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EMT, the cytoskeleton, and cancer cell invasion

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Abstract

The metastatic process, i.e. the dissemination of cancer cells throughout the body to seed secondary tumors at distant sites, requires cancer cells to leave the primary tumor and to acquire migratory and invasive capabilities. In a process of epithelial-mesenchymal transition (EMT), besides changing their adhesive repertoire, cancer cells employ developmental processes to gain migratory and invasive properties that involve a dramatic reorganization of the actin cytoskeleton and the concomitant formation of membrane protrusions required for invasive growth. The molecular processes underlying such cellular changes are still only poorly understood, and the various migratory organelles, including lamellipodia, filopodia, invadopodia and podosomes, still require a better functional and molecular characterization. Notably, direct experimental evidence linking the formation of migratory membrane protrusions and the process of EMT and tumor metastasis is still lacking. In this review, we have summarized recent novel insights into the molecular processes and players underlying EMT on one side and the formation of invasive membrane protrusions on the other side.

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References

  1. Thiery, J. P., & Sleeman, J. P. (2006). Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol, 7, 131–142.

    PubMed  CAS  Google Scholar 

  2. Grunert, S., Jechlinger, M., & Beug, H. (2003). Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol, 4, 657–665.

    PubMed  Google Scholar 

  3. Zavadil, J., & Bottinger, E. P. (2005). TGF-beta and epithelial-to-mesenchymal transitions. Oncogene, 24, 5764–5774.

    PubMed  CAS  Google Scholar 

  4. Savagner, P., Yamada, K. M., & Thiery, J. P. (1997). The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition. J Cell Biol, 137, 1403–1419.

    PubMed  CAS  Google Scholar 

  5. Lo, H. W., Hsu, S. C., Xia, W., Cao, X., Shih, J. Y., & Wei, Y. (2007). Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res, 67, 9066–9076.

    PubMed  CAS  Google Scholar 

  6. Graham, T. R., Zhau, H. E., Odero-Marah, V. A., Osunkoya, A. O., Kimbro, K. S., & Tighiouart, M. (2008). Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res, 68, 2479–2488.

    PubMed  CAS  Google Scholar 

  7. Lee, J. M., Dedhar, S., Kalluri, R., & Thompson, E. W. (2006). The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol, 172(7), 973–981.

    PubMed  CAS  Google Scholar 

  8. Acevedo, V. D., Gangula, R. D., Freeman, K. W., Li, R., Zhang, Y., & Wang, F. (2007). Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. Cancer Cell, 12, 559–571.

    PubMed  CAS  Google Scholar 

  9. Leong, K. G., Niessen, K., Kulic, I., Raouf, A., Eaves, C., & Pollet, I. (2007). Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med, 204, 2935–2948.

    PubMed  CAS  Google Scholar 

  10. Shintani, Y., Maeda, M., Chaika, N., Johnson, K. R., & Wheelock, M. J. (2008). Collagen I promotes epithelial-to-mesenchymal transition in lung cancer cells via transforming growth factor-beta signaling. Am J Respir Cell Mol Biol, 38, 95–104.

    PubMed  CAS  Google Scholar 

  11. Zoltan-Jones, A., Huang, L., Ghatak, S., & Toole, B. P. (2003). Elevated hyaluronan production induces mesenchymal and transformed properties in epithelial cells. J Biol Chem, 278, 45801–45810.

    PubMed  CAS  Google Scholar 

  12. Bhowmick, N. A., Ghiassi, M., Bakin, A., Aakre, M., Lundquist, C. A., & Engel, M. E. (2001). Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell, 12, 27–36.

    PubMed  CAS  Google Scholar 

  13. Bakin, A. V., Rinehart, C., Tomlinson, A. K., & Arteaga, C. L. (2002). p38 mitogen-activated protein kinase is required for TGFbeta-mediated fibroblastic transdifferentiation and cell migration. J Cell Sci, 115, 3193–3206.

    PubMed  CAS  Google Scholar 

  14. Janda, E., Lehmann, K., Killisch, I., Jechlinger, M., Herzig, M., & Downward, J. (2002). Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol, 156, 299–313.

    PubMed  CAS  Google Scholar 

  15. Bakin, A. V., Tomlinson, A. K., Bhowmick, N. A., Moses, H. L., & Arteaga, C. L. (2000). Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem, 275, 36803–36810.

    PubMed  CAS  Google Scholar 

  16. Lee, Y. I., Kwon, Y. J., & Joo, C. K. (2004). Integrin-linked kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition. Biochem Biophys Res Commun, 316, 997–1001.

    PubMed  CAS  Google Scholar 

  17. Zavadil, J., Cermak, L., Soto-Nieves, N., & Bottinger, E. P. (2004). Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J, 23, 1155–1165.

    PubMed  CAS  Google Scholar 

  18. Gregory, P. A., Bert, A. G., Paterson, E. L., Barry, S. C., Tsykin, A., & Farshid, G. (2008). The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol, 10, 593–601.

    PubMed  CAS  Google Scholar 

  19. Sarrio, D., Rodriguez-Pinilla, S. M., Hardisson, D., Cano, A., Moreno-Bueno, G., & Palacios, J. (2008). Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res, 68, 989–997.

    PubMed  CAS  Google Scholar 

  20. Brabletz, T., Hlubek, F., Spaderna, S., Schmalhofer, O., Hiendlmeyer, E., & Jung, A. (2005). Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs, 179(1–2), 56–65.

    PubMed  CAS  Google Scholar 

  21. Tarin, D., Thompson, E. W., & Newgreen, D. F. (2005). The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res, 65, 5996–6000 discussion 6000-1.

    PubMed  CAS  Google Scholar 

  22. Friedl, P. (2004). Prespecification and plasticity: shifting mechanisms of cell migration. Curr Opin Cell Biol, 16, 14–23.

    PubMed  CAS  Google Scholar 

  23. Wicki, A., Lehembre, F., Wick, N., Hantusch, B., Kerjaschki, D., & Christofori, G. (2006). Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell, 9, 261–272.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  27. Stehbens, S. J., Paterson, A. D., Crampton, M. S., Shewan, A. M., Ferguson, C., Akhmanova, A., et al. (2006). Dynamic microtubules regulate the local concentration of E-cadherin at cell-cell contacts. J Cell Sci, 119(Pt 9), 1801–1811.

    PubMed  CAS  Google Scholar 

  28. Ireton, R. C., Davis, M. A., van Hengel, J., Mariner, D. J., Barnes, K., & Thoreson, M. A. (2002). A novel role for p120 catenin in E-cadherin function. J Cell Biol, 159(3), 465–476.

    PubMed  CAS  Google Scholar 

  29. Davis, M. A., Ireton, R. C., & Reynolds, A. B. (2003). A core function for p120-catenin in cadherin turnover. J Cell Biol, 163, 525–534.

    PubMed  CAS  Google Scholar 

  30. Thoreson, M. A., Anastasiadis, P. Z., Daniel, J. M., Ireton, R. C., Wheelock, M. J., Johnson, K. R., et al. (2000). Selective uncoupling of p120(ctn) from E-cadherin disrupts strong adhesion. J Cell Biol, 148(1), 189–202.

    PubMed  CAS  Google Scholar 

  31. Wildenberg, G. A., Dohn, M. R., Carnahan, R. H., Davis, M. A., Lobdell, N. A., Settleman, J., et al. (2006). p120-catenin and p190RhoGAP regulate cell-cell adhesion by coordinating antagonism between Rac and Rho. Cell, 127, 1027–1039.

    PubMed  CAS  Google Scholar 

  32. Noren, N. K., Niessen, C. M., Gumbiner, B. M., & Burridge, K. (2001). Cadherin engagement regulates Rho family GTPases. J Biol Chem, 276, 33305–33308.

    PubMed  CAS  Google Scholar 

  33. Noren, N. K., Liu, B. P., Burridge, K., & Kreft, B. (2000). p120 catenin regulates the actin cytoskeleton via Rho family GTPases. J Cell Biol, 150, 567–580.

    PubMed  CAS  Google Scholar 

  34. Comoglio, P. M., Boccaccio, C., & Trusolino, L. (2003). Interactions between growth factor receptors and adhesion molecules: breaking the rules. Curr Opin Cell Biol, 15, 565–571.

    PubMed  CAS  Google Scholar 

  35. Chattopadhyay, N., Wang, Z., Ashman, L. K., Brady-Kalnay, S. M., & Kreidberg, J. A. (2003). alpha3beta1 integrin-CD151, a component of the cadherin-catenin complex, regulates PTPmu expression and cell-cell adhesion. J Cell Biol, 163, 1351–1362.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  37. Shigeta, M., Sanzen, N., Ozawa, M., Gu, J., Hasegawa, H., & Sekiguchi, K. (2003). CD151 regulates epithelial cell-cell adhesion through PKC- and Cdc42-dependent actin cytoskeletal reorganization. J Cell Biol, 163, 165–176.

    PubMed  CAS  Google Scholar 

  38. Helwani, F. M., Kovacs, E. M., Paterson, A. D., Verma, S., Ali, R. G., & Fanning, A. S. (2004). Cortactin is necessary for E-cadherin-mediated contact formation and actin reorganization. J Cell Biol, 164, 899–910.

    PubMed  CAS  Google Scholar 

  39. Canonici, A., Steelant, W., Rigot, V., Khomitch-Baud, A., Boutaghou-Cherid, H., Bruyneel, E., et al. (2008). Insulin-like growth factor-I receptor, E-cadherin and alpha v integrin form a dynamic complex under the control of alpha-catenin. Int J Cancer, 122, 572–582.

    PubMed  CAS  Google Scholar 

  40. Reshetnikova, G., Troyanovsky, S., & Rimm, D. L. (2007). Definition of a direct extracellular interaction between Met and E-cadherin. Cell Biol Int, 31, 366–373.

    PubMed  CAS  Google Scholar 

  41. Bissell, M. J., & Radisky, D. (2001). Putting tumours in context. Nat Rev Cancer, 1, 46–54.

    PubMed  CAS  Google Scholar 

  42. Cavallaro, U., & Christofori, G. (2004). Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer, 4, 118–132.

    PubMed  CAS  Google Scholar 

  43. Perl, A. K., Wilgenbus, P., Dahl, U., Semb, H., & Christofori, G. (1998). A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature, 392, 190–193.

    PubMed  CAS  Google Scholar 

  44. Peinado, H., Olmeda, D., & Cano, A. (2007). Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer, 7, 415–428.

    PubMed  CAS  Google Scholar 

  45. Kouzarides, T. (2007). Chromatin modifications and their function. Cell, 128, 693–705.

    PubMed  CAS  Google Scholar 

  46. Jenuwein, T., & Allis, C. D. (2001). Translating the histone code. Science, 293, 1074–1080.

    PubMed  CAS  Google Scholar 

  47. Zhang, Y., & Reinberg, D. (2001). Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev, 15, 2343–2360.

    PubMed  CAS  Google Scholar 

  48. Herranz, N., Pasini, D., Diaz, V. M., Franci, C., Gutierrez, A., & Dave, N. (2008). Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor. Mol Cell Biol, 28(15), 4772–4781.

    PubMed  CAS  Google Scholar 

  49. Hou, Z., Peng, H., Ayyanathan, K., Yan, K. P., Langer, E. M., & Longmore, G. D. (2008). The LIM protein AJUBA recruits protein arginine methyltransferase 5 to mediate SNAIL-dependent transcriptional repression. Mol Cell Biol, 28, 3198–3207.

    PubMed  CAS  Google Scholar 

  50. Berger, S. L. (2007). The complex language of chromatin regulation during transcription. Nature, 447, 407–412.

    PubMed  CAS  Google Scholar 

  51. Zhu, W., Leber, B., & Andrews, D. W. (2001). Cytoplasmic O-glycosylation prevents cell surface transport of E-cadherin during apoptosis. EMBO J, 20, 5999–6007.

    PubMed  CAS  Google Scholar 

  52. Lochter, A., Galosy, S., Muschler, J., Freedman, N., Werb, Z., & Bissell, M. J. (1997). Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J Cell Biol, 139, 1861–1872.

    PubMed  CAS  Google Scholar 

  53. Marambaud, P., Shioi, J., Serban, G., Georgakopoulos, A., Sarner, S., & Nagy, V. (2002). A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J, 21, 1948–1956.

    PubMed  CAS  Google Scholar 

  54. Maretzky, T., Reiss, K., Ludwig, A., Buchholz, J., Scholz, F., & Proksch, E. (2005). ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation. Proc Natl Acad Sci U S A, 102, 9182–9187.

    PubMed  CAS  Google Scholar 

  55. Steinhusen, U., Weiske, J., Badock, V., Tauber, R., Bommert, K., & Huber, O. (2001). Cleavage and shedding of E-cadherin after induction of apoptosis. J Biol Chem, 276, 4972–4980.

    PubMed  CAS  Google Scholar 

  56. Ferber, E. C., Kajita, M., Wadlow, A., Tobiansky, L., Niessen, C., & Ariga, H. (2008). A role for the cleaved cytoplasmic domain of E-cadherin in the nucleus. J Biol Chem, 283, 12691–12700.

    PubMed  CAS  Google Scholar 

  57. Gumbiner, B. M. (2000). Regulation of cadherin adhesive activity. J Cell Biol, 148, 399–404.

    PubMed  CAS  Google Scholar 

  58. Fujita, Y., Krause, G., Scheffner, M., Zechner, D., Leddy, H. E., & Behrens, J. (2002). Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nat Cell Biol, 4, 222–231.

    PubMed  CAS  Google Scholar 

  59. Koenig, A., Mueller, C., Hasel, C., Adler, G., & Menke, A. (2006). Collagen type I induces disruption of E-cadherin-mediated cell-cell contacts and promotes proliferation of pancreatic carcinoma cells. Cancer Res, 66, 4662–4671.

    PubMed  CAS  Google Scholar 

  60. Janda, E., Nevolo, M., Lehmann, K., Downward, J., Beug, H., & Grieco, M. (2006). Raf plus TGFbeta-dependent EMT is initiated by endocytosis and lysosomal degradation of E-cadherin. Oncogene, 25, 7117–7130.

    PubMed  CAS  Google Scholar 

  61. Lu, Z., Ghosh, S., Wang, Z., & Hunter, T. (2003). Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell, 4, 499–515.

    PubMed  CAS  Google Scholar 

  62. Akhtar, N., & Hotchin, N. A. (2001). RAC1 regulates adherens junctions through endocytosis of E-cadherin. Mol Biol Cell, 12, 847–862.

    PubMed  CAS  Google Scholar 

  63. Steeg, P. S., Bevilacqua, G., Kopper, L., Thorgeirsson, U. P., Talmadge, J. E., & Liotta, L. A. (1988). Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst, 80, 200–204.

    PubMed  CAS  Google Scholar 

  64. Palacios, F., Schweitzer, J. K., Boshans, R. L., D, , & Souza-Schorey, C. (2002). ARF6-GTP recruits Nm23-H1 to facilitate dynamin-mediated endocytosis during adherens junctions disassembly. Nat Cell Biol, 4, 929–936.

    PubMed  CAS  Google Scholar 

  65. Kon, S., Tanabe, K., Watanabe, T., Sabe, H., & Satake, M. (2008). Clathrin dependent endocytosis of E-cadherin is regulated by the Arf6GAP isoform SMAP1. Exp Cell Res, 314, 1415–1428.

    PubMed  CAS  Google Scholar 

  66. Tanabe, K., Torii, T., Natsume, W., Braesch-Andersen, S., Watanabe, T., & Satake, M. (2005). A novel GTPase-activating protein for ARF6 directly interacts with clathrin and regulates clathrin-dependent endocytosis. Mol Biol Cell, 16, 1617–1628.

    PubMed  CAS  Google Scholar 

  67. Clevers, H. (2006). Wnt/beta-catenin signaling in development and disease. Cell, 127, 469–480.

    PubMed  CAS  Google Scholar 

  68. Arce, L., Yokoyama, N. N., & Waterman, M. L. (2006). Diversity of LEF/TCF action in development and disease. Oncogene, 25, 7492–7504.

    PubMed  CAS  Google Scholar 

  69. Wong, N. A., & Pignatelli, M. (2002). Beta-catenin—a linchpin in colorectal carcinogenesis? Am J Pathol, 160, 389–401.

    PubMed  CAS  Google Scholar 

  70. Vignjevic, D., Kojima, S., Aratyn, Y., Danciu, O., Svitkina, T., & Borisy, G. G. (2006). Role of fascin in filopodial protrusion. J Cell Biol, 174, 863–875.

    PubMed  CAS  Google Scholar 

  71. Vignjevic, D., Schoumacher, M., Gavert, N., Janssen, K. P., Jih, G., & Lae, M. (2007). Fascin, a novel target of beta-catenin-TCF signaling, is expressed at the invasive front of human colon cancer. Cancer Res, 67, 6844–6853.

    PubMed  CAS  Google Scholar 

  72. van, Roy, F. M., & McCrea, P. D. (2005). A role for Kaiso-p120ctn complexes in cancer? Nat Rev Cancer, 5, 956–964.

    PubMed  Google Scholar 

  73. Nieman, M. T., Prudoff, R. S., Johnson, K. R., & Wheelock, M. J. (1999). N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J Cell Biol, 147, 631–644.

    PubMed  CAS  Google Scholar 

  74. Hulit, J., Suyama, K., Chung, S., Keren, R., Agiostratidou, G., Shan, W., & Dong, X. (2007). N-cadherin signaling potentiates mammary tumor metastasis via enhanced extracellular signal-regulated kinase activation. Cancer Res, 67, 3106–3116.

    PubMed  CAS  Google Scholar 

  75. Gravdal, K., Halvorsen, O. J., Haukaas, S. A., & Akslen, L. A. (2007). A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent iportance for the progress of prostate cancer. Clin Cancer Res, 13, 7003–7011.

    PubMed  CAS  Google Scholar 

  76. Hazan, R. B., Qiao, R., Keren, R., Badano, I., & Suyama, K. (2004). Cadherin switch in tumor progression. Ann N Y Acad Sci, 1014, 155–163.

    PubMed  CAS  Google Scholar 

  77. Shintani, Y., Fukumoto, Y., Chaika, N., Svoboda, R., Wheelock, M. J., & Johnson, K. R. (2008). Collagen I-mediated up-regulation of N-cadherin requires cooperative signals from integrins and discoidin domain receptor 1. J Cell Biol, 180, 1277–1289.

    PubMed  CAS  Google Scholar 

  78. Alexander, N. R., Tran, N. L., Rekapally, H., Summers, C. E., Glackin, C., & Heimark, R. L. (2006). N-cadherin gene expression in prostate carcinoma is modulated by integrin-dependent nuclear translocation of Twist1. Cancer Res, 66, 3365–3369.

    PubMed  CAS  Google Scholar 

  79. Yang, Z., Zhang, X., Gang, H., Li, X., Li, Z., & Wang, T. (2007). Up-regulation of gastric cancer cell invasion by Twist is accompanied by N-cadherin and fibronectin expression. Biochem Biophys Res Commun, 358, 925–930.

    PubMed  CAS  Google Scholar 

  80. Niu, R. F., Zhang, L., Xi, G. M., Wei, X. Y., Yang, Y., & Shi, Y. R. (2007). Up-regulation of Twist induces angiogenesis and correlates with metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res, 26, 385–394.

    PubMed  CAS  Google Scholar 

  81. Bard, L., Boscher, C., Lambert, M., Mege, R. M., Choquet, D., & Thoumine, O. (2008). A molecular clutch between the actin flow and N-cadherin adhesions drives growth cone migration. J Neurosci, 28, 5879–5890.

    PubMed  CAS  Google Scholar 

  82. El, Sayegh, T. Y., Arora, P. D., Fan, L., Laschinger, C. A., Greer, P. A., & McCulloch, C. A. (2005). Phosphorylation of N-cadherin-associated cortactin by Fer kinase regulates N-cadherin mobility and intercellular adhesion strength. Mol Biol Cell, 16, 5514–5527.

    PubMed  Google Scholar 

  83. Kim, L., & Wong, T. W. (1995). The cytoplasmic tyrosine kinase FER is associated with the catenin-like substrate pp120 and is activated by growth factors. Mol Cell Biol, 15, 4553–4561.

    PubMed  CAS  Google Scholar 

  84. Comunale, F., Causeret, M., Favard, C., Cau, J., Taulet, N., & Charrasse, S. (2007). Rac1 and RhoA GTPases have antagonistic functions during N-cadherin-dependent cell-cell contact formation in C2C12 myoblasts. Biol Cell, 99, 503–517.

    PubMed  CAS  Google Scholar 

  85. Xu, G., Craig, A. W., Greer, P., Miller, M., Anastasiadis, P. Z., & Lilien, J. (2004). Continuous association of cadherin with beta-catenin requires the non-receptor tyrosine-kinase Fer. J Cell Sci, 117, 3207–3219.

    PubMed  CAS  Google Scholar 

  86. Xu, G., Arregui, C., Lilien, J., & Balsamo, J. (2002). PTP1B modulates the association of beta-catenin with N-cadherin through binding to an adjacent and partially overlapping target site. J Biol Chem, 277, 49989–49997.

    PubMed  CAS  Google Scholar 

  87. Theisen, C. S., Wahl 3rd, J. K., Johnson, K. R., & Wheelock, M. J. (2007). NHERF links the N-cadherin/catenin complex to the platelet-derived growth factor receptor to modulate the actin cytoskeleton and regulate cell motility. Mol Biol Cell, 18, 1220–1232.

    PubMed  CAS  Google Scholar 

  88. Heldin, C. H., Ostman, A., & Ronnstrand, L. (1998). Signal transduction via platelet-derived growth factor receptors. Biochim Biophys Acta, 1378, F79–113.

    PubMed  CAS  Google Scholar 

  89. Kong, D., Wang, Z., Sarkar, S. H., Li, Y., Banerjee, S., & Saliganan, A. (2008). Platelet-derived growth factor-D overexpression contributes to epithelial-mesenchymal transition of PC3 prostate cancer cells. Stem Cells, 26, 1425–1435.

    PubMed  CAS  Google Scholar 

  90. Sander, E. E., ten Klooster, J. P., van Delft, S., van der Kammen, R. A., & Collard, J. G. (1999). Rac downregulates Rho activity: reciprocal balance between both GTPases determines cellular morphology and migratory behavior. J Cell Biol, 147, 1009–1022.

    PubMed  CAS  Google Scholar 

  91. Pertz, O., Hodgson, L., Klemke, R. L., & Hahn, K. M. (2006). Spatiotemporal dynamics of RhoA activity in migrating cells. Nature, 440, 1069–1072.

    PubMed  CAS  Google Scholar 

  92. Ridley, A. J., Paterson, H. F., Johnston, C. L., Diekmann, D., & Hall, A. (1992). The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell, 70, 401–410.

    PubMed  CAS  Google Scholar 

  93. Nimnual, A. S., Taylor, L. J., & Bar-Sagi, D. (2003). Redox-dependent downregulation of Rho by Rac. Nat Cell Biol, 5, 236–241.

    PubMed  CAS  Google Scholar 

  94. Anastasiadis, P. Z., Moon, S. Y., Thoreson, M. A., Mariner, D. J., Crawford, H. C., Zheng, Y., et al. (2000). Inhibition of RhoA by p120 catenin. Nat Cell Biol, 2, 637–644.

    PubMed  CAS  Google Scholar 

  95. Cavallaro, U., Niedermeyer, J., Fuxa, M., & Christofori, G. (2001). N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling. Nat Cell Biol, 3, 650–657.

    PubMed  CAS  Google Scholar 

  96. Williams, E. J., Williams, G., Howell, F. V., Skaper, S. D., Walsh, F. S., & Doherty, P. (2001). Identification of an N-cadherin motif that can interact with the fibroblast growth factor receptor and is required for axonal growth. J Biol Chem, 276, 43879–43886.

    PubMed  CAS  Google Scholar 

  97. Hazan, R. B., Phillips, G. R., Qiao, R. F., Norton, L., & Aaronson, S. A. (2000). Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J Cell Biol, 148, 779–790.

    PubMed  CAS  Google Scholar 

  98. Suyama, K., Shapiro, I., Guttman, M., & Hazan, R. B. (2002). A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer Cell, 2, 301–314.

    PubMed  CAS  Google Scholar 

  99. Francavilla, C., Loeffler, S., Piccini, D., Kren, A., Christofori, G., & Cavallaro, U. (2007). Neural cell adhesion molecule regulates the cellular response to fibroblast growth factor. J Cell Sci, 120, 4388–4394.

    PubMed  CAS  Google Scholar 

  100. Sanchez-Heras, E., Howell, F. V., Williams, G., & Doherty, P. (2006). The fibroblast growth factor receptor acid box is essential for interactions with N-cadherin and all of the major isoforms of neural cell adhesion molecule. J Biol Chem, 281, 35208–35216.

    PubMed  CAS  Google Scholar 

  101. Christofori, G. (2006). New signals from the invasive front. Nature, 441, 444–450.

    PubMed  CAS  Google Scholar 

  102. Marambaud, P., Wen, P. H., Dutt, A., Shioi, J., Takashima, A., & Siman, R. (2003). A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell, 114, 635–645.

    PubMed  CAS  Google Scholar 

  103. Shoval, I., Ludwig, A., & Kalcheim, C. (2007). Antagonistic roles of full-length N-cadherin and its soluble BMP cleavage product in neural crest delamination. Development, 134, 491–501.

    PubMed  CAS  Google Scholar 

  104. Uemura, K., Kihara, T., Kuzuya, A., Okawa, K., Nishimoto, T., Bito, H., & Ninomiya, H. (2006). Activity-dependent regulation of beta-catenin via epsilon-cleavage of N-cadherin. Biochem Biophys Res Commun, 345, 951–958.

    PubMed  CAS  Google Scholar 

  105. Tadokoro, S., Shattil, S. J., Eto, K., Tai, V., Liddington, R. C., dePereda, J. M., et al. (2003). Talin binding to integrin beta tails: a final common step in integrin activation. Science, 302, 103–106.

    PubMed  CAS  Google Scholar 

  106. Deryugina, E. I., Bourdon, M. A., Jungwirth, K., Smith, J. W., & Strongin, A. Y. (2000). Functional activation of integrin alpha V beta 3 in tumor cells expressing membrane-type 1 matrix metalloproteinase. Int J Cancer, 86, 15–23.

    PubMed  CAS  Google Scholar 

  107. Legate, K. R., Montanez, E., Kudlacek, O., & Fassler, R. (2006). ILK, PINCH and parvin: the tIPP of integrin signalling. Nat Rev Mol Cell Biol, 7, 20–31.

    PubMed  CAS  Google Scholar 

  108. Mercurio, A. M., & Rabinovitz, I. (2001). Towards a mechanistic understanding of tumor invasion-lessons from the alpha6beta 4 integrin. Semin Cancer Biol, 11, 129–141.

    PubMed  CAS  Google Scholar 

  109. Trusolino, L., Bertotti, A., & Comoglio, P. M. (2001). A signaling adapter function for alpha 6beta 4 integrin in the control of HGF-dependent invasive growth. Cell, 107, 643–654.

    PubMed  CAS  Google Scholar 

  110. Mariotti, A., Kedeshian, P. A., Dans, M., Curatola, A. M., Gagnoux-Palacios, L., & Giancotti, F. G. (2001). EGF-R signaling through Fyn kinase disrupts the function of integrin alpha6beta4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion. J Cell Biol, 155, 447–458.

    PubMed  CAS  Google Scholar 

  111. Gambaletta, D., Marchetti, A., Benedetti, L., Mercurio, A. M., Sacchi, A., & Falcioni, R. (2000). Cooperative signaling between alpha (6)beta(4) integrin and ErbB-2 receptor is required to promote phosphatidylinositol 3-kinase-dependent invasion. J Biol Chem, 275, 10604–10610.

    PubMed  CAS  Google Scholar 

  112. Ivaska, J., Reunanen, H., Westermarck, J., Koivisto, L., Kahari, V. M., & Heino, J. (1999). Integrin alpha2beta1 mediates isoform-specific activation of p38 and upregulation of collagen gene transcription by a mechanism involving the alpha2 cytoplasmic tail. J Cell Biol, 147, 401–416.

    PubMed  CAS  Google Scholar 

  113. Ellinger-Ziegelbauer, H., Kelly, K., & Siebenlist, U. (1999). Cell cycle arrest and reversion of Ras-induced transformation by a conditionally activated form of mitogen-activated protein kinase kinase kinase 3. Mol Cell Biol, 19, 3857–3868.

    PubMed  CAS  Google Scholar 

  114. Munger, J. S., Huang, X., Kawakatsu, H., Griffiths, M. J., Dalton, S. L., & Wu, J. (1999). The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell, 96, 319–328.

    PubMed  CAS  Google Scholar 

  115. Mu, D., Cambier, S., Fjellbirkeland, L., Baron, J. L., Munger, J. S., & Kawakatsu, H. (2002). The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J Cell Biol, 157, 493–507.

    PubMed  CAS  Google Scholar 

  116. Wipff, P. J., & Hinz, B. (2008). Integrins and the activation of latent transforming growth factor beta1—An intimate relationship. Eur J Cell Biol, 87(8–9), 601–615.

    PubMed  CAS  Google Scholar 

  117. Haraguchi, M., Okubo, T., Miyashita, Y., Miyamoto, Y., Hayashi, M., & Crotti, T. N. (2008). Snail regulates cell-matrix adhesion by regulation of the expression of integrins and basement membrane proteins. J Biol Chem, 283(35), 23514–23523.

    PubMed  CAS  Google Scholar 

  118. Sharma, M., & Henderson, B. R. (2007). IQ-domain GTPase-activating protein 1 regulates beta-catenin at membrane ruffles and its role in macropinocytosis of N-cadherin and adenomatous polyposis coli. J Biol Chem, 282, 8545–8556.

    PubMed  CAS  Google Scholar 

  119. Ellerbroek, S. M., Wu, Y. I., Overall, C. M., & Stack, M. S. (2001). Functional interplay between type I collagen and cell surface matrix metalloproteinase activity. J Biol Chem, 276, 24833–24842.

    PubMed  CAS  Google Scholar 

  120. Wolf, K., Muller, R., Borgmann, S., Brocker, E. B., & Friedl, P. (2003). Amoeboid shape change and contact guidance: T-lymphocyte crawling through fibrillar collagen is independent of matrix remodeling by MMPs and other proteases. Blood, 102, 3262–3269.

    PubMed  CAS  Google Scholar 

  121. Cao, J., Chiarelli, C., Richman, O., Zarrabi, K., Kozarekar, P., & Zucker, S. (2008). Membrane type 1 matrix metalloproteinase induces epithelial-to-mesenchymal transition in prostate cancer. J Biol Chem, 283, 6232–6240.

    PubMed  CAS  Google Scholar 

  122. Pulyaeva, H., Bueno, J., Polette, M., Birembaut, P., Sato, H., & Seiki, M. (1997). MT1-MMP correlates with MMP-2 activation potential seen after epithelial to mesenchymal transition in human breast carcinoma cells. Clin Exp Metastasis, 15, 111–120.

    PubMed  CAS  Google Scholar 

  123. Bhowmick, N. A., Zent, R., Ghiassi, M., McDonnell, M., & Moses, H. L. (2001). Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity. J Biol Chem, 276, 46707–46713.

    PubMed  CAS  Google Scholar 

  124. Bravo-Cordero, J. J., Marrero-Diaz, R., Megias, D., Genis, L., Garcia-Grande, A., & Garcia, M. A. (2007). MT1-MMP proinvasive activity is regulated by a novel Rab8-dependent exocytic pathway. EMBO J, 26, 1499–1510.

    PubMed  CAS  Google Scholar 

  125. Sheppard, D. (2005). Integrin-mediated activation of latent transforming growth factor beta. Cancer Metastasis Rev, 24, 395–402.

    PubMed  CAS  Google Scholar 

  126. Roberts, A. B., & Wakefield, L. M. (2003). The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci U S A, 100, 8621–8623.

    PubMed  CAS  Google Scholar 

  127. Bates, R. C. (2005). Colorectal cancer progression: integrin alphavbeta6 and the epithelial-mesenchymal transition (EMT). Cell Cycle, 4, 1350–1352.

    PubMed  CAS  Google Scholar 

  128. Bates, R. C., Bellovin, D. I., Brown, C., Maynard, E., Wu, B., & Kawakatsu, H. (2005). Transcriptional activation of integrin beta6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J Clin Invest, 115, 339–347.

    PubMed  CAS  Google Scholar 

  129. Araya, J., Cambier, S., Morris, A., Finkbeiner, W., & Nishimura, S. L. (2006). Integrin-mediated transforming growth factor-beta activation regulates homeostasis of the pulmonary epithelial-mesenchymal trophic unit. Am J Pathol, 169, 405–415.

    PubMed  CAS  Google Scholar 

  130. Li, Y., Dai, C., Wu, C., & Liu, Y. (2007). PINCH-1 promotes tubular epithelial-to-mesenchymal transition by interacting with integrin-linked kinase. J Am Soc Nephrol, 18, 2534–2543.

    PubMed  CAS  Google Scholar 

  131. Bagnato, A., & Rosano, L. (2007). Epithelial-mesenchymal transition in ovarian cancer progression: a crucial role for the endothelin axis. Cells Tissues Organs, 185, 85–94.

    PubMed  CAS  Google Scholar 

  132. Oloumi, A., McPhee, T., & Dedhar, S. (2004). Regulation of E-cadherin expression and beta-catenin/Tcf transcriptional activity by the integrin-linked kinase. Biochim Biophys Acta, 1691, 1–15.

    PubMed  CAS  Google Scholar 

  133. Etienne-Manneville, S., & Hall, A. (2002). Rho GTPases in cell biology. Nature, 420, 629–635.

    PubMed  CAS  Google Scholar 

  134. Burridge, K. (2004). Wennerberg, K. Rho and Rac take center stage. Cell, 116, 167–179.

    PubMed  CAS  Google Scholar 

  135. Sahai, E., & Marshall, C. J. (2002). RHO-GTPases and cancer. Nat Rev Cancer, 2, 133–142.

    PubMed  Google Scholar 

  136. Hall, A. (2005). Rho GTPases and the control of cell behaviour. Biochem Soc Trans, 33, 891–895.

    PubMed  CAS  Google Scholar 

  137. Ridley, A. J. (2006). Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol, 16, 522–529.

    PubMed  CAS  Google Scholar 

  138. Lozano, E., Betson, M., & Braga, V. M. (2003). Tumor progression: Small GTPases and loss of cell-cell adhesion. Bioessays, 25, 452–463.

    PubMed  CAS  Google Scholar 

  139. Cozzolino, M., Stagni, V., Spinardi, L., Campioni, N., Fiorentini, C., & Salvati, E. (2003). p120 Catenin is required for growth factor-dependent cell motility and scattering in epithelial cells. Mol Biol Cell, 14, 1964–1977.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  142. Zondag, G. C., Evers, E. E., ten Klooster, J. P., Janssen, L., van der Kammen, R. A., & Collard, J. G. (2000). Oncogenic Ras downregulates Rac activity, which leads to increased Rho activity and epithelial-mesenchymal transition. J Cell Biol, 149, 775–782.

    PubMed  CAS  Google Scholar 

  143. Radisky, D. C., Levy, D. D., Littlepage, L. E., Liu, H., Nelson, C. M., & Fata, J. E. (2005). Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature, 436, 123–127.

    PubMed  CAS  Google Scholar 

  144. Clark, E. A., Golub, T. R., Lander, E. S., & Hynes, R. O. (2000). Genomic analysis of metastasis reveals an essential role for Rock. Nature, 406, 532–535.

    PubMed  CAS  Google Scholar 

  145. Hakem, A., Sanchez-Sweatman, O., You-Ten, A., Duncan, G., Wakeham, A., & Khokha, R. (2005). Rock is dispensable for embryogenesis and tumor initiation but essential for metastasis. Genes Dev, 19, 1974–1979.

    PubMed  CAS  Google Scholar 

  146. Nakaya, Y., Sukowati, E. W., Wu, Y., & Sheng, G. (2008). RhoA and microtubule dynamics control cell-basement membrane interaction in EMT during gastrulation. Nat Cell Biol, 10, 765–775.

    PubMed  CAS  Google Scholar 

  147. Hordijk, P. L., ten, Klooster, J. P., van, der, Kammen, R. A., Michiels, F., Oomen, L. C., & Collard, J. G. (1997). Inhibition of invasion of epithelial cells by Tiam1-Rac signaling. Science, 278, 1464–1466.

    PubMed  CAS  Google Scholar 

  148. Malliri, A., van, Es, S., Huveneers, S., & Collard, J. G. (2004). The Rac exchange factor Tiam1 is required for the establishment and maintenance of cadherin-based adhesions. J Biol Chem, 279, 30092–30098.

    PubMed  CAS  Google Scholar 

  149. Malliri, A., van der Kammen, R. A., Clark, K., van der Valk, M., Michiels, F., & Collard, J. G. (2002). Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature, 417, 867–871.

    PubMed  CAS  Google Scholar 

  150. Krueger, E. W., Orth, J. D., Cao, H., & McNiven, M. A. (2003). A dynamin-cortactin-Arp2/3 complex mediates actin reorganization in growth factor-stimulated cells. Mol Biol Cell, 14, 1085–1096.

    PubMed  CAS  Google Scholar 

  151. Ballestrem, C., Wehrle-Haller, B., & Imhof, B. A. (1998). Actin dynamics in living mammalian cells. J Cell Sci, 111, 1649–1658.

    PubMed  CAS  Google Scholar 

  152. Suetsugu, S., Yamazaki, D., Kurisu, S., & Takenawa, T. (2003). Differential roles of WAVE1 and WAVE2 in dorsal and peripheral ruffle formation for fibroblast cell migration. Dev Cell, 5, 595–609.

    PubMed  CAS  Google Scholar 

  153. Orth, J. D., & McNiven, M. A. (2006). Get off my back! Rapid receptor internalization through circular dorsal ruffles. Cancer Res, 66, 11094–11096.

    PubMed  CAS  Google Scholar 

  154. Vieira, A. V., Lamaze, C., & Schmid, S. L. (1996). Control of EGF receptor signaling by clathrin-mediated endocytosis. Science, 274, 2086–2089.

    PubMed  CAS  Google Scholar 

  155. Dharmawardhane, S., Schurmann, A., Sells, M. A., Chernoff, J., Schmid, S. L., & Bokoch, G. M. (2000). Regulation of macropinocytosis by p21-activated kinase-1. Mol Biol Cell, 11, 3341–3352.

    PubMed  CAS  Google Scholar 

  156. Plattner, R., Kadlec, L., DeMali, K. A., Kazlauskas, A., & Pendergast, A. M. (1999). c-Abl is activated by growth factors and Src family kinases and has a role in the cellular response to PDGF. Genes Dev, 13, 2400–2411.

    PubMed  CAS  Google Scholar 

  157. Yang, Y., Pan, X., Lei, W., Wang, J., Shi, J., Li, F., & Song, J. (2006). Regulation of transforming growth factor-beta 1-induced apoptosis and epithelial-to-mesenchymal transition by protein kinase A and signal transducers and activators of transcription 3. Cancer Res, 66, 8617–8624.

    PubMed  CAS  Google Scholar 

  158. Finn, R. S., Dering, J., Ginther, C., Wilson, C. A., Glaspy, P., & Tchekmedyian, N. (2007). Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro. Breast Cancer Res Treat, 105, 319–326.

    PubMed  CAS  Google Scholar 

  159. Srinivasan, D., & Plattner, R. (2006). Activation of Abl tyrosine kinases promotes invasion of aggressive breast cancer cells. Cancer Res, 66, 5648–5655.

    PubMed  CAS  Google Scholar 

  160. Watanabe, T., Wang, S., Noritake, J., Sato, K., Fukata, M., & Takefuji, M. (2004). Interaction with IQGAP1 links APC to Rac1, Cdc42, and actin filaments during cell polarization and migration. Dev Cell, 7, 871–883.

    PubMed  CAS  Google Scholar 

  161. Etienne-Manneville, S., & Hall, A. (2003). Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell polarity. Nature, 421, 753–756.

    PubMed  CAS  Google Scholar 

  162. Sharma, M., Leung, L., Brocardo, M., Henderson, J., Flegg, C., & Henderson, B. R. (2006). Membrane localization of adenomatous polyposis coli protein at cellular protrusions: targeting sequences and regulation by beta-catenin. J Biol Chem, 281, 17140–17149.

    PubMed  CAS  Google Scholar 

  163. Goicoechea, S. M., Arneman, D., & Otey, C. A. (2008). The role of palladin in actin organization and cell motility. Eur J Cell Biol, 87(8–9), 517–525.

    PubMed  CAS  Google Scholar 

  164. Goicoechea, S., Arneman, D., Disanza, A., Garcia-Mata, R., Scita, G., & Otey, C. A. (2006). Palladin binds to Eps8 and enhances the formation of dorsal ruffles and podosomes in vascular smooth muscle cells. J Cell Sci, 119, 3316–3324.

    PubMed  CAS  Google Scholar 

  165. Ronty, M., Taivainen, A., Heiska, L., Otey, C., Ehler, E., & Song, W. K. (2007). Palladin interacts with SH3 domains of SPIN90 and Src and is required for Src-induced cytoskeletal remodeling. Exp Cell Res, 313, 2575–2585.

    PubMed  Google Scholar 

  166. Griffith, O. L., Melck, A., Jones, S. J., & Wiseman, S. M. (2006). Meta-analysis and meta-review of thyroid cancer gene expression profiling studies identifies important diagnostic biomarkers. J Clin Oncol, 24, 5043–5051.

    PubMed  CAS  Google Scholar 

  167. Matoskova, B., Wong, W. T., Salcini, A. E., Pelicci, P. G., & Di, Fiore, P. P. (1995). Constitutive phosphorylation of eps8 in tumor cell lines: relevance to malignant transformation. Mol Cell Biol, 15, 3805–3812.

    PubMed  CAS  Google Scholar 

  168. Yao, J., Weremowicz, S., Feng, B., Gentleman, R. C., Marks, J. R., & Gelman, R. (2006). Combined cDNA array comparative genomic hybridization and serial analysis of gene expression analysis of breast tumor progression. Cancer Res, 66, 4065–4078.

    PubMed  CAS  Google Scholar 

  169. Ryu, B., Jones, J., Hollingsworth, M. A., Hruban, R. H., & Kern, S. E. (2001). Invasion-specific genes in malignancy: serial analysis of gene expression comparisons of primary and passaged cancers. Cancer Res, 61, 1833–1838.

    PubMed  CAS  Google Scholar 

  170. Wang, W., Goswami, S., Lapidus, K., Wells, A. L., Wyckoff, J. B., & Sahai, E. (2004). Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors. Cancer Res, 64, 8585–8594.

    PubMed  CAS  Google Scholar 

  171. Ronty, M. J., Leivonen, S. K., Hinz, B., Rachlin, A., Otey, C. A., & Kahari, V. M. (2006). Isoform-specific regulation of the actin-organizing protein palladin during TGF-beta1-induced myofibroblast differentiation. J Invest Dermatol, 126, 2387–2396.

    PubMed  Google Scholar 

  172. Ibarra, N., Pollitt, A., & Insall, R. H. (2005). Regulation of actin assembly by SCAR/WAVE proteins. Biochem Soc Trans, 33, 1243–1246.

    PubMed  CAS  Google Scholar 

  173. LeClainche, C., & Carlier, M. F. (2008). Regulation of actin assembly associated with protrusion and adhesion in cell migration. Physiol Rev, 88, 489–513.

    CAS  Google Scholar 

  174. Innocenti, M., Zucconi, A., Disanza, A., Frittoli, E., Areces, L. B., & Steffen, A. (2004). Abi1 is essential for the formation and activation of a WAVE2 signalling complex. Nat Cell Biol, 6, 319–327.

    PubMed  CAS  Google Scholar 

  175. Iwaya, K., Norio, K., & Mukai, K. (2007). Coexpression of Arp2 and WAVE2 predicts poor outcome in invasive breast carcinoma. Mod Pathol, 20, 339–343.

    PubMed  CAS  Google Scholar 

  176. Iwaya, K., Oikawa, K., Semba, S., Tsuchiya, B., Mukai, Y., & Otsubo, T. (2007). Correlation between liver metastasis of the colocalization of actin-related protein 2 and 3 complex and WAVE2 in colorectal carcinoma. Cancer Sci, 98, 992–999.

    PubMed  CAS  Google Scholar 

  177. Khoury, H., Dankort, D. L., Sadekova, S., Naujokas, M. A., Muller, W. J., & Park, M. (2001). Distinct tyrosine autophosphorylation sites mediate induction of epithelial mesenchymal like transition by an activated ErbB-2/Neu receptor. Oncogene, 20, 788–799.

    PubMed  CAS  Google Scholar 

  178. Wang, L., Lee, J. F., Lin, C. Y., & Lee, M. J. (2008). Rho GTPases mediated integrin alpha v beta 3 activation in sphingosine-1-phosphate stimulated chemotaxis of endothelial cells. Histochem Cell Biol, 129, 579–588.

    PubMed  CAS  Google Scholar 

  179. Mori, H., Tomari, T., Koshikawa, N., Kajita, M., Itoh, Y., & Sato, H. (2002). CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain. EMBO J, 21, 3949–3959.

    PubMed  CAS  Google Scholar 

  180. Coopman, P. J., Do, M. T., Thompson, E. W., & Mueller, S. C. (1998). Phagocytosis of cross-linked gelatin matrix by human breast carcinoma cells correlates with their invasive capacity. Clin Cancer Res, 4, 507–515.

    PubMed  CAS  Google Scholar 

  181. Wang, W., Wyckoff, J. B., Frohlich, V. C., Oleynikov, Y., Huttelmaier, S., & Zavadil, J. (2002). Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling. Cancer Res, 62, 6278–6288.

    PubMed  CAS  Google Scholar 

  182. Svitkina, T. M., Bulanova, E. A., Chaga, O. Y., Vignjevic, D. M., Kojima, S., & Vasiliev, J. M. (2003). Mechanism of filopodia initiation by reorganization of a dendritic network. J Cell Biol, 160, 409–421.

    PubMed  CAS  Google Scholar 

  183. Pelosi, G., Pastorino, U., Pasini, F., Maissoneuve, P., Fraggetta, F., & Iannucci, A. (2003). Independent prognostic value of fascin immunoreactivity in stage I nonsmall cell lung cancer. Br J Cancer, 88, 537–547.

    PubMed  CAS  Google Scholar 

  184. Hashimoto, Y., Shimada, Y., Kawamura, J., Yamasaki, S., & Imamura, M. (2004). The prognostic relevance of fascin expression in human gastric carcinoma. Oncology, 67, 262–270.

    PubMed  CAS  Google Scholar 

  185. Rodriguez-Pinilla, S. M., Sarrio, D., Honrado, E., Hardisson, D., Calero, F., & Benitez, J. (2006). Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin Cancer Res, 12, 1533–1539.

    PubMed  CAS  Google Scholar 

  186. Mongiu, A. K., Weitzke, E. L., Chaga, O. Y., & Borisy, G. G. (2007). Kinetic-structural analysis of neuronal growth cone veil motility. J Cell Sci, 120, 1113–1125.

    PubMed  CAS  Google Scholar 

  187. Saltel, F., Destaing, O., Bard, F., Eichert, D., & Jurdic, P. (2004). Apatite-mediated actin dynamics in resorbing osteoclasts. Mol Biol Cell, 15, 5231–5241.

    PubMed  CAS  Google Scholar 

  188. Linder, S. (2007). The matrix corroded: podosomes and invadopodia in extracellular matrix degradation. Trends Cell Biol, 17, 107–117.

    PubMed  CAS  Google Scholar 

  189. Linder, S., & Kopp, P. (2005). Podosomes at a glance. J Cell Sci, 118, 2079–2082.

    PubMed  CAS  Google Scholar 

  190. Ayala, I., Baldassarre, M., Caldieri, G., & Buccione, R. (2006). Invadopodia: a guided tour. Eur J Cell Biol, 85, 159–164.

    PubMed  CAS  Google Scholar 

  191. Block, M. R., Badowski, C., Millon-Fremillon, A., Bouvard, D., Bouin, A. P., & Faurobert, E. (2008). Podosome-type adhesions and focal adhesions, so alike yet so different. Eur J Cell Biol, 87(8–9), 491–506.

    PubMed  CAS  Google Scholar 

  192. Kelly, T., Yan, Y., Osborne, R. L., Athota, A. B., Rozypal, T. L., & Colclasure, J. C. (1998). Proteolysis of extracellular matrix by invadopodia facilitates human breast cancer cell invasion and is mediated by matrix metalloproteinases. Clin Exp Metastasis, 16, 501–512.

    PubMed  CAS  Google Scholar 

  193. Tague, S. E., Muralidharan, V., D, , & Souza-Schorey, C. (2004). ADP-ribosylation factor 6 regulates tumor cell invasion through the activation of the MEK/ERK signaling pathway. Proc Natl Acad Sci U S A, 101, 9671–9676.

    PubMed  CAS  Google Scholar 

  194. Artym, V. V., Zhang, Y., Seillier-Moiseiwitsch, F., Yamada, K. M., & Mueller, S. C. (2006). Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function. Cancer Res, 66, 3034–3043.

    PubMed  CAS  Google Scholar 

  195. Angers-Loustau, A., Hering, R., Werbowetski, T. E., Kaplan, D. R., & Del, Maestro, R. F. (2004). SRC regulates actin dynamics and invasion of malignant glial cells in three dimensions. Mol Cancer Res, 2, 595–605.

    PubMed  CAS  Google Scholar 

  196. Clark, E. S., Whigham, A. S., Yarbrough, W. G., & Weaver, A. M. (2007). Cortactin is an essential regulator of matrix metalloproteinase secretion and extracellular matrix degradation in invadopodia. Cancer Res, 67, 4227–4235.

    PubMed  CAS  Google Scholar 

  197. Yamaguchi, H., Lorenz, M., Kempiak, S., Sarmiento, C., Coniglio, S., & Symons, M. (2005). Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin. J Cell Biol, 168, 441–452.

    PubMed  CAS  Google Scholar 

  198. Oxmann, D., Held-Feindt, J., Stark, A. M., Hattermann, K., Yoneda, T., & Mentlein, R. (2008). Endoglin expression in metastatic breast cancer cells enhances their invasive phenotype. Oncogene, 27, 3567–3575.

    PubMed  CAS  Google Scholar 

  199. Nakahara, H., Nomizu, M., Akiyama, S. K., Yamada, Y., Yeh, Y., & Chen, W. T. (1996). A mechanism for regulation of melanoma invasion. Ligation of alpha6beta1 integrin by laminin G peptides. J Biol Chem, 271, 27221–27224.

    PubMed  CAS  Google Scholar 

  200. Wyckoff, J., Wang, W., Lin, E. Y., Wang, Y., Pixley, F., & Stanley, E. R. (2004). A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res, 64, 7022–7029.

    PubMed  CAS  Google Scholar 

  201. Yamaguchi, H., Pixley, F., & Condeelis, J. (2006). Invadopodia and podosomes in tumor invasion. Eur J Cell Biol, 85, 213–218.

    PubMed  CAS  Google Scholar 

  202. Rafii, S., & Lyden, D. (2006). S100 chemokines mediate bookmarking of premetastatic niches. Nat Cell Biol, 8, 1321–1323.

    PubMed  CAS  Google Scholar 

  203. Cortesio, C. L., Chan, K. T., Perrin, B. J., Burton, N. O., Zhang, S., & Zhang, Z. Y. (2008). Calpain 2 and PTP1B function in a novel pathway with Src to regulate invadopodia dynamics and breast cancer cell invasion. J Cell Biol, 180, 957–971.

    PubMed  CAS  Google Scholar 

  204. Webb, B. A., Jia, L., Eves, R., & Mak, A. S. (2007). Dissecting the functional domain requirements of cortactin in invadopodia formation. Eur J Cell Biol, 86, 189–206.

    PubMed  CAS  Google Scholar 

  205. Bowden, E. T., Onikoyi, E., Slack, R., Myoui, A., Yoneda, T., & Yamada, K. M. (2006). Co-localization of cortactin and phosphotyrosine identifies active invadopodia in human breast cancer cells. Exp Cell Res, 312, 1240–1253.

    PubMed  CAS  Google Scholar 

  206. Bharti, S., Inoue, H., Bharti, K., Hirsch, D. S., Nie, Z., & Yoon, H. Y. (2007). Src-dependent phosphorylation of ASAP1 regulates podosomes. Mol Cell Biol, 27, 8271–8283.

    PubMed  CAS  Google Scholar 

  207. Badowski, C., Pawlak, G., Grichine, A., Chabadel, A., Oddou, C., & Jurdic, P. (2008). Paxillin Phosphorylation Controls Invadopodia/Podosomes Spatiotemporal Organization. Mol Biol Cell, 19, 633–645.

    PubMed  CAS  Google Scholar 

  208. Oikawa, T., Itoh, T., & Takenawa, T. (2008). Sequential signals toward podosome formation in NIH-src cells. J Cell Biol, 182(1), 157–169.

    PubMed  CAS  Google Scholar 

  209. Seals, D. F., Azucena Jr., E. F., Pass, I., Tesfay, L., Gordon, R., & Woodrow, M. (2005). The adaptor protein Tks5/Fish is required for podosome formation and function, and for the protease-driven invasion of cancer cells. Cancer Cell, 7, 155–165.

    PubMed  CAS  Google Scholar 

  210. Mueller, S. C., & Chen, W. T. (1991). Cellular invasion into matrix beads: localization of beta 1 integrins and fibronectin to the invadopodia. J Cell Sci, 99, 213–225.

    PubMed  CAS  Google Scholar 

  211. Deryugina, E. I., Ratnikov, B., Monosov, E., Postnova, T. I., DiScipio, R., & Smith, J. W. (2001). MT1-MMP initiates activation of pro-MMP-2 and integrin alphavbeta3 promotes maturation of MMP-2 in breast carcinoma cells. Exp Cell Res, 263, 209–223.

    PubMed  CAS  Google Scholar 

  212. Galliher, A. J., & Schiemann, W. P. (2007). Src phosphorylates Tyr284 in TGF-beta type II receptor and regulates TGF-beta stimulation of p38 MAPK during breast cancer cell proliferation and invasion. Cancer Res, 67, 3752–3758.

    PubMed  CAS  Google Scholar 

  213. Terauchi, M., Kajiyama, H., Yamashita, M., Kato, M., Tsukamoto, H., & Umezu, T. (2007). Possible involvement of TWIST in enhanced peritoneal metastasis of epithelial ovarian carcinoma. Clin Exp Metastasis, 24, 329–339.

    PubMed  CAS  Google Scholar 

  214. Nakahara, H., Mueller, S. C., Nomizu, M., Yamada, Y., Yeh, Y., & Chen, W. T. (1998). Activation of beta1 integrin signaling stimulates tyrosine phosphorylation of p190RhoGAP and membrane-protrusive activities at invadopodia. J Biol Chem, 273, 9–12.

    PubMed  CAS  Google Scholar 

  215. Chuang, Y. Y., Tran, N. L., Rusk, N., Nakada, M., Berens, M. E., & Symons, M. (2004). Role of synaptojanin 2 in glioma cell migration and invasion. Cancer Res, 64, 8271–8275.

    PubMed  CAS  Google Scholar 

  216. Sakurai-Yageta, M., Recchi, C., Le, Dez, G., Sibarita, J. B., Daviet, L., & Camonis, J. (2008). The interaction of IQGAP1 with the exocyst complex is required for tumor cell invasion downstream of Cdc42 and RhoA. J Cell Biol, 181, 985–998.

    PubMed  CAS  Google Scholar 

  217. Buccione, R., Orth, J. D., & McNiven, M. A. (2004). Foot and mouth: podosomes, invadopodia and circular dorsal ruffles. Nat Rev Mol Cell Biol, 5, 647–657.

    PubMed  CAS  Google Scholar 

  218. Gimona, M., Buccione, R., Courtneidge, S. A., & Linder, S. (2008). Assembly and biological role of podosomes and invadopodia. Curr Opin Cell Biol, 20, 235–241.

    PubMed  CAS  Google Scholar 

  219. Vignjevic, D., & Montagnac, G. (2008). Reorganisation of the dendritic actin network during cancer cell migration and invasion. Semin Cancer Biol, 18, 12–22.

    PubMed  CAS  Google Scholar 

  220. Weaver, A. M. (2008). Invadopodia. Curr Biol, 18, 362–364.

    Google Scholar 

  221. Varon, C., Tatin, F., Moreau, V., Van Obberghen-Schilling, E., Fernandez-Sauze, S., Reuzeau, E., et al. (2006). Transforming growth factor beta induces rosettes of podosomes in primary aortic endothelial cells. Mol Cell Biol, 26, 3582–3594.

    PubMed  CAS  Google Scholar 

  222. Frame, M. C. (2004). Newest findings on the oldest oncogene; how activated src does it. J Cell Sci, 117, 989–998.

    PubMed  CAS  Google Scholar 

  223. Xie, L., Law, B. K., Aakre, M. E., Edgerton, M., Shyr, Y., Bhowmick, N. A., et al. (2003). Transforming growth factor beta-regulated gene expression in a mouse mammary gland epithelial cell line. Breast Cancer Res, 5, S187–198.

    Google Scholar 

  224. Fonsatti, E., Altomonte, M., Nicotra, M. R., Natali, P. G., & Maio, M. (2003). Endoglin (CD105): a powerful therapeutic target on tumor-associated angiogenetic blood vessels. Oncogene, 22, 6557–6563.

    PubMed  CAS  Google Scholar 

  225. Mercado-Pimentel, M. E., Hubbard, A. D., & Runyan, R. B. (2007). Endoglin and Alk5 regulate epithelial-mesenchymal transformation during cardiac valve formation. Dev Biol, 304, 420–432.

    PubMed  CAS  Google Scholar 

  226. Lua, B. L., & Low, B. C. (2004). BPGAP1 interacts with cortactin and facilitates its translocation to cell periphery for enhanced cell migration. Mol Biol Cell, 15, 2873–2883.

    PubMed  CAS  Google Scholar 

  227. Head, J. A., Jiang, D., Li, M., Zorn, L. J., Schaefer, E. M., Parsons, J. T., & Weed, S. A. (2003). Cortactin tyrosine phosphorylation requires Rac1 activity and association with the cortical actin cytoskeleton. Mol Biol Cell, 14, 3216–3229.

    PubMed  CAS  Google Scholar 

  228. Lee, S. H. (2005). Interaction of nonreceptor tyrosine-kinase Fer and p120 catenin is involved in neuronal polarization. Mol Cells, 20, 256–262.

    PubMed  CAS  Google Scholar 

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Acknowledgements

We apologize to all colleagues whose important work we could not cite due to space restrictions. Research in the laboratory of the authors has been supported by the EU-FP6 framework program BRECOSM LSHC-CT-2004-503224, the EU-FP7 framework program TUMIC 2008-201662, the NCCR Molecular Oncology of the Swiss National Science Foundation, the Swiss Cancer League, and the Krebsliga Beider Basel.

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  1. Institute of Biochemistry and Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland

    Mahmut Yilmaz & Gerhard Christofori

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  1. Mahmut Yilmaz
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  2. Gerhard Christofori
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Correspondence to Gerhard Christofori.

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Yilmaz, M., Christofori, G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev 28, 15–33 (2009). https://doi.org/10.1007/s10555-008-9169-0

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