Cancer and Metastasis Reviews

, Volume 27, Issue 2, pp 303–314 | Cite as

Signal cross talks for sustained MAPK activation and cell migration: the potential role of reactive oxygen species



Signal transduction exerted by the microenvironment around the primary tumor locus may trigger tumor metastasis especially at the migration stage. Sustained mitogen activated protein kinase (MAPK) signaling involved in uncontrolled tumor cell migration rely on the cross talks between integrin, receptor tyrosine kinase (RTK) and protein kinase C (PKC). The molecular mechanisms for cross talking between these migration-related signal cascades leading to sustained cell migration are reviewed, focusing on the focal adhesion scaffold protein paxillin as the platform for signal integration. We proposed reactive oxygen species (ROS) as the critical signal messenger sustaining these signal cascades. For the cross talk of integrin with RTK, ROS may suppress paxillin-associated protein tyrosine phosphatase (PTP–PEST) relieving its negative regulatory effects. For the cross talk of integrin with PKC, PKC itself may phosphorylate integrin or paxillin-associated focal adhesion proteins to induce generation of ROS which may reactivate PKC. In the future, ROS will be validated as the promising therapeutic targets for prevention of tumor metastasis.


MAPK activation Cell migration Receptor tyrosine kinase Integrin Reactive oxygen species Protein kinase C 


  1. 1.
    Christofori, G. (2006). New signals from the invasive front (review). Nature, 441(7092), 444–450.PubMedCrossRefGoogle Scholar
  2. 2.
    Cairns, R. A., Khokha, R., & Hill, R. P. (2003). Molecular mechanisms of tumor invasion and metastasis: An integrated view. Current Molecular Medicine, 3(7), 659–671.PubMedCrossRefGoogle Scholar
  3. 3.
    Sung, S. Y., Hsieh, C. L., Wu, D., Chung, L. W., & Johnstone, P. A. (2007). Tumor microenvironment promotes cancer progression, metastasis, and therapeutic resistance. Current Problems in Cancer, 31(2), 36–100.PubMedCrossRefGoogle Scholar
  4. 4.
    Ridley, A. J., Schwartz, M. A., Burridge, K., Firtel, R. A., Ginsberg, M. H., Borisy, G., et al. (2003). Cell migration: Integrating signals from front to back. Science, 302(5651), 1704–1709.PubMedCrossRefGoogle Scholar
  5. 5.
    Gao, C. F., & Vande Woude, G. F. (2005). HGF/SF-Met signaling in tumor progression. Cell Research, 15(1), 49–51.PubMedCrossRefGoogle Scholar
  6. 6.
    Bierie, B., & Moses, H. L. (2006). Tumour microenvironment: TGFbeta: The molecular Jekyll and Hyde of cancer. Nature Reviews Cancer, 6(7), 506–520.PubMedCrossRefGoogle Scholar
  7. 7.
    Kim, H., & Muller, W. J. (1999). The role of the epidermal growth factor receptor family in mammary tumorigenesis and metastasis. Experimental Cell Research, 253(1), 78–87.PubMedCrossRefGoogle Scholar
  8. 8.
    Qiang, Y. W., Walsh, K., Yao, L., Kedei, N., Blumberg, P. M., Rubin, J. S., et al. (2005). Wnts induce migration and invasion of myeloma plasma cells. Blood, 106(5), 1786–1793.PubMedCrossRefGoogle Scholar
  9. 9.
    Johnson, G. L., & Lapadat, R. (2002). Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science, 298(5600), 1911–1912.PubMedCrossRefGoogle Scholar
  10. 10.
    Huang, C., Jacobson, K., & Schaller, M. D. (2004). MAP kinases and cell migration. Journal of Cell Science, 117(Pt 20), 4619–4628.PubMedCrossRefGoogle Scholar
  11. 11.
    Galabova-Kovacs, G., Kolbus, A., Matzen, D., Meissl, K., Piazzolla, D., Rubiolo, C., et al. (2006). ERK and beyond: insights from B-Raf and Raf-1 conditional knockouts. Cell Cycle, 5(14), 1514–1518.PubMedGoogle Scholar
  12. 12.
    von Kriegsheim, A., Pitt, A., Grindlay, G. J., Kolch, W., & Dhillon, A. S. (2006). Regulation of the Raf–MEK–ERK pathway by protein phosphatase 5. Nature Cell Biology, 8(9), 1011–1016.CrossRefGoogle Scholar
  13. 13.
    Rajalingam, K., Wunder, C., Brinkmann, V., Churin, Y., Hekman, M., Sievers, C., et al. (2005). Prohibitin is required for Ras-induced Raf–MEK–ERK activation and epithelial cell migration. Nature Cell Biology, 7(8), 837–843.PubMedCrossRefGoogle Scholar
  14. 14.
    Giehl, K. (2005). Oncogenic Ras in tumour progression and metastasis. Biological Chemistry, 386(3), 193–205.PubMedCrossRefGoogle Scholar
  15. 15.
    Shin, I., Kim, S., Song, H., Kim, H. R., & Moon, A. (2005). H-Ras-specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells. Journal of Biological Chemistry, 280(15), 14675–14683.PubMedCrossRefGoogle Scholar
  16. 16.
    Veit, C., Genze, F., Menke, A., Hoeffert, S., Gress, T. M., Gierschik, P., et al. (2004). Activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase is required for glial cell line-derived neurotrophic factor-induced migration and invasion of pancreatic carcinoma cells. Cancer Research, 64(15), 5291–5300.PubMedCrossRefGoogle Scholar
  17. 17.
    Woods, D., Cherwinski, H., Venetsanakos, E., Bhat, A., Gysin, S., Humbert, M., et al. (2001). Induction of beta3-integrin gene expression by sustained activation of the Ras-regulated Raf-MEK-extracellular signal-regulated kinase signaling pathway. Molecular and Cellular Biology, 21(9), 3192–3205.PubMedCrossRefGoogle Scholar
  18. 18.
    Imamichi, Y., & Menke, A. (2007). Signaling pathways involved in collagen-induced disruption of the E-cadherin complex during epithelial–mesenchymal transition. Cells Tissues Organs, 185(1–3), 180–190.PubMedCrossRefGoogle Scholar
  19. 19.
    Yan, F., Hui, Y. N., Li, Y. J., Guo, C. M., & Meng, H. (2007). Epidermal growth factor receptor in cultured human retinal pigment epithelial cells. Ophthalmologica, 221(4), 244–250.PubMedCrossRefGoogle Scholar
  20. 20.
    Matsumoto, T., Yokote, K., Tamura, K., Takemoto, M., Ueno, H., Saito, Y., et al. (1999). Platelet-derived growth factor activates p38 mitogen-activated protein kinase through a Ras-dependent pathway that is important for actin reorganization and cell migration. Journal of Biological Chemistry, 274(20), 13954–13960.PubMedCrossRefGoogle Scholar
  21. 21.
    Guo, W., & Giancotti, F. G. (2004). Integrin signalling during tumour progression. Nature Reviews. Molecular cell biology, 5(10), 816–826.PubMedCrossRefGoogle Scholar
  22. 22.
    Kurayoshi, M., Oue, N., Yamamoto, H., Kishida, M., Inoue, A., Asahara, T., et al. (2006). Expression of Wnt-5a is correlated with aggressiveness of gastric cancer by stimulating cell migration and invasion. Cancer Research, 66(21), 10439–10448.PubMedCrossRefGoogle Scholar
  23. 23.
    Abassi, Y. A., & Vuori, K. (2002). Tyrosine 221 in Crk regulates adhesion-dependent membrane localization of Crk and Rac and activation of Rac signaling. EMBO Journal, 21(17), 4571–4582.PubMedCrossRefGoogle Scholar
  24. 24.
    Hsia, D. A., Mitra, S. K., Hauck, C. R., Streblow, D. N., Nelson, J. A., Ilic, D., et al. (2003). Differential regulation of cell motility and invasion by FAK. Journal of Cell Biology, 160(5), 753–767.PubMedCrossRefGoogle Scholar
  25. 25.
    Rucci, N., DiGiacinto, C., Orru, L., Millimaggi, D., Baron, R., & Teti, A. (2005). A novel protein kinase C alpha-dependent signal to ERK1/2 activated by alphaVbeta3 integrin in osteoclasts and in Chinese hamster ovary (CHO) cells. Journal of Cell Science, 118(Pt 15), 3263–3275.PubMedCrossRefGoogle Scholar
  26. 26.
    Desban, N., Lissitzky, J. C., Rousselle, P., & Duband, J. L. (2006). alpha1beta1-integrin engagement to distinct laminin-1 domains orchestrates spreading, migration and survival of neural crest cells through independent signaling pathways. Journal of Cell Science, 119(Pt 15), 3206–3218.PubMedCrossRefGoogle Scholar
  27. 27.
    Kermorgant, S., Zicha, D., & Parker, P. J. (2004). PKC controls HGF-dependent c-Met traffic, signalling and cell migration. EMBO Journal, 23(19), 3721–3734.PubMedCrossRefGoogle Scholar
  28. 28.
    Tian, Y. C., Chen, Y. C., Chang, C. T., Hung, C. C., Wu, M. S., Phillips, A., et al. (2007). Epidermal growth factor and transforming growth factor-beta1 enhance HK-2 cell migration through a synergistic increase of matrix metalloproteinase and sustained activation of ERK signaling pathway. Experimental Cell Research, 313(11), 2367–2377.PubMedCrossRefGoogle Scholar
  29. 29.
    Mercer, K., Giblett, S., Oakden, A., Brown, J., Marais, R., & Pritchard, C. (2005). A-Raf and Raf-1 work together to influence transient ERK phosphorylation and Gl/S cell cycle progression. Oncogene, 24(33), 5207–5217.PubMedCrossRefGoogle Scholar
  30. 30.
    Kim, S. J., Kim, S. Y., Kwon, C. H., & Kim, Y. K. (2007). Differential effect of FGF and PDGF on cell proliferation and migration in osteoblastic cells. Growth Factors, 25(2), 77–86.PubMedCrossRefGoogle Scholar
  31. 31.
    McCawley, L. J., Li, S., Wattenberg, E. V., & Hudson, L. G. (1999). Sustained activation of the mitogen-activated protein kinase pathway. A mechanism underlying receptor tyrosine kinase specificity for matrix metalloproteinase-9 induction and cell migration. Journal of Biological Chemistry, 274(7), 4347–4353.PubMedCrossRefGoogle Scholar
  32. 32.
    Krueger, J. S., Keshamouni, V. G., Atanaskova, N., & Reddy, K. B. (2001). Temporal and quantitative regulation of mitogen-activated protein kinase (MAPK) modulates cell motility and invasion. Oncogene, 20(31), 4209–4218.PubMedCrossRefGoogle Scholar
  33. 33.
    lin, E. J., Opresko, L. K., Wells, A., Wiley, H. S., & Lauffenburger, D. A. (2007). EGF-receptor- mediated mammary epithelial cell migration is driven by sustained ERK signaling from autocrine stimulation. Journal of Cell Science, 120(Pt 20), 3688–3699.Google Scholar
  34. 34.
    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(4), 301–314.PubMedCrossRefGoogle Scholar
  35. 35.
    Pukac, L., Huangpu, J., & Karnovsky, M. J. (1998). Platelet-derived growth factor-BB, insulin-like growth factor-I, and phorbol ester activate different signaling pathways for stimulation of vascular smooth muscle cell migration. Experimental Cell Research, 242(2), 548–560.PubMedCrossRefGoogle Scholar
  36. 36.
    Wu, W. S., Tsai, R. K., Chang, C. H., Wang, S., Wu, J. R., & Chang, Y. X. (2006). Reactive oxygen species mediated sustained activation of protein kinase C alpha and extracellular signal-regulated kinase for migration of human hepatoma cell Hepg2. Molecular Cancer Research, 4(10), 747–758.PubMedCrossRefGoogle Scholar
  37. 37.
    Levy, Y., Ronen, D., Bershadsky, A. D., & Zick, Y. (2003). Sustained induction of ERK, protein kinase B, and p70 S6 kinase regulates cell spreading and formation of F-actin microspikes upon ligation of integrins by galectin-8, a mammalian lectin. Journal of Biological Chemistry, 278(16), 14533–14542.PubMedCrossRefGoogle Scholar
  38. 38.
    Meier, F., Busch, S., Gast, D., Goppert, A., Altevogt, P., Maczey, E., et al. (2006). The adhesion molecule L1 (CD171) promotes melanoma progression. International Journal of Cancer, 119(3), 549–555.CrossRefGoogle Scholar
  39. 39.
    Woods, D., Cherwinski, H., Venetsanakos, E., Bhat, A., Gysin, S., Humbert, M., et al. (2001). Induction of beta3-integrin gene expression by sustained activation of the Ras-regulated Raf-MEK-extracellular signal-regulated kinase signaling pathway. Molecular and Cellular Biology, 21(9), 3192–3205.PubMedCrossRefGoogle Scholar
  40. 40.
    Katz, M., Amit, I., & Yarden, Y. (2007). Regulation of MAPKs by growth factors and receptor tyrosine kinases. Biochimica et Biophysica Acta, 1773(8), 1161–1176.PubMedGoogle Scholar
  41. 41.
    Silletti, S., Yebra, M., Perez, B., Cirulli, V., McMahon, M., & Montgomery, A. M. (2004). Extracellular signal-regulated kinase (ERK)-dependent gene expression contributes to L1 cell adhesion molecule-dependent motility and invasion. Journal of Biological Chemistry, 279(28), 28880–28888.PubMedCrossRefGoogle Scholar
  42. 42.
    Ishibe, S., Joly, D., Liu, Z. X., & Cantley, L. G. (2004). Paxillin serves as an ERK-regulated scaffold for coordinating FAK and Rac activation in epithelial morphogenesis. Molecular Cell, 16(2), 257–267.PubMedCrossRefGoogle Scholar
  43. 43.
    Giancotti, F. G., & Ruoslahti, E. (1999). Integrin signaling. Science, 285(5430), 1028–1032.PubMedCrossRefGoogle Scholar
  44. 44.
    Mitra, S. K., & Schlaepfer, D. D. (2006). Integrin-regulated FAK-Src signaling in normal and cancer cells. Current Opinion in Cell Biology, 18(5), 516–523.PubMedCrossRefGoogle Scholar
  45. 45.
    Hood, J. D., & Cheresh, D. A. (2002). Role of integrins in cell invasion and migration. Nature Reviews. Cancer, 2(2), 91–100.PubMedCrossRefGoogle Scholar
  46. 46.
    Chiarugi, P., & Fiaschi, T. (2007). Redox signalling in anchorage-dependent cell growth. Cell Signal, 19(4), 672–682.PubMedCrossRefGoogle Scholar
  47. 47.
    Friedman, A., & Perrimon, N. (2006). A functional RNAi screen for regulators of receptor tyrosine kinase and ERK signalling. Nature, 444(7116), 230–234.PubMedCrossRefGoogle Scholar
  48. 48.
    Giancotti, F. G., & Tarone, G. (2003). Positional control of cell fate through joint integrin/receptor protein kinase signaling. Annual Review of Cell and Developmental Biology, 19, 173–206.PubMedCrossRefGoogle Scholar
  49. 49.
    Borges, E., Jan, Y., & Ruoslahti, E. (2000). Platelet-derived growth factor receptor beta and vascular endothelial growth factor receptor 2 bind to the beta 3 integrin through its extracellular domain. Journal of Biological Chemistry, 275(51), 39867–39873.PubMedCrossRefGoogle Scholar
  50. 50.
    Short, S. M., Boyer, J. L., & Juliano, R. L. (2000). Integrins regulate the linkage between upstream and downstream events in G protein-coupled receptor signaling to mitogen-activated protein kinase. Journal of Biological Chemistry, 275(17), 12970–12977.PubMedCrossRefGoogle Scholar
  51. 51.
    Guo, W., Pylayeva, Y., Pepe, A., Yoshioka, T., Muller, W. J., Inghirami, G., et al. (2006). Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell, 126(3), 489–502.PubMedCrossRefGoogle Scholar
  52. 52.
    Clemmons, D. R., & Maile, L. A. (2005). Interaction between insulin-like growth factor-I receptor and alphaVbeta3 integrin linked signaling pathways: cellular responses to changes in multiple signaling inputs. Molecular Endocrinology, 19(1), 1–11.PubMedCrossRefGoogle Scholar
  53. 53.
    Miyamoto, S., Teramoto, H., Gutkind, J. S., & Yamada, K. M. (1996). Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. Journal of Cell Biology, 135(6 Pt 1), 1633–1642.PubMedCrossRefGoogle Scholar
  54. 54.
    Turner, C. E. (2000). Paxillin interactions. Journal of Cell Science, 113(Pt 23), 4139–4140.PubMedGoogle Scholar
  55. 55.
    Gilcrease, M. Z. (2007). Integrin signaling in epithelial cells. Cancer Letters, 247(1), 1–25.PubMedCrossRefGoogle Scholar
  56. 56.
    Li, F., Zhang, Y., & Wu, C. (1999). Integrin-linked kinase is localized to cell-matrix focal adhesions but not cell-cell adhesion sites and the focal adhesion localization of integrin-linked kinase is regulated by the PINCH-binding ANK repeats. Journal of Cell Science, 112(Pt 24), 4589–4599.PubMedGoogle Scholar
  57. 57.
    Tu, Y., Li, F., & Wu, C. (1998). Nck-2, a novel Src homology2/3-containing adaptor protein that interacts with the LIM-only protein PINCH and components of growth factor receptor kinase-signaling pathways. Molecular Biology of the Cell, 9(12), 3367–3382.PubMedGoogle Scholar
  58. 58.
    ffrench-Constant, C., & Colognato, H. (2004). Integrins: Versatile integrators of extracellular signals. Trends in Cell Biology, 14(12), 678–686.PubMedCrossRefGoogle Scholar
  59. 59.
    Chan, P. C., Chen, S. Y., Chen, C. H., & Chen, H. C. (2006). Crosstalk between hepatocyte growth factor and integrin signaling pathways. Journal of Biomedical Science, 13(2), 215–223.PubMedCrossRefGoogle Scholar
  60. 60.
    Playford, M. P., & Schaller, M. D. (2004). The interplay between Src and integrins in normal and tumor biology. Oncogene, 23, 7928–7946.PubMedCrossRefGoogle Scholar
  61. 61.
    Mitra, S. K., & Schlaepfer, D. D. (2006). Integrin-regulated FAK-Src signaling in normal and cancer cells. Current Opinion in Cell Biology, 18(5), 516–523.PubMedCrossRefGoogle Scholar
  62. 62.
    Zaidel-Bar, R., Milo, R., Kam, Z., & Geiger, B. (2007). A paxillin tyrosine phosphorylation switch regulates the assembly and form of cell-matrix adhesions. Journal of Cell Science, 120(Pt 1), 137–148.PubMedGoogle Scholar
  63. 63.
    Brown, M. C., & Turner, C. E. (2004). Paxillin: adapting to change. Physiological Reviews, 84(4), 1315–1339.PubMedCrossRefGoogle Scholar
  64. 64.
    Waters, C. M., Connell, M. C., Pyne, S., & Pyne, N. J. (2005). c-Src is involved in regulating signal transmission from PDGFbeta receptor-GPCR(s) complexes in mammalian cells. Cell Signal, 17(2), 263–277.PubMedCrossRefGoogle Scholar
  65. 65.
    Mon, N. N., Ito, S., Senga, T., & Hamaguchi, M. (2006). FAK signaling in neoplastic disorders: a linkage between inflammation and cancer. Annals of the New York Academy of Sciences, 1086, 199–212.PubMedCrossRefGoogle Scholar
  66. 66.
    Park, S. Y., Li, H., & Avraham, S. (2007). RAFTK/Pyk2 regulates EGF-induced PC12 cell spreading and movement. Cell Signal, 19(2), 289–300.PubMedCrossRefGoogle Scholar
  67. 67.
    Monami, G., Gonzalez, E. M., Hellman, M., Gomella, L. G., Baffa, R., Iozzo, R. V., et al. (2006). Proepithelin promotes migration and invasion of 5637 bladder cancer cells through the activation of ERK1/2 and the formation of a paxillin/FAK/ERK complex. Cancer Research, 66(14), 7103–7110.PubMedCrossRefGoogle Scholar
  68. 68.
    Lesslie, D. P., Summy, J. M., Parikh, N. U., Fan, F., Trevino, J. G., Sawyer, T. K., et al. (2006). Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases. British Journal of Cancer, 94(11), 1710–1717.PubMedGoogle Scholar
  69. 69.
    Ishibe, S., Joly, D., Zhu, X., & Cantley, L. G. (2003). Phosphorylation-dependent paxillin–ERK association mediates hepatocyte growth factor-stimulated epithelial morphogenesis. Molecular Cell, 12(5), 1275–1285.PubMedCrossRefGoogle Scholar
  70. 70.
    Manser, E., Loo, T. H., Koh, C. G., Zhao, Z. S., Chen, X. Q., Tan, L., et al. (1998). PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. Molecular Cell, 1(2), 183–192.PubMedCrossRefGoogle Scholar
  71. 71.
    West, K. A., Zhang, H., Brown, M. C., Nikolopoulos, S. N., Riedy, M. C., Horwitz, A. F., et al. (2001). The LD4 motif of paxillin regulates cell spreading and motility through an interaction with paxillin kinase linker (PKL). Journal of Cell Biology, 154(1), 161–176.PubMedCrossRefGoogle Scholar
  72. 72.
    Nayal, A., Webb, D. J., Brown, C. M., Schaefer, E. M., Vicente-Manzanares, M., & Horwitz, A. R. (2006). Paxillin phosphorylation at Ser273 localizes a GIT1–PIX–PAK complex and regulates adhesion and protrusion dynamics. Journal of Cell Biology, 173(4), 587–589.PubMedCrossRefGoogle Scholar
  73. 73.
    Turner, C. E., Brown, M. C., Perrotta, J. A., Riedy, M. C., Nikolopoulos, S. N., McDonald, A. R., et al. (1999). Paxillin LD4 motif binds PAK and PIX through a novel 95-kD ankyrin repeat, ARF–GAP protein: A role in cytoskeletal remodeling. Journal of Cell Biology, 145(4), 851–863.PubMedCrossRefGoogle Scholar
  74. 74.
    Lamorte, L., Rodrigues, S., Sangwan, V., Turner, C. E., & Park, M. (2003). Crk associates with a multimolecular paxillin/GIT2/beta-PIX complex and promotes Rac-dependent relocalization of paxillin to focal contacts. Molecular Biology of the Cell, 14(7), 2818–2831.PubMedCrossRefGoogle Scholar
  75. 75.
    Shen, Y., Lyons, P., Cooley, M., Davidson, D., Veillette, A., Salgia, R., et al. (2000). The noncatalytic domain of protein–tyrosine phosphatase–PEST targets paxillin for dephosphorylation in vivo. Journal of Biological Chemistry, 275(2), 1405–1413.PubMedCrossRefGoogle Scholar
  76. 76.
    Sastry, S. K., Lyons, P. D., Schaller, M. D., & Burridge, K. (2002). PTP–PEST controls motility through regulation of Rac1. Journal of Cell Science, 115(Pt 22), 4305–4316.PubMedCrossRefGoogle Scholar
  77. 77.
    Jamieson, J. S., Tumbarello, D. A., Hallé, M., Brown, M. C., Tremblay, M. L., & Turner, C. E. (2005). Paxillin is essential for PTP–PEST-dependent regulation of cell spreading and motility: a role for paxillin kinase linker. Journal of Cell Science, 118(Pt 24), 5835–5847.PubMedCrossRefGoogle Scholar
  78. 78.
    Griner, E. M., & Kazanietz, M. G. (2007). Protein kinase C and other diacylglycerol effectors in cancer. Nature Reviews Cancer, 7(4), 281–294.PubMedCrossRefGoogle Scholar
  79. 79.
    Wu, W. S. (2006). The signaling mechanism of ROS in tumor progression. Cancer and Metastasis Reviews, 25(4), 695–705.PubMedCrossRefGoogle Scholar
  80. 80.
    Lipscomb, E. A., & Mercurio, A. M. (2005). Mobilization and activation of a signaling competent alpha6beta4integrin underlies its contribution to carcinoma progression. Cancer and Metastasis Reviews, 24(3), 413–423.PubMedCrossRefGoogle Scholar
  81. 81.
    Oka, M., & Kikkawa, U. (2005). Protein kinase C in melanoma. Cancer and Metastasis Reviews, 24(2), 287–300.PubMedCrossRefGoogle Scholar
  82. 82.
    Kiley, S. C., Clark, K. J., Goodnough, M., Welch, D. R., & Jaken, S. (1999). Protein kinase C delta involvement in mammary tumor cell metastasis. Cancer Research, 59(13), 3230–3238.PubMedGoogle Scholar
  83. 83.
    Pan, Q., Bao, L. W., Kleer, C. G., Sabel, M. S., Griffith, K. A., Teknos, T. N., et al. (2005). Protein kinase C epsilon is a predictive biomarker of aggressive breast cancer and a validated target for RNA interference anticancer therapy. Cancer Research, 65(18), 8366–8371.PubMedCrossRefGoogle Scholar
  84. 84.
    Gopalakrishna, R., & Jaken, S. (2000). Protein kinase C signaling and oxidative stress. Free Radical Biology & Medicine, 28(9), 1349–1361.CrossRefGoogle Scholar
  85. 85.
    Gomez, D. E., Skilton, G., Alonso, D. F., & Kazanietz, M. G. (1999). The role of protein kinase C and novel phorbol ester receptors in tumor cell invasion and metastasis (review). Oncology Reports, 6(6), 1363–1370.PubMedGoogle Scholar
  86. 86.
    Guan, C. X., Cui, Y. R., Zhang, M., Bai, H. B., Khunkhun, R., & Fang, X. (2007). Intracellular signaling molecules involved in vasoactive intestinal peptide-mediated wound healing in human bronchial epithelial cells. Peptides, 28(9), 1667–1673.PubMedCrossRefGoogle Scholar
  87. 87.
    Keshamouni, V. G., Mattingly, R. R., & Reddy, K. B. (2002). Mechanism of 17-beta-estradiol-induced Erk1/2 activation in breast cancer cells. A role for HER2 AND PKC-delta. Journal of Biological Chemistry, 277(25), 22558–22565.PubMedCrossRefGoogle Scholar
  88. 88.
    Besson, A., Davy, A., Robbins, S. M., & Yong, V. W. (2001). Differential activation of ERKs to focal adhesions by PKC epsilon is required for PMA-induced adhesion and migration of human glioma cells. Oncogene, 20(50), 7398–7407.PubMedCrossRefGoogle Scholar
  89. 89.
    Pukac, L., Huangpu, J., & Karnovsky, M. J. (1998). Platelet-derived growth factor-BB, insulin-like growth factor-I, and phorbol ester activate different signaling pathways for stimulation of vascular smooth muscle cell migration. Experimental Cell Research, 242(2), 548–560.PubMedCrossRefGoogle Scholar
  90. 90.
    Rigot, V., Lehmann, M., Andre, F., Daemi, N., Marvaldi, J., & Luis, J. (1998). Integrin ligation and PKC activation are required for migration of colon carcinoma cells. Journal of Cell Science, 111(Pt 20), 3119–3127.PubMedGoogle Scholar
  91. 91.
    Larsson, C. (2006). Protein kinase C and the regulation of the actin cytoskeleton. Cellular Signalling, 18(3), 276–284.PubMedCrossRefGoogle Scholar
  92. 92.
    Disatnik, M. H., & Rando, T. A. (1999). Integrin-mediated muscle cell spreading. The role of protein kinase C in outside-in and inside-out signaling and evidence of integrin cross-talk. Journal of Biological Chemistry, 274(45), 32486–32492.PubMedCrossRefGoogle Scholar
  93. 93.
    Rabinovitz, I., Tsomo, L., & Mercurio, A. M. (2004). Protein kinase C-alpha phosphorylation of specific serines in the connecting segment of the beta 4 integrin regulates the dynamics of type II hemidesmosomes. Molecular and Cellular Biology, 24(10), 4351–4360.PubMedCrossRefGoogle Scholar
  94. 94.
    Parsons, M., Keppler, M. D., Kline, A., Messent, A., Humphries, M. J., Gilchrist, R., et al. (2002). Site-directed perturbation of protein kinase C- integrin interaction blocks carcinoma cell chemotaxis. Molecular and Cellular Biology, 22(16), 5897–5911.PubMedCrossRefGoogle Scholar
  95. 95.
    Nomura, N., Nomura, M., Sugiyama, K., & Hamada, J. (2007). Src regulates phorbol 12-myristate 13-acetate-activated PKC-induced migration via Cas/Crk/Rac1 signaling pathway in glioblastoma cells. International Journal of Molecular Medicine, 20(4), 511–519.PubMedGoogle Scholar
  96. 96.
    Lee, M. S., Kim, Y. B., Lee, S. Y., Kim, J. G., Kim, S. H., Ye, S. K., et al. (2006). Integrin signaling and cell spreading mediated by phorbol 12-myristate 13-acetate treatment. Journal of Cellular Biochemistry, 99(1), 88–95.PubMedCrossRefGoogle Scholar
  97. 97.
    De Nichilo, M. O., & Yamada, K. M. (1996). Integrin alpha v beta 5-dependent serine phosphorylation of paxillin in cultured human macrophages adherent to vitronectin. Journal of Biological Chemistry, 271(18), 11016–11022.PubMedCrossRefGoogle Scholar
  98. 98.
    Doan, A. T., & Huttenlocher, A. (2007). RACK1 regulates Src activity and modulates paxillin dynamics during cell migration. Experimental Cell Research, 313(12), 2667–2679.PubMedCrossRefGoogle Scholar
  99. 99.
    Poli, G., Leonarduzzi, G., Biasi, F., & Chiarpotto, E. (2004). Oxidative stress and cell signalling. Current Medicinal Chemistry, 11(9), 1163–1182.PubMedGoogle Scholar
  100. 100.
    Aslan, M., & Ozben, T. (2003). Oxidants in receptor tyrosine kinase signal transduction pathways. Antioxidants & Redox Signalling, 5(6), 781–788.CrossRefGoogle Scholar
  101. 101.
    Chiarugi, P. (2005). PTPs versus PTKs: the redox side of the coin. Free Radical Research, 39(4), 353–364.PubMedCrossRefGoogle Scholar
  102. 102.
    Giles, G. I. (2006). The redox regulation of thiol dependent signaling pathways in cancer. Current Pharmaceutical Design, 12(34), 4427–4443.PubMedCrossRefGoogle Scholar
  103. 103.
    Chandel, N. S., & Budinger, G. R. (2007). The cellular basis for diverse responses to oxygen. Free Radical Biology & Medicine, 42(2), 165–174.CrossRefGoogle Scholar
  104. 104.
    Pervaiz, S. (2006). Pro-oxidant milieu blunts scissors: insight into tumor progression, drug resistance, and novel druggable targets. Current Pharmaceutical Design, 12(34), 4469–4477.PubMedCrossRefGoogle Scholar
  105. 105.
    Cheng, G. C., Schulze, P. C., Lee, R. T., Sylvan, J., Zetter, B. R., & Huang, H. (2004). Oxidative stress and thioredoxin-interacting protein promote intravasation of melanoma cells. Experimental Cell Research, 300(2), 297–307.PubMedCrossRefGoogle Scholar
  106. 106.
    Ferraro, D., Corso, S., Fasano, E., Panieri, E., Santangelo, R., Borrello, S., et al. (2006). Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS). Oncogene, 25(26), 3689–3698.PubMedCrossRefGoogle Scholar
  107. 107.
    Park, I. J., Hwang, J. T., Kim, Y. M., Ha, J., & Park, O. J. (2006). Differential modulation of AMPK signaling pathways by low or high levels of exogenous reactive oxygen species in colon cancer cells. Annals of the New York Academy of Sciences, 1091, 102–109.PubMedCrossRefGoogle Scholar
  108. 108.
    Jagadeeswaran, R., Jagadeeswaran, S., Bindokas, V. P., & Salgia, R. (2007). Activation of HGF/c-Met pathway contributes to the reactive oxygen species generation and motility of small cell lung cancer cells. American Journal of Physiology Lung Cellular and Molecular Physiology, 292(6), L1488–1494.PubMedCrossRefGoogle Scholar
  109. 109.
    Nishigori, C., Hattori, Y., & Toyokuni, S. (2004). Role of reactive oxygen species in skin carcinogenesis. Antioxidants & Redox Signalling, 6(3), 561–570.CrossRefGoogle Scholar
  110. 110.
    Miura, D., Miura, Y., & Yagasaki, K. (2004). Resveratrol inhibits hepatoma cell invasion by suppressing gene expression of hepatocyte growth factor via its reactive oxygen species-scavenging property. Clinical & Experimental Metastasis, 21(5), 445–451.CrossRefGoogle Scholar
  111. 111.
    Nimnual, A. S., Taylor, L. J., & Bar-Sagi, D. (2003). Redox-dependent downregulation of Rho by Rac. Nature Cell Biology, 5(3), 236–241.PubMedCrossRefGoogle Scholar
  112. 112.
    Voncken, J. W., van Schaick, H., Kaartinen, V., Deemer, K., Coates, T., Landing, B., et al. (1995). Increased neutrophil respiratory burst in bcr-null mutants. Cell, 80(5), 719–728.PubMedCrossRefGoogle Scholar
  113. 113.
    Bokoch, G. M., & Knaus, U. G. (2003). NADPH oxidases: not just for leukocytes anymore!. Trends in Biochemical Sciences, 28(9), 502–508.PubMedCrossRefGoogle Scholar
  114. 114.
    Choi, M. H., Lee, I. K., Kim, G. W., Kim, B. U., Han, Y. H., Yu, D. Y., et al. (2005). Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II. Nature, 435(7040), 347–353.PubMedCrossRefGoogle Scholar
  115. 115.
    Arakaki, N., Kajihara, T., Arakaki, R., Ohnishi, T., Kazi, J. A., Nakashima, H., et al. (1999). Involvement of oxidative stress in tumor cytotoxic activity of hepatocyte growth factor/scatter factor. Journal of Biological Chemistry, 274(19), 13541–13546.PubMedCrossRefGoogle Scholar
  116. 116.
    Colavitti, R., Pani, G., Bedogni, B., Anzevino, R., Borrello, S., Waltenberger, J., et al. (2002). Reactive oxygen species as downstream mediators of angiogenic signaling by vascular endothelial growth factor receptor-2/KDR. Journal of Biological Chemistry, 277(5), 3101–3108.PubMedCrossRefGoogle Scholar
  117. 117.
    Werner, E., & Werb, Z. (2002). Integrins engage mitochondrial function for signal transduction by a mechanism dependent on Rho GTPases. Journal of Biological Chemistry, 158(2), 357–368.Google Scholar
  118. 118.
    Kamata, H., Honda, S., Maeda, S., Chang, L., Hirata, H., & Karin, M. (2005). Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell, 120(5), 649–661.PubMedCrossRefGoogle Scholar
  119. 119.
    Chen, C. C., Young, J. L., Monzon, R. I., Chen, N., Todorovic, V., & Lau, L. F. (2007). Cytotoxicity of TNFalpha is regulated by integrin-mediated matrix signaling. EMBO Journal, 26(5), 1257–1267.PubMedCrossRefGoogle Scholar
  120. 120.
    Chiarugi, P. (2003). Reactive oxygen species as mediators of cell adhesion. Italian Journal of Biochemistry, 52(1), 28–32.PubMedGoogle Scholar
  121. 121.
    Chiarugi, P., Pani, G., Giannoni, E., Taddei, L., Colavitti, R., Raugei, G., et al. (2003). Reactive oxygen species as essential mediators of cell adhesion: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion. Journal of Cell Biology, 161(5), 933–944.PubMedCrossRefGoogle Scholar
  122. 122.
    Choi, M. H., Lee, I. K., Kim, G. W., Kim, B. U., Han, Y. H., Yu, D. Y., et al. (2005). Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II. Nature, 435(7040), 347–353.PubMedCrossRefGoogle Scholar
  123. 123.
    Meng, T. C., Fukada, T., & Tonks, N. K. (2002). Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Molecular Cell, 9(2), 387–399.PubMedCrossRefGoogle Scholar
  124. 124.
    Lee, J. K., Edderkaoui, M., Truong, P., Ohno, I., Jang, K. T., Berti, A., et al. (2007). NADPH oxidase promotes pancreatic cancer cell survival via inhibiting JAK2 dephosphorylation by tyrosine phosphatases. Gastroenterology, 133(5), 1637–1648.PubMedCrossRefGoogle Scholar
  125. 125.
    Gozin, A., Franzini, E., Andrieu, V., Da Costa, L., Rollet-Labelle, E., & Pasquier, C. (1998). Reactive oxygen species activate focal adhesion kinase, paxillin and p130cas tyrosine phosphorylation in endothelial cells. Free Radical Biology & Medicine, 25(9), 1021–1032.CrossRefGoogle Scholar
  126. 126.
    Ushio-Fukai, M., Tang, Y., Fukai, T., Dikalov, S. I., Ma, Y., Fujimoto, M., et al. (2002). Novel role of gp91(phox) containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis. Circulation Research, 91(12), 1160–1167.PubMedCrossRefGoogle Scholar
  127. 127.
    Wu, R. F., Xu, Y. C., Ma, Z., Nwariaku, F. E., Sarosi Jr, G. A., & Terada, L. S. (2005). Subcellular targeting of oxidants during endothelial cell migration. Journal of Cell Biology, 171(5), 893–904.PubMedCrossRefGoogle Scholar
  128. 128.
    Xu, Y. C., Wu, R. F., Gu, Y., Yang, Y. S., Yang, M. C., Nwariaku, F. E., et al. (2002). Involvement of TRAF4 in oxidative activation of c-Jun N-terminal kinase. Journal of Biological Chemistry, 277(31), 28051–28057.PubMedCrossRefGoogle Scholar
  129. 129.
    Zhang, J., Zhang, L. X., Meltzer, P. S., Barrett, J. C., & Trent, J. M. (2000). Molecular cloning of human Hic-5, a potential regulator involved in signal transduction and cellular senescence. Molecular Carcinogenesis, 27(3), 177–183.PubMedCrossRefGoogle Scholar
  130. 130.
    Turner, C. E., Brown, M. C., Perrotta, J. A., Riedy, M. C., Nikolopoulos, S. N., McDonald, A. R., et al. (1999). Paxillin LD4 motif binds PAK and PIX through a novel 95-kD ankyrin repeat, ARF-GAP protein: A role in cytoskeletal remodeling. Journal of Cell Biology, 145(4), 851–863.PubMedCrossRefGoogle Scholar
  131. 131.
    Matsuya, M., Sasaki, H., Aoto, H., Mitaka, T., Nagura, K., Ohba, T., et al. (1998). Cell adhesion kinase beta forms a complex with a new member, Hic-5, of proteins localized at focal adhesions. Journal of Biological Chemistry, 273(2), 1003–1014.PubMedCrossRefGoogle Scholar
  132. 132.
    Nishiya, N., Iwabuchi, Y., Shibanuma, M., Côté, J. F., Tremblay, M. L., & Nose, K. (1999). Hic-5, a paxillin homologue, binds to the protein-tyrosine phosphatase PEST (PTP–PEST) through its LIM 3 domain. Journal of Biological Chemistry, 274(14), 9847–9853.PubMedCrossRefGoogle Scholar
  133. 133.
    Lee, K., & Esselman, W. J. (2002). Inhibition of PTPs by H(2)O(2) regulates the activation of distinct MAPK pathways. Free Radical Biology & Medicine, 33(8), 1121–1132.CrossRefGoogle Scholar
  134. 134.
    Greene, E. L., Lu, G., Zhang, D., & Egan, B. M. (2001). Signaling events mediating the additive effects of oleic acid and angiotensin II on vascular smooth muscle cell migration. Hypertension, 37(2), 308–312.PubMedGoogle Scholar
  135. 135.
    Gopalakrishna, R., & Jaken, S. (2000). Protein kinase C signaling and oxidative stress. Free Radical Biology & Medicine, 28(9), 1349–1361.CrossRefGoogle Scholar
  136. 136.
    Shackelford, R. E., Kaufmann, W. K., & Paules, R. S. (2000). Oxidative stress and cell cycle checkpoint function. Free Radical Biology & Medicine, 28(9), 1387–1404.CrossRefGoogle Scholar
  137. 137.
    Lin, D., & Takemoto, D. J. (2005). Oxidative activation of protein kinase Cgamma through the C1 domain. Effects on gap junctions. Journal of Biological Chemistry, 280(14), 13682–13693.PubMedCrossRefGoogle Scholar
  138. 138.
    Inoguchi, T., Sonta, T., Tsubouchi, H., Etoh, T., Kakimoto, M., Sonoda, N., et al. (2003). Protein kinase C-dependent increase in reactive oxygen species (ROS) production in vascular tissues of diabetes: role of vascular NAD(P)H oxidase. Journal of the American Society of Nephrology, 14(8 Suppl 3), S227–232.PubMedCrossRefGoogle Scholar
  139. 139.
    Lee, H. B., Yu, M. R., Yang, Y., Jiang, Z., & Ha, H. (2003). Reactive oxygen species-regulated signaling pathways in diabetic nephropathy. Journal of The American Society of Nephrology, 14(8 Suppl 3), S241–245.PubMedCrossRefGoogle Scholar
  140. 140.
    Frey, R. S., Gao, X., Javaid, K., Siddiqui, S. S., Rahman, A., & Malik, A. B. (2006). Phosphatidylinositol 3-kinase gamma signaling through protein kinase Czeta induces NADPH oxidase-mediated oxidant generation and NF-kappaB activation in endothelial cells. Journal of Biological Chemistry, 281(23), 16128–16138.PubMedCrossRefGoogle Scholar
  141. 141.
    Kwan, J., Wang, H., Munk, S., Xia, L., Goldberg, H. J., & Whiteside, C. I. (2005). In high glucose protein kinase C-zeta activation is required for mesangial cell generation of reactive oxygen species. Kidney International, 68(6), 2526–2541.PubMedCrossRefGoogle Scholar
  142. 142.
    Xia, L., Wang, H., Goldberg, H. J., Munk, S., Fantus, I. G., & Whiteside, C. I. (2006). Mesangial cell NADPH oxidase upregulation in high glucose is protein kinase C dependent and required for collagen IV expression. American Journal of Physiology, Renal Physiology, 290(2), F345–356.CrossRefGoogle Scholar
  143. 143.
    Talior, I., Tennenbaum, T., Kuroki, T., & Eldar-Finkelman, H. (2005). PKC-delta-dependent activation of oxidative stress in adipocytes of obese and insulin-resistant mice: role for NADPH oxidase. American Journal of Physiology: Endocrinology and Metabolism, 288(2), E405–411.PubMedCrossRefGoogle Scholar
  144. 144.
    Lee, H. B., Yu, M. R., Song, J. S., & Ha, H. (2004). Reactive oxygen species amplify protein kinase C signaling in high glucose-induced fibronectin expression by human peritoneal mesothelial cells. Kidney International, 65(4), 1170–1179.PubMedCrossRefGoogle Scholar
  145. 145.
    Takahashi, A., Ohtani, N., Yamakoshi, K., Iida, S., Tahara, H., Nakayama, K., et al. (2006). Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nature Cell Biology, 8(11), 1291–1297.PubMedCrossRefGoogle Scholar
  146. 146.
    Chen, C. C. (1999). Protein kinase C alpha, delta, epsilon and zeta in C6 glioma cells. TPA induces translocation and down-regulation of conventional and new PKC isoforms but not atypical PKC zeta. FEBS Letters, 332(1–2), 169–173.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Department of Medical TechnologyTzu Chi UniversityHualienTaiwan
  2. 2.Graduate Institute of MedicineTzu Chi UniversityHualienTaiwan
  3. 3.Research Centre for Hepatology, Department of Internal MedicineBuddhist Tzu Chi General Hospital and Tzu Chi UniversityHualienTaiwan

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