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Cadherin-mediated regulation of microtubule dynamics

Abstract

Epithelial polarization and neuronal outgrowth require the assembly of microtubule arrays that are not associated with centrosomes. As these processes generally involve contact interactions mediated by cadherins, we investigated the potential role of cadherin signalling in the stabilization of non-centrosomal microtubules. Here we show that expression of cadherins in centrosome-free cytoplasts increases levels of microtubule polymer and changes the behaviour of microtubules from treadmilling to dynamic instability. This effect is not a result of cadherin expression per se but depends on the formation of cell–cell contacts. The effect of cell–cell contacts is mimicked by application of beads coated with stimulatory anti-cadherin antibody and is suppressed by overexpression of the cytoplasmic cadherin tail. We therefore propose that cadherins initiate a signalling pathway that alters microtubule organization by stabilizing microtubule ends.

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Figure 1: Expression of cadherins in CHO cells.
Figure 2: Effect of cadherin expression and cell–cell contacts in centrosome-free cytoplasts.
Figure 3: Quantification of microtubule fluorescence in isolated and contacting cytoplasts.
Figure 4: Microtubule organization and dynamics in isolated and contacting cytoplasts.
Figure 5: Effect of N-cadherin-inhibitory antibody on integrity of adherens junctions and microtubule organization.
Figure 6: Effect of N-cadherin-stimulatory beads on microtubule organization.
Figure 7: Effect of overexpression of cytoplasmic N-cadherin tail on microtubule organization in contacting, N-cadherin-expressing cytoplasts.

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References

  1. Kellogg, D. R., Moritz, M. & Alberts, B. M. The centrosome and cellular organization. Annu. Rev. Biochem. 63, 639–674 (1994).

    Article  CAS  Google Scholar 

  2. Gelfand, V. I. & Bershadsky, A. D. Microtubule dynamics: mechanism, regulation, and function. Annu. Rev. Cell Biol. 7, 93–116 (1991).

    Article  CAS  Google Scholar 

  3. Keating, T. J. & Borisy, G. G. Centrosomal and non-centrosomal microtubules. Biol. Cell. 91, 321–329 (1999).

    Article  CAS  Google Scholar 

  4. Bacallao, R. et al. The subcellular organization of Madin–Darby canine kidney cells during the formation of a polarized epithelium. J. Cell Biol. 109, 2817–2832 (1989).

    Article  CAS  Google Scholar 

  5. Bray, D. & Bunge, M. B. Serial analysis of microtubules in cultured rat sensory axons. J. Neurocytol. 10, 589–605 (1981).

    Article  CAS  Google Scholar 

  6. Baas, P. W., Deitch, J. S., Black, M. M. & Banker, G. A. Polarity orientation of microtubules in hippocampal neurons: uniformity in the axon and nonuniformity in the dendrite. Proc. Natl Acad. Sci. USA 85, 8335–8339 (1988).

    Article  CAS  Google Scholar 

  7. Kamal, A. & Goldstein, L. S. Connecting vesicle transport to the cytoskeleton. Curr. Opin. Cell Biol. 12, 503–508 (2000).

    Article  CAS  Google Scholar 

  8. Wadsworth, P. & McGrail, M. Interphase microtubule dynamics are cell type-specific. J. Cell Sci. 95, 23–32 (1990).

    PubMed  Google Scholar 

  9. Pepperkok, R., Bre, M. H., Davoust, J. & Kreis, T. E. Microtubules are stabilized in confluent epithelial cells but not in fibroblasts. J. Cell Biol. 111, 3003–3012 (1990).

    Article  CAS  Google Scholar 

  10. Lim, S. S., Sammak, P. J. & Borisy, G. G. Progressive and spatially differentiated stability of microtubules in developing neuronal cells. J. Cell Biol. 109, 253–263 (1989).

    Article  CAS  Google Scholar 

  11. Sammak, P. J. & Borisy, G. G. Direct observation of microtubule dynamics in living cells. Nature 332, 724–726 (1988).

    Article  CAS  Google Scholar 

  12. Schulze, E. & Kirschner, M. New features of microtubule behaviour observed in vivo. Nature 334, 356–359 (1988).

    Article  CAS  Google Scholar 

  13. Yap, A. S., Brieher, W. M. & Gumbiner, B. M. Molecular and functional analysis of cadherin-based adherens junctions. Annu. Rev. Cell Dev. Biol. 13, 119–146 (1997).

    Article  CAS  Google Scholar 

  14. Takeichi, M. Cadherin cell adhesion receptors as a morphogenetic regulator. Science 251, 1451–1455 (1991).

    Article  CAS  Google Scholar 

  15. Knudsen, K. A., Frankowski, C., Johnson, K. R. & Wheelock, M. J. A role for cadherins in cellular signaling and differentiation. J. Cell. Biochem. (Suppl.) 30–31, 168–176 (1998).

    Article  Google Scholar 

  16. McNeill, H., Ozawa, M., Kemler, R. & Nelson, W. J. Novel function of the cell adhesion molecule uvomorulin as an inducer of cell surface polarity. Cell 62, 309–316 (1990).

    Article  CAS  Google Scholar 

  17. Doherty, P. & Walsh, F. S. Signal transduction events underlying neurite outgrowth stimulated by cell adhesion molecules. Curr. Opin. Neurobiol. 4, 49–55 (1994).

    Article  CAS  Google Scholar 

  18. Rodionov, V., Nadezhdina, E. & Borisy, G. Centrosomal control of microtubule dynamics. Proc. Natl Acad. Sci. USA 96, 115–120 (1999).

    Article  CAS  Google Scholar 

  19. Karsenti, E., Kobayashi, S., Mitchison, T. & Kirschner, M. Role of the centrosome in organizing the interphase microtubule array: properties of cytoplasts containing or lacking centrosomes. J. Cell Biol. 98, 1763–1776 (1984).

    Article  CAS  Google Scholar 

  20. Cassimeris, L., Pryer, N. K. & Salmon, E. D. Real-time observations of microtubule dynamic instability in living cells. J. Cell Biol. 107, 2223–2231 (1988).

    Article  CAS  Google Scholar 

  21. Keating, T. J., Peloquin, J. G., Rodionov, V. I., Momcilovic, D. & Borisy, G. G. Microtubule release from the centrosome. Proc. Natl Acad. Sci. USA 94, 5078–5083 (1997).

    Article  CAS  Google Scholar 

  22. Yu, W., Centonze, V. E., Ahmad, F. J. & Baas, P. W. Microtubule nucleation and release from the neuronal centrosome. J. Cell Biol. 122, 349–359 (1993).

    Article  CAS  Google Scholar 

  23. Baas, P. W. & Ahmad, F. J. The plus ends of stable microtubules are the exclusive nucleating structures for microtubules in the axon. J. Cell Biol. 116, 1231–1241 (1992).

    Article  CAS  Google Scholar 

  24. Zheng, Y., Wong, M. L., Alberts, B. & Mitchison, T. Nucleation of microtubule assembly by a gamma-tubulin-containing ring complex. Nature 378, 578–583 (1995).

    Article  CAS  Google Scholar 

  25. Wiese, C. & Zheng, Y. A new function for the gamma -tubulin ring complex as a microtubule minus-end cap. Nature Cell Biol. 2, 358–364 (2000).

    Article  CAS  Google Scholar 

  26. Keating, T. J. & Borisy, G. G. Immunostructural evidence for the template mechanism of microtubule nucleation. Nature Cell Biol. 2, 352–357 (2000).

    Article  CAS  Google Scholar 

  27. Moritz, M., Braunfeld, M. B., Guenebaut, V., Heuser, J. & Agard, D. A. Structure of the gamma-tubulin ring complex: a template for microtubule nucleation. Nature Cell Biol. 2, 365–370 (2000).

    Article  CAS  Google Scholar 

  28. Levenberg, S., Katz, B. Z., Yamada, K. M. & Geiger, B. Long-range and selective autoregulation of cell-cell or cell-matrix adhesions by cadherin or integrin ligands. J. Cell Sci. 111, 347–357 (1998).

    CAS  PubMed  Google Scholar 

  29. Sadot, E., Simcha, I., Shtutman, M., Ben-Ze'ev, A. & Geiger, B. Inhibition of beta-catenin-mediated transactivation by cadherin derivatives. Proc. Natl Acad. Sci. USA 95, 15339–15344 (1998).

    Article  CAS  Google Scholar 

  30. Margolis, R. L. & Wilson, L. Microtubule treadmilling: what goes around comes around. Bioessays 20, 830–836 (1998).

    Article  CAS  Google Scholar 

  31. Volk, T. & Geiger, B. A 135-kd membrane protein of intercellular adherens junctions. EMBO J. 3, 2249–2260 (1984).

    Article  CAS  Google Scholar 

  32. Volberg, T., Geiger, B., Kartenbeck, J. & Franke, W. W. Changes in membrane–microfilament interaction in intercellular adherens junctions upon removal of extracellular Ca2+ ions. J. Cell Biol. 102, 1832–1842 (1986).

    Article  CAS  Google Scholar 

  33. Volk, T. & Geiger, B. A-CAM: a 135-kD receptor of intercellular adherens junctions. II. Antibody-mediated modulation of junction formation. J. Cell Biol. 103, 1451–1464 (1986).

    Article  CAS  Google Scholar 

  34. Goichberg, P. & Geiger, B. Direct involvement of N-cadherin-mediated signaling in muscle differentiation. Mol. Biol. Cell 9, 3119–3131 (1998).

    Article  CAS  Google Scholar 

  35. Ben-Ze'ev, A. & Geiger, B. Differential molecular interactions of beta-catenin and plakoglobin in adhesion, signaling and cancer. Curr. Opin. Cell Biol. 10, 629–639 (1998).

    Article  CAS  Google Scholar 

  36. Cavallo, R., Rubenstein, D. & Peifer, M. Armadillo and dTCF: a marriage made in the nucleus. Curr. Opin. Genet. Dev. 7, 459–466 (1997).

    Article  CAS  Google Scholar 

  37. Damalas, A. et al. Excess beta-catenin promotes accumulation of transcriptionally active p53. EMBO J. 18, 3054–3063 (1999).

    Article  CAS  Google Scholar 

  38. Carmeliet, P. et al. Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98, 147–157 (1999).

    Article  CAS  Google Scholar 

  39. Polakis, P. The adenomatous polyposis coli (APC) tumor suppressor. Biochim. Biophys. Acta 1332, F127–147 (1997).

    CAS  Google Scholar 

  40. Munemitsu, S. et al. The APC gene product associates with microtubules in vivo and promotes their assembly in vitro. Cancer Res. 54, 3676–3681 (1994).

    CAS  Google Scholar 

  41. Morrison, E. E., Wardleworth, B. N., Askham, J. M., Markham, A. F. & Meredith, D. M. EB1, a protein which interacts with the APC tumour suppressor, is associated with the microtubule cytoskeleton throughout the cell cycle. Oncogene 17, 3471–3477 (1998).

    Article  CAS  Google Scholar 

  42. Kaufmann, U., Kirsch, J., Irintchev, A., Wernig, A. & Starzinski-Powitz, A. The M-cadherin catenin complex interacts with microtubules in skeletal muscle cells: implications for the fusion of myoblasts. J. Cell Sci. 112, 55–68 (1999).

    CAS  PubMed  Google Scholar 

  43. Anastasiadis, P. Z. & Reynolds, A. B. The p120 catenin family: complex roles in adhesion, signaling and cancer. J. Cell Sci. 113, 1319–1334 (2000).

    CAS  PubMed  Google Scholar 

  44. Kahana, J. A. & Cleveland, D. W. Beyond nuclear transport. Ran–GTP as a determinant of spindle assembly. J. Cell Biol. 146, 1205–1210 (1999).

    Article  CAS  Google Scholar 

  45. Lawler, S. Microtubule dynamics: if you need a shrink try stathmin/Op18. Curr. Biol. 8, R212–214 (1998).

    Article  CAS  Google Scholar 

  46. Desai, A., Verma, S., Mitchison, T. J. & Walczak, C. E. Kin I kinesins are microtubule-destabilizing enzymes. Cell 96, 69–78 (1999).

    Article  CAS  Google Scholar 

  47. Drewes, G., Ebneth, A. & Mandelkow, E. M. MAPs, MARKs and microtubule dynamics. Trends Biochem. Sci. 23, 307–311 (1998).

    Article  CAS  Google Scholar 

  48. Bershadsky, A., Chausovsky, A., Becker, E., Lyubimova, A. & Geiger, B. Involvement of microtubules in the control of adhesion-dependent signal transduction. Curr. Biol. 6, 1279–1289 (1996).

    Article  CAS  Google Scholar 

  49. Rodionov, V. I., Lim, S. S., Gelfand, V. I. & Borisy, G. G. Microtubule dynamics in fish melanophores. J. Cell Biol. 126, 1455–1464 (1994).

    Article  CAS  Google Scholar 

  50. Svitkina, T. M. & Borisy, G. G. Correlative light and electron microscopy of the cytoskeleton of cultured cells. Methods Enzymol. 298, 570–592 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank B. Geiger for help and encouragement, V. Rodionov for advice on the cytoplast assay and live cell imaging, J. Peloquin and S. Limbach for technical assistance, and E. Sadot for cadherin constructs. This work was supported in part by grants from the Israel Science Foundation, Minerva Foundation (Munich, Germany) and Crown Endowment Fund to A.B. A.C. acknowledges the travel grant from the Journal of Cell Science (The Company of Biologists Limited); G.G.B. acknowledges support from NIH grant GM25062.

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Correspondence to Gary G. Borisy.

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Chausovsky, A., Bershadsky, A. & Borisy, G. Cadherin-mediated regulation of microtubule dynamics. Nat Cell Biol 2, 797–804 (2000). https://doi.org/10.1038/35041037

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