Cancer and Metastasis Reviews

, Volume 28, Issue 1–2, pp 15–33 | Cite as

EMT, the cytoskeleton, and cancer cell invasion



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.


Actin cytoskeleton Cancer Cell adhesion EMT Metastasis Tumorigenesis 


  1. 1.
    Thiery, J. P., & Sleeman, J. P. (2006). Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol, 7, 131–142.PubMedGoogle Scholar
  2. 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.PubMedGoogle Scholar
  3. 3.
    Zavadil, J., & Bottinger, E. P. (2005). TGF-beta and epithelial-to-mesenchymal transitions. Oncogene, 24, 5764–5774.PubMedGoogle Scholar
  4. 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.PubMedGoogle Scholar
  5. 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.PubMedGoogle Scholar
  6. 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.PubMedGoogle Scholar
  7. 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.PubMedGoogle Scholar
  8. 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.PubMedGoogle Scholar
  9. 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.PubMedGoogle Scholar
  10. 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.PubMedGoogle Scholar
  11. 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.PubMedGoogle Scholar
  12. 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.PubMedGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.PubMedGoogle Scholar
  15. 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.PubMedGoogle Scholar
  16. 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.PubMedGoogle Scholar
  17. 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.PubMedGoogle Scholar
  18. 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.PubMedGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. 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.PubMedGoogle Scholar
  22. 22.
    Friedl, P. (2004). Prespecification and plasticity: shifting mechanisms of cell migration. Curr Opin Cell Biol, 16, 14–23.PubMedGoogle Scholar
  23. 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.PubMedGoogle Scholar
  24. 24.
    Yamada, S., Pokutta, S., Drees, F., Weis, W. I., & Nelson, W. J. (2005). Deconstructing the cadherin-catenin-actin complex. Cell, 123, 889–901.PubMedGoogle Scholar
  25. 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.PubMedGoogle Scholar
  26. 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.PubMedGoogle Scholar
  27. 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.PubMedGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 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.PubMedGoogle Scholar
  30. 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.PubMedGoogle Scholar
  31. 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.PubMedGoogle Scholar
  32. 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.PubMedGoogle Scholar
  33. 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.PubMedGoogle Scholar
  34. 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.PubMedGoogle Scholar
  35. 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.PubMedGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 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.PubMedGoogle Scholar
  38. 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.PubMedGoogle Scholar
  39. 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.PubMedGoogle Scholar
  40. 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.PubMedGoogle Scholar
  41. 41.
    Bissell, M. J., & Radisky, D. (2001). Putting tumours in context. Nat Rev Cancer, 1, 46–54.PubMedGoogle Scholar
  42. 42.
    Cavallaro, U., & Christofori, G. (2004). Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer, 4, 118–132.PubMedGoogle Scholar
  43. 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.PubMedGoogle Scholar
  44. 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.PubMedGoogle Scholar
  45. 45.
    Kouzarides, T. (2007). Chromatin modifications and their function. Cell, 128, 693–705.PubMedGoogle Scholar
  46. 46.
    Jenuwein, T., & Allis, C. D. (2001). Translating the histone code. Science, 293, 1074–1080.PubMedGoogle Scholar
  47. 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.PubMedGoogle Scholar
  48. 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.PubMedGoogle Scholar
  49. 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.PubMedGoogle Scholar
  50. 50.
    Berger, S. L. (2007). The complex language of chromatin regulation during transcription. Nature, 447, 407–412.PubMedGoogle Scholar
  51. 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.PubMedGoogle Scholar
  52. 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.PubMedGoogle Scholar
  53. 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.PubMedGoogle Scholar
  54. 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.PubMedGoogle Scholar
  55. 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.PubMedGoogle Scholar
  56. 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.PubMedGoogle Scholar
  57. 57.
    Gumbiner, B. M. (2000). Regulation of cadherin adhesive activity. J Cell Biol, 148, 399–404.PubMedGoogle Scholar
  58. 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.PubMedGoogle Scholar
  59. 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.PubMedGoogle Scholar
  60. 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.PubMedGoogle Scholar
  61. 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.PubMedGoogle Scholar
  62. 62.
    Akhtar, N., & Hotchin, N. A. (2001). RAC1 regulates adherens junctions through endocytosis of E-cadherin. Mol Biol Cell, 12, 847–862.PubMedGoogle Scholar
  63. 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.PubMedGoogle Scholar
  64. 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.PubMedGoogle Scholar
  65. 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.PubMedGoogle Scholar
  66. 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.PubMedGoogle Scholar
  67. 67.
    Clevers, H. (2006). Wnt/beta-catenin signaling in development and disease. Cell, 127, 469–480.PubMedGoogle Scholar
  68. 68.
    Arce, L., Yokoyama, N. N., & Waterman, M. L. (2006). Diversity of LEF/TCF action in development and disease. Oncogene, 25, 7492–7504.PubMedGoogle Scholar
  69. 69.
    Wong, N. A., & Pignatelli, M. (2002). Beta-catenin—a linchpin in colorectal carcinogenesis? Am J Pathol, 160, 389–401.PubMedGoogle Scholar
  70. 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.PubMedGoogle Scholar
  71. 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.PubMedGoogle Scholar
  72. 72.
    van, Roy, F. M., & McCrea, P. D. (2005). A role for Kaiso-p120ctn complexes in cancer? Nat Rev Cancer, 5, 956–964.PubMedGoogle Scholar
  73. 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.PubMedGoogle Scholar
  74. 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.PubMedGoogle Scholar
  75. 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.PubMedGoogle Scholar
  76. 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.PubMedGoogle Scholar
  77. 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.PubMedGoogle Scholar
  78. 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.PubMedGoogle Scholar
  79. 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.PubMedGoogle Scholar
  80. 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.PubMedGoogle Scholar
  81. 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.PubMedGoogle Scholar
  82. 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.PubMedGoogle Scholar
  83. 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.PubMedGoogle Scholar
  84. 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.PubMedGoogle Scholar
  85. 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.PubMedGoogle Scholar
  86. 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.PubMedGoogle Scholar
  87. 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.PubMedGoogle Scholar
  88. 88.
    Heldin, C. H., Ostman, A., & Ronnstrand, L. (1998). Signal transduction via platelet-derived growth factor receptors. Biochim Biophys Acta, 1378, F79–113.PubMedGoogle Scholar
  89. 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.PubMedGoogle Scholar
  90. 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.PubMedGoogle Scholar
  91. 91.
    Pertz, O., Hodgson, L., Klemke, R. L., & Hahn, K. M. (2006). Spatiotemporal dynamics of RhoA activity in migrating cells. Nature, 440, 1069–1072.PubMedGoogle Scholar
  92. 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.PubMedGoogle Scholar
  93. 93.
    Nimnual, A. S., Taylor, L. J., & Bar-Sagi, D. (2003). Redox-dependent downregulation of Rho by Rac. Nat Cell Biol, 5, 236–241.PubMedGoogle Scholar
  94. 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.PubMedGoogle Scholar
  95. 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.PubMedGoogle Scholar
  96. 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.PubMedGoogle Scholar
  97. 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.PubMedGoogle Scholar
  98. 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.PubMedGoogle Scholar
  99. 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.PubMedGoogle Scholar
  100. 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.PubMedGoogle Scholar
  101. 101.
    Christofori, G. (2006). New signals from the invasive front. Nature, 441, 444–450.PubMedGoogle Scholar
  102. 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.PubMedGoogle Scholar
  103. 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.PubMedGoogle Scholar
  104. 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.PubMedGoogle Scholar
  105. 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.PubMedGoogle Scholar
  106. 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.PubMedGoogle Scholar
  107. 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.PubMedGoogle Scholar
  108. 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.PubMedGoogle Scholar
  109. 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.PubMedGoogle Scholar
  110. 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.PubMedGoogle Scholar
  111. 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.PubMedGoogle Scholar
  112. 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.PubMedGoogle Scholar
  113. 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.PubMedGoogle Scholar
  114. 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.PubMedGoogle Scholar
  115. 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.PubMedGoogle Scholar
  116. 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.PubMedGoogle Scholar
  117. 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.PubMedGoogle Scholar
  118. 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.PubMedGoogle Scholar
  119. 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.PubMedGoogle Scholar
  120. 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.PubMedGoogle Scholar
  121. 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.PubMedGoogle Scholar
  122. 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.PubMedGoogle Scholar
  123. 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.PubMedGoogle Scholar
  124. 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.PubMedGoogle Scholar
  125. 125.
    Sheppard, D. (2005). Integrin-mediated activation of latent transforming growth factor beta. Cancer Metastasis Rev, 24, 395–402.PubMedGoogle Scholar
  126. 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.PubMedGoogle Scholar
  127. 127.
    Bates, R. C. (2005). Colorectal cancer progression: integrin alphavbeta6 and the epithelial-mesenchymal transition (EMT). Cell Cycle, 4, 1350–1352.PubMedGoogle Scholar
  128. 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.PubMedGoogle Scholar
  129. 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.PubMedGoogle Scholar
  130. 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.PubMedGoogle Scholar
  131. 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.PubMedGoogle Scholar
  132. 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.PubMedGoogle Scholar
  133. 133.
    Etienne-Manneville, S., & Hall, A. (2002). Rho GTPases in cell biology. Nature, 420, 629–635.PubMedGoogle Scholar
  134. 134.
    Burridge, K. (2004). Wennerberg, K. Rho and Rac take center stage. Cell, 116, 167–179.PubMedGoogle Scholar
  135. 135.
    Sahai, E., & Marshall, C. J. (2002). RHO-GTPases and cancer. Nat Rev Cancer, 2, 133–142.PubMedGoogle Scholar
  136. 136.
    Hall, A. (2005). Rho GTPases and the control of cell behaviour. Biochem Soc Trans, 33, 891–895.PubMedGoogle Scholar
  137. 137.
    Ridley, A. J. (2006). Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol, 16, 522–529.PubMedGoogle Scholar
  138. 138.
    Lozano, E., Betson, M., & Braga, V. M. (2003). Tumor progression: Small GTPases and loss of cell-cell adhesion. Bioessays, 25, 452–463.PubMedGoogle Scholar
  139. 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.PubMedGoogle Scholar
  140. 140.
    Anastasiadis, P. Z. (2007). p120-ctn: A nexus for contextual signaling via Rho GTPases. Biochim Biophys Acta, 1773, 34–46.PubMedGoogle Scholar
  141. 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.PubMedGoogle Scholar
  142. 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.PubMedGoogle Scholar
  143. 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.PubMedGoogle Scholar
  144. 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.PubMedGoogle Scholar
  145. 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.PubMedGoogle Scholar
  146. 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.PubMedGoogle Scholar
  147. 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.PubMedGoogle Scholar
  148. 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.PubMedGoogle Scholar
  149. 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.PubMedGoogle Scholar
  150. 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.PubMedGoogle Scholar
  151. 151.
    Ballestrem, C., Wehrle-Haller, B., & Imhof, B. A. (1998). Actin dynamics in living mammalian cells. J Cell Sci, 111, 1649–1658.PubMedGoogle Scholar
  152. 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.PubMedGoogle Scholar
  153. 153.
    Orth, J. D., & McNiven, M. A. (2006). Get off my back! Rapid receptor internalization through circular dorsal ruffles. Cancer Res, 66, 11094–11096.PubMedGoogle Scholar
  154. 154.
    Vieira, A. V., Lamaze, C., & Schmid, S. L. (1996). Control of EGF receptor signaling by clathrin-mediated endocytosis. Science, 274, 2086–2089.PubMedGoogle Scholar
  155. 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.PubMedGoogle Scholar
  156. 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.PubMedGoogle Scholar
  157. 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.PubMedGoogle Scholar
  158. 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.PubMedGoogle Scholar
  159. 159.
    Srinivasan, D., & Plattner, R. (2006). Activation of Abl tyrosine kinases promotes invasion of aggressive breast cancer cells. Cancer Res, 66, 5648–5655.PubMedGoogle Scholar
  160. 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.PubMedGoogle Scholar
  161. 161.
    Etienne-Manneville, S., & Hall, A. (2003). Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell polarity. Nature, 421, 753–756.PubMedGoogle Scholar
  162. 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.PubMedGoogle Scholar
  163. 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.PubMedGoogle Scholar
  164. 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.PubMedGoogle Scholar
  165. 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.PubMedGoogle Scholar
  166. 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.PubMedGoogle Scholar
  167. 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.PubMedGoogle Scholar
  168. 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.PubMedGoogle Scholar
  169. 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.PubMedGoogle Scholar
  170. 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.PubMedGoogle Scholar
  171. 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.PubMedGoogle Scholar
  172. 172.
    Ibarra, N., Pollitt, A., & Insall, R. H. (2005). Regulation of actin assembly by SCAR/WAVE proteins. Biochem Soc Trans, 33, 1243–1246.PubMedGoogle Scholar
  173. 173.
    LeClainche, C., & Carlier, M. F. (2008). Regulation of actin assembly associated with protrusion and adhesion in cell migration. Physiol Rev, 88, 489–513.Google Scholar
  174. 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.PubMedGoogle Scholar
  175. 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.PubMedGoogle Scholar
  176. 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.PubMedGoogle Scholar
  177. 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.PubMedGoogle Scholar
  178. 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.PubMedGoogle Scholar
  179. 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.PubMedGoogle Scholar
  180. 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.PubMedGoogle Scholar
  181. 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.PubMedGoogle Scholar
  182. 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.PubMedGoogle Scholar
  183. 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.PubMedGoogle Scholar
  184. 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.PubMedGoogle Scholar
  185. 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.PubMedGoogle Scholar
  186. 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.PubMedGoogle Scholar
  187. 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.PubMedGoogle Scholar
  188. 188.
    Linder, S. (2007). The matrix corroded: podosomes and invadopodia in extracellular matrix degradation. Trends Cell Biol, 17, 107–117.PubMedGoogle Scholar
  189. 189.
    Linder, S., & Kopp, P. (2005). Podosomes at a glance. J Cell Sci, 118, 2079–2082.PubMedGoogle Scholar
  190. 190.
    Ayala, I., Baldassarre, M., Caldieri, G., & Buccione, R. (2006). Invadopodia: a guided tour. Eur J Cell Biol, 85, 159–164.PubMedGoogle Scholar
  191. 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.PubMedGoogle Scholar
  192. 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.PubMedGoogle Scholar
  193. 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.PubMedGoogle Scholar
  194. 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.PubMedGoogle Scholar
  195. 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.PubMedGoogle Scholar
  196. 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.PubMedGoogle Scholar
  197. 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.PubMedGoogle Scholar
  198. 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.PubMedGoogle Scholar
  199. 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.PubMedGoogle Scholar
  200. 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.PubMedGoogle Scholar
  201. 201.
    Yamaguchi, H., Pixley, F., & Condeelis, J. (2006). Invadopodia and podosomes in tumor invasion. Eur J Cell Biol, 85, 213–218.PubMedGoogle Scholar
  202. 202.
    Rafii, S., & Lyden, D. (2006). S100 chemokines mediate bookmarking of premetastatic niches. Nat Cell Biol, 8, 1321–1323.PubMedGoogle Scholar
  203. 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.PubMedGoogle Scholar
  204. 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.PubMedGoogle Scholar
  205. 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.PubMedGoogle Scholar
  206. 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.PubMedGoogle Scholar
  207. 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.PubMedGoogle Scholar
  208. 208.
    Oikawa, T., Itoh, T., & Takenawa, T. (2008). Sequential signals toward podosome formation in NIH-src cells. J Cell Biol, 182(1), 157–169.PubMedGoogle Scholar
  209. 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.PubMedGoogle Scholar
  210. 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.PubMedGoogle Scholar
  211. 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.PubMedGoogle Scholar
  212. 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.PubMedGoogle Scholar
  213. 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.PubMedGoogle Scholar
  214. 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.PubMedGoogle Scholar
  215. 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.PubMedGoogle Scholar
  216. 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.PubMedGoogle Scholar
  217. 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.PubMedGoogle Scholar
  218. 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.PubMedGoogle Scholar
  219. 219.
    Vignjevic, D., & Montagnac, G. (2008). Reorganisation of the dendritic actin network during cancer cell migration and invasion. Semin Cancer Biol, 18, 12–22.PubMedGoogle Scholar
  220. 220.
    Weaver, A. M. (2008). Invadopodia. Curr Biol, 18, 362–364.Google Scholar
  221. 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.PubMedGoogle Scholar
  222. 222.
    Frame, M. C. (2004). Newest findings on the oldest oncogene; how activated src does it. J Cell Sci, 117, 989–998.PubMedGoogle Scholar
  223. 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. 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.PubMedGoogle Scholar
  225. 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.PubMedGoogle Scholar
  226. 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.PubMedGoogle Scholar
  227. 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.PubMedGoogle Scholar
  228. 228.
    Lee, S. H. (2005). Interaction of nonreceptor tyrosine-kinase Fer and p120 catenin is involved in neuronal polarization. Mol Cells, 20, 256–262.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Institute of Biochemistry and Genetics, Department of BiomedicineUniversity of BaselBaselSwitzerland

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