates cadherin junctions in health and disease.

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Figure 1: Cadherin–junctional cytoskeleton cooperation through physical interactions between cadherins and actin filaments.
Figure 2: Cadherin–actin cooperation through control of actin dynamics at junctions.
Figure 3: The impact of a dynamic actin cytoskeleton on cadherin biology.

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References

  1. Niessen, C., Leckband, D. & Yap, A. S. Tissue organization by classical cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation. Physiol. Rev. 91, 691–731 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Otani, T., Ichii, T., Aono, S. & Takeichi, M. Cdc42 GEF Tuba regulates the junctional configuration of simple epithelial cells. J. Cell Biol. 175, 135–146 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Harrison, O. J. et al. The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins. Structure 19, 244–256 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kovacs, E. M. et al. N-WASP regulates the epithelial junctional actin cytoskeleton through a non-canonical post-nucleation pathway. Nature Cell Biol. 13, 934–943 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Tepass, U. & Hartenstein, V. The development of cellular junctions in the Drosophila embryo. Dev. Biol. 161, 563–596 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Hirokawa, N., Keller, T. C. 3rd, Chasan, R. & Mooseker, M. S. Mechanism of brush border contractility studied by the quick-freeze, deep-etch method. J. Cell Biol. 96, 1325–1336 (1983).

    Article  CAS  PubMed  Google Scholar 

  7. Tang, V. W. & Brieher, W. M. α-actinin-4/FSGS1 is required for Arp2/3-dependent actin assembly at the adherens junction. J. Cell Biol. 196, 115–130 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Huveneers, S. et al. Vinculin associates with endothelial VE-cadherin junctions to control force-dependent remodeling. J. Cell Biol. 196, 641–652 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Costa, M. et al. A putative catenin–cadherin system mediates morphogenesis of the Caenorhabditis elegans embryo. J. Cell Biol. 141, 297–308 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rauzi, M., Lenne, P. F. & Lecuit, T. Planar polarized actomyosin contractile flows control epithelial junction remodelling. Nature 468, 1110–1114 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Martin, A. C., Kaschube, M. & Wieschaus, E. F. Pulsed contractions of an actin–myosin network drive apical constriction. Nature 457, 495–499 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Abe, K. & Takeichi, M. EPLIN mediates linkage of the cadherin catenin complex to F-actin and stabilizes the circumferential actin belt. Proc. Natl Acad. Sci. USA 105, 13–19 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Pokutta, S., Drees, F., Takai, Y., Nelson, W. J. & Weis, W. I. Biochemical and structural definition of the l-afadin- and actin- binding sites of α-catenin. J. Biol. Chem. 277, 18868–18874 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Rimm, D. L. Koslov, E. R., Kebriaei, P., Cianci, C. D. & Morrow, J. S. a1(E)-Catenin is an actin-binding and -bundling protein mediating the attachment of F-actin to the membrane adhesion complex. Proc. Natl Acad. Sci. USA 92, 8813–8817 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yamada, S., Pokutta, S., Drees, F., Weis, W. I. & Nelson, W. J. Deconstructing the cadherin–catenin–actin complex. Cell 123, 889–901 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yonemura, S. Wada, Y., Watanabe, T., Nagafuchi, A. & Shibata, M. α-catenin as a tension transducer that induces adherens junction development. Nature Cell Biol. 12, 533–542 (2010).

    Article  CAS  PubMed  Google Scholar 

  17. Choi, H. J. et al. αE-catenin is an autoinhibited molecule that coactivates vinculin. Proc. Natl Acad. Sci. USA 109, 8576–8581 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Vasioukhin, V., Bauer, C., Yin, M. & Fuchs, E. Directed actin polymerization is the driving force for epithelial cell–cell adhesion. Cell 100, 209–219 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Ivanov, A. I., Hunt, D., Utech, M., Nusrat, A. & Parkos, C. A. Differential roles for actin polymerization and a myosin II motor in assembly of the epithelial apical junctional complex. Mol. Biol. Cell 16, 2636–2650 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kovacs, E. M., Goodwin, M., Ali, R. G., Paterson, A. D. & Yap, A. S. Cadherin-directed actin assembly: E-cadherin physically associates with the Arp2/3 complex to direct actin assembly in nascent adhesive contacts. Curr. Biol. 12, 379–382 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Lambert, M., Choquet, D. & Mege, R. M. Dynamics of ligand-induced, Rac1-dependent anchoring of cadherins to the actin cytoskeleton. J. Cell Biol. 157, 469–479 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pollard, T. D., Blanchoin, L. & Mullins, R. D. Molecular mechanisms controlling actin filament dynamics in nonmuscle cells. Annu. Rev. Biophys. Biomol. Struct. 29, 545–576 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Chesarone, M. A. & Goode, B. L. Actin nucleation and elongation factors: mechanisms and interplay. Curr. Opin. Cell Biol. 21, 28–37 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mangold, S. et al. Hepatocyte growth factor acutely perturbs actin filament anchorage at the epithelial zonula adherens. Curr. Biol. 21, 503–507 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Zhang, J. et al. Actin at cell–cell junctions is composed of two dynamic and functional populations. J. Cell Sci. 118, 5549–5562 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Cavey, M., Rauzi, M., Lenne, P. F. & Lecuit, T. A two-tiered mechanism for stabilization and immobilization of E-cadherin. Nature 453, 751–756 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Carramusa, L., Ballestrem, C., Zilberman, Y. & Bershadsky, A. D. Mammalian diaphanous-related formin Dia1 controls the organization of E-cadherin mediated cell–cell junctions. J. Cell Sci. 120, 3870–3882 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Kobielak, A., Pasolli, H. A. & Fuchs, E. Mammalian formin-1 participates in adherens junctions and polymerization of linear actin cables. Nature Cell Biol. 6, 21–30 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Homem, C. C. & Peifer, M. Diaphanous regulates myosin and adherens junctions to control cell contractility and protrusive behavior during morphogenesis. Development 135, 1005–1018 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Yamazaki, D., Oikawa, T. & Takenawa, T. Rac–WAVE-mediated actin reorganization is required for organization and maintenance of cell–cell adhesion. J. Cell Sci. 120, 86–100 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Nandadasa, S., Tao, Q., Menon, N. R., Heasman, J. & Wylie, C. N- and E-cadherins in Xenopus are specifically required in the neural and non-neural ectoderm, respectively, for F-actin assembly and morphogenetic movements. Development 136, 1327–1338 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Padrick, S. B. & Rosen, M. K. Physical mechanisms of signal integration by WASP family proteins. Annu. Rev. Biochem. 79, 707–735 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Helwani, F. M. et al. Cortactin is necessary for E-cadherin-mediated contact formation and actin reorganization. J. Cell Biol. 164, 899–910 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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 

  35. 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 

  36. Scott, J. A. et al. Ena/VASP proteins can regulate distinct modes of actin organization at cadherin-adhesive contacts. Mol. Biol. Cell 17, 1085–1095 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bear, J. E. & Gertler, F. B. Ena/VASP: towards resolving a pointed controversy at the barbed end. J. Cell Sci. 122, 1947–1953 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hansen, S. D. & Mullins, R. D. VASP is a processive actin polymerase that requires monomeric actin for barbed end association. J. Cell Biol. 191, 571–584 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Furman, C. et al. Ena/VASP is required for endothelial barrier function in vivo. J. Cell Biol. 179, 761–775 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Weber, K. L., Fischer, R. S. & Fowler, V. M. Tmod3 regulates polarized epithelial cell morphology. J. Cell Sci. 120, 3625–3632 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. El Sayegh, T. Y. et al. Phosphatidylinositol-4,5 bisphosphate produced by PIP5KIγ regulates gelsolin, actin assembly, and adhesion strength of N-cadherin junctions. Mol. Biol. Cell 18, 3026–3038 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ammer, A. G. & Weed, S. A. Cortactin branches out: roles in regulating protrusive actin dynamics. Cell Motil. Cytoskeleton 65, 687–707 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ratheesh, A. et al. Centralspindlin and α-catenin regulate Rho signalling at the epithelial zonula adherens. Nature Cell Biol. 14, 818–828 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Yamada, S. & Nelson, W. J. Localized zones of Rho and Rac activities drive initiation and expansion of epithelial cell cell adhesion. J. Cell Biol. 178, 517–527 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Brawley, C. M. & Rock, R. S. Unconventional myosin traffic in cells reveals a selective actin cytoskeleton. Proc. Natl Acad. Sci. USA 106, 9685–9690 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chen, H., Bernstein, B. W. & Bamburg, J. R. Regulating actin-filament dynamics in vivo. Trends Biochem. Sci. 25, 19–23 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Gandhi, M., Achard, V., Blanchoin, L. & Goode, B. L. Coronin switches roles in actin disassembly depending on the nucleotide state of actin. Mol. Cell 34, 364–374 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gates, J. et al. Enabled plays key roles in embryonic epithelial morphogenesis in Drosophila. Development 134, 2027–2039 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Yarar, D., Waterman-Storer, C. M. & Schmid, S. L. A dynamic actin cytoskeleton functions at multiple stages of clathrin-mediated endocytosis. Mol. Biol. Cell 16, 964–975 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Le, T. L., Yap, A. S. & Stow, J. L. Recycling of E-cadherin: a potential mechanism for regulating cadherin dynamics. J. Cell Biol. 146, 219–232 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Izumi, G. et al. Endocytosis of E-cadherin regulated by Rac and Cdc42 small G proteins through IQGAP1 and actin filaments. J. Cell Biol. 166, 237–248 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Georgiou, M., Marinari, E., Burden, J. & Baum, B. Cdc42, Par6, and aPKC regulate Arp2/3-mediated endocytosis to control local adherens junction stability. Curr. Biol. 18, 1631–1638 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Leibfried, A., Fricke, R., Morgan, M. J., Bogdan, S. & Bellaiche, Y. Drosophila Cip4 and WASp define a branch of the Cdc42–Par6–aPKC pathway regulating E-cadherin endocytosis. Curr. Biol. 18, 1639–1648 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Levayer, R., Pelissier-Monier, A. & Lecuit, T. Spatial regulation of Dia and Myosin-II by RhoGEF2 controls initiation of E-cadherin endocytosis during epithelial morphogenesis. Nature Cell Biol. 13, 529–540 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Muller, H. A. & Wieschaus, E. armadillo, bazooka, and stardust are critical for early stages in formation of the zonula adherens and maintenance of the polarized blastoderm epithelium in Drosophila. J. Cell Biol. 134, 149–163 (1996).

    Article  CAS  PubMed  Google Scholar 

  56. Yap, A. S., Brieher, W. M., Pruschy, M. & Gumbiner, B. M. Lateral clustering of the adhesive ectodomain: a fundamental determinant of cadherin function. Curr. Biol. 7, 308–315 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Sawyer, J. K. et al. A contractile actomyosin network linked to adherens junctions by Canoe/afadin helps drive convergent extension. Mol. Biol. Cell 22, 2491–2508 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sawyer, J. M. et al. Apical constriction: a cell shape change that can drive morphogenesis. Dev. Biol. 341, 5–19 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Vicente-Manzanares, M., Ma, X., Adelstein, R. S. & Horwitz, A. R. Non-muscle myosin II takes centre stage in cell adhesion and migration. Nature Rev. Mol. Cell Biol. 10, 778–790 (2009).

    Article  CAS  Google Scholar 

  60. Smutny, M. et al. Myosin II isoforms identify distinct functional modules that support integrity of the epithelial zonula adherens. Nature Cell Biol. 12, 696–702 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Kametani, Y. & Takeichi, M. Basal-to-apical cadherin flow at cell junctions. Nature Cell Biol. 9, 92–98 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Kwiatkowski, A. V. et al. In vitro and in vivo reconstitution of the cadherin–catenin–actin complex from Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 107, 14591–14596 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Fernandez-Gonzalez, R., Simoes Sde, M., Roper, J. C., Eaton, S. & Zallen, J. A. Myosin II dynamics are regulated by tension in intercalating cells. Dev. Cell 17, 736–743 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Fernandez-Gonzalez, R. & Zallen, J. A. Oscillatory behaviors and hierarchical assembly of contractile structures in intercalating cells. Phys. Biol. 8, 045005 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Martin, A. C., Gelbart, M., Fernandez-Gonzalez, R., Kaschube, M. & Wieschaus, E. Integration of contractile forces during tissue invagination. J. Cell Biol. 188, 735–749 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Roh-Johnson, M. et al. Triggering a cell shape change by exploiting preexisting actomyosin contractions. Science 335, 1232–1235 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Smutny, M. et al. Multicomponent analysis of junctional movements regulated by myosin II isoforms at the epithelial zonula adherens. PLoS ONE 6, e22458 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gomez, G. A., McLachlan, R. W. & Yap, A. S. Productive tension: force-sensing and homeostasis of cell–cell junctions. Trends Cell Biol. 21, 499–505 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Maddugoda, M. P., Crampton, M. S., Shewan, A. M. & Yap, A. S. Myosin VI and vinculin cooperate during the morphogenesis of cadherin cell–cell contacts in mammalian epithelial cells. J. Cell Biol. 178, 529–540 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yang, Q., Zhang, X. F., Pollard, T. D. & Forscher, P. Arp2/3 complex-dependent actin networks constrain myosin II function in driving retrograde actin flow. J. Cell Biol. 197, 939–956 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Reymann, A. C. et al. Actin network architecture can determine myosin motor activity. Science 336, 1310–1314 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Medeiros, N. A., Burnette, D. T. & Forscher, P. Myosin II functions in actin-bundle turnover in neuronal growth cones. Nature Cell Biol. 8, 215–226 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Kuo, J. C. et al. Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation. Nature Cell Biol. 13, 383–393 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Cossart, P. Illuminating the landscape of host–pathogen interactions with the bacterium Listeria monocytogenes. Proc. Natl Acad. Sci. USA 108, 19484–19491 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Berx, G. & van Roy, F. Involvement of members of the cadherin superfamily in cancer. Cold Spring Harb. Perspect. Biol. 1, a003129 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Hermiston, M. L. & Gordon, J. I. Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science 270, 1203–1207 (1995).

    Article  CAS  PubMed  Google Scholar 

  77. D'Agati, V. D., Kaskel, F. J. & Falk, R. J. Focal segmental glomerulosclerosis. N. Engl. J. Med. 365, 2398–2411 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Mengaud, J., Ohayon, H., Gounon, P., Mege, R.-M. & Cossart, P. E-cadherin is the receptor for internalin, a surface protein required for entry of L. monocytogenes into epithelial cells. Cell 84, 923–932 (1996).

    Article  CAS  PubMed  Google Scholar 

  79. Ireton, K. & Cossart, P. Host–pathogen interactions during entry and actin-based movement of Listeria monocytogenes. Annu. Rev. Genet. 31, 113–138 (1997).

    Article  CAS  PubMed  Google Scholar 

  80. Sousa, S. et al. Src, cortactin and Arp2/3 complex are required for E-cadherin-mediated internalization of Listeria into cells. Cell. Microbiol. 9, 2629–2643 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Ren, G. et al. Cortactin is a functional target of E-cadherin-activated Src family kinases in MCF7 epithelial monolayers. J. Biol. Chem. 284, 18913–18922 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Rajabian, T. et al. The bacterial virulence factor InlC perturbs apical cell junctions and promotes cell-to-cell spread of Listeria. Nature Cell Biol. 11, 1212–1218 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Kovacs, E. M., Verma, S., Thomas, S. G. & Yap, A. S. Tuba and N-WASP function cooperatively to position the central lumen during epithelial cyst morphogenesis. Cell Adh. Migr. 5, 344–350 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank B. Brieher, M. Way, R. Parton and all their colleagues in the laboratory for many stimulating conversations, and the anonymous reviewers for thoughtful suggestions. A.S.Y. is supported by grants (APP1010489) and a Research Fellowship (631383) from the National Health and Medical Research Council of Australia, Australian Research Council (DP 0988935) and Kids Cancer Project of the Oncology Children's Foundation. A.R. was supported by a grant from the Human Frontiers Science Program.

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Ratheesh, A., Yap, A. A bigger picture: classical cadherins and the dynamic actin cytoskeleton. Nat Rev Mol Cell Biol 13, 673–679 (2012). https://doi.org/10.1038/nrm3431

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