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Mutated APC and Asef are involved in the migration of colorectal tumour cells

Nature Cell Biology volume 5, pages 211–215 (2003)Cite this article

Abstract

The tumour suppressor adenomatous polyposis coli (APC) is mutated in sporadic and familial colorectal tumours1,2. APC binds to β-catenin, a key component of the Wnt signalling pathway, and induces its degradation1,2,3,4,5. APC interacts with microtubules and accumulates at their plus ends in membrane protrusions6,7,8,9, and associates with the plasma membrane in an actin-dependent manner10. In addition, APC interacts with the Rac-specific guanine nucleotide exchange factor Asef and stimulates its activity, thereby regulating the actin cytoskeletal network and cell morphology11. Here we show that overexpression of Asef decreases E-cadherin-mediated cell–cell adhesion and promotes the migration of epithelial Madin–Darby canine kidney cells. Both of these activities are stimulated by truncated APC proteins expressed in colorectal tumour cells. Experiments based on RNA interference and dominant-negative mutants show that both Asef and mutated APC are required for the migration of colorectal tumour cells expressing truncated APC. These results suggest that the APC–Asef complex functions in cell migration as well as in E-cadherin-mediated cell–cell adhesion, and that truncated APC present in colorectal tumour cells contributes to their aberrant migratory properties.

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Figure 1: Effects of Asef and APC on MDCK morphology and adhesion.
Figure 2: Effects of Asef and APC on cell migration.
Figure 3: Dominant-negative mutants and RNAi of Asef and APC.
Figure 4: Effects of Asef and APC on colorectal tumour cell motility.

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References

  1. Kinzler, K.W. & Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 87, 159–170 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Fearnhead, N.S., Britton, M.P. & Bodmer, W.F. The ABC of APC. Hum. Mol. Genet. 10, 721–733 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Bienz, M. & Clevers, H. Linking colorectal cancer to Wnt signaling. Cell 103, 311–320 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Peifer, M. & Polakis, P. Wnt signaling in oncogenesis and embryogenesis — look outside the nucleus. Science 287, 1606–1609 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Akiyama, T. Wnt/β-catenin signaling. Cytokine Growth Factor Rev. 11, 273–282 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. 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  PubMed  Google Scholar 

  7. Smith, K.J. et al. Wild-type but not mutant APC associates with the microtubule cytoskeleton. Cancer Res. 54, 3672–3675 (1994).

    CAS  PubMed  Google Scholar 

  8. Nathke, I.S., Adams, C.L., Polakis, P., Sellin, J.H. & Nelson, W.I.J. The adenomatous polyposis coli tumor suppressor protein localizes to plasma membrane sites involved in active cell migration. J. Cell Biol. 134, 165–179 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Mimori-Kiyosue, Y., Shiina, N. & Tsukita, S. Adenomatous polyposis coli (APC) protein moves along microtubules and concentrates at their growing ends in epithelial cells. J. Cell Biol. 148, 505–518 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rosin-Arbesfeld, R., Ihrke, G. & Bienz, M. Actin-dependent membrane association of the APC tumor suppressor in polarized mammalian epithelial cells. EMBO J. 20, 5929–5939 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kawasaki, Y. et al. Asef, a link between the tumor suppressor APC and G-protein signaling. Science 289, 1194–1197 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Hall, A. Rho GTPase and the actin cytoskeleton. Science 279, 509–514 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Van Aelst, L. & D'Souza-Schorey, C. Rho GTPases and signaling network. Genes Dev. 11, 2295–2322 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Whitehead, I.P., Campbell. S., Rossman, K.L. & Der, C.J. Dbl family proteins. Biochim. Biophys. Acta 1332, F1–F23 (1997).

    CAS  PubMed  Google Scholar 

  15. Keely, P.J., Westwick, J.K., Whitehead, I.P., Der, C.J. & Parise, L.V. Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K. Nature 390, 632–636 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Sander, E.E. et al. Matrix-dependent Tiam1/Rac signaling in epithelial cells promotes either cell–cell adhesion or cell migration and is regulated by phosphatidylinositol 3-kinase. J. Cell Biol. 143, 1385–1398 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hordijk, P.L. et al. Inhibition of invasion of epithelial cells by Tiam1–Rac signaling. Science 278, 1464–1466 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Takaishi, K., Sasaki, T., Kotani, H., Nishioka, H. & Takai, Y. Regulation of cell–cell adhesion by Rac and Rho small G proteins in MDCK cells. J. Cell Biol. 139, 1047–1059 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Braga, V.M.M. Betson, M., Li, X. & Lamarche-Vane, N. Activation of the small GTPase Rac is sufficient to disrupt cadherin-dependent cell–cell adhesion in normal human keratinocytes. Mol. Biol. Cell 11, 3703–3721 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Miyoshi, Y. et al. Somatic mutation of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum. Mol. Genet. 1, 229–233 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Nagawa, H. & Nakamura, Y. Mutations of the APC (adenomatous polyposis coli) gene. Hum. Mutat. 2, 425–434 (1993).

    Article  Google Scholar 

  22. Paddison, P.J., Caudy, A.A., Bernstein, E., Hannon, G.J. & Conklin, D.S. Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev. 16, 948–958 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rowan, A.J. et al. APC mutation in sporadic colorectal tumors: a mutational hotspot and interdependence of the two hit. Proc. Natl Acad. Sci. USA 97, 3352–3357 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wong, M.H., Hermiston, M.L., Syder, A.J. & Gordon, J.I. Forced expression of the tumor suppressor adenomatous polyposis coli protein induces disordered cell migration in the intestinal epithelium. Proc. Natl Acad. Sci. USA 93, 9588–9593 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Oshima, H., Oshima, M., Kobayashi, M., Tsutsumi, M., Taketo, M.M. Morphological and molecular processes of polyp formation in Apc (Δ716) knockout mice. Cancer Res. 57, 1644–1649 (1997).

    CAS  PubMed  Google Scholar 

  26. Klemke, R.L. et al. Regulation of cell motility by mitogen-activated protein kinase. J. Cell Biol. 137, 481–492 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sells, M.A., Boyd, J.T. & Chernoff, J. p21-activated kinase 1 (Pak1) regulates cell motility in mammalian fibroblasts. J. Cell Biol. 145, 837–849 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank G. J. Hannon for pSHAG-1, and M. Lamphier for reading the manuscript. This work was supported by Grants-in-Aid for Scientific Research on Priority Areas and the Organization for Pharmaceutical Safety and Research.

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  1. Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113, Japan

    Yoshihiro Kawasaki, Rina Sato & Tetsu Akiyama

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Correspondence to Tetsu Akiyama.

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Kawasaki, Y., Sato, R. & Akiyama, T. Mutated APC and Asef are involved in the migration of colorectal tumour cells. Nat Cell Biol 5, 211–215 (2003). https://doi.org/10.1038/ncb937

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