Table of Contents
Journal of Signal Transduction
Volume 2012, Article ID 289243, 10 pages
http://dx.doi.org/10.1155/2012/289243
Review Article

The Roles of Mitogen-Activated Protein Kinase Pathways in TGF-β-Induced Epithelial-Mesenchymal Transition

First Department of Pathology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, Wakayama 641-0012, Japan

Received 15 August 2011; Revised 22 October 2011; Accepted 23 October 2011

Academic Editor: Karl Matter

Copyright © 2012 Ting Gui et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. H. J. Schaeffer and M. J. Weber, “Mitogen-activated protein kinases: specific messages from ubiquitous messengers,” Molecular and Cellular Biology, vol. 19, no. 4, pp. 2435–2444, 1999. View at Google Scholar · View at Scopus
  2. L. Chang and M. Karin, “Mammalian MAP kinase signalling cascades,” Nature, vol. 410, no. 6824, pp. 37–40, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  3. E. F. Wagner and A. R. Nebreda, “Signal integration by JNK and p38 MAPK pathways in cancer development,” Nature Reviews Cancer, vol. 9, no. 8, pp. 537–549, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  4. L. Bardwell and K. Shah, “Analysis of mitogen-activated protein kinase activation and interactions with regulators and substrates,” Methods, vol. 40, no. 3, pp. 213–223, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. S. J. Lee, T. Zhou, and E. J. Goldsmith, “Crystallization of MAP kinases,” Methods, vol. 40, no. 3, pp. 224–233, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. Z. Yao, S. Yoon, E. Kalie, Z. Raviv, and R. Seger, “Calcium regulation of EGF-induced ERK5 activation: role of Lad1-MEKK2 interaction,” PLoS One, vol. 5, no. 9, Article ID e12627, pp. 1–10, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  7. X. Guo and X. F. Wang, “Signaling cross-talk between TGF-β/BMP and other pathways,” Cell Research, vol. 19, no. 1, pp. 71–88, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  8. K. H. Wrighton, X. Lin, and X. H. Feng, “Phospho-control of TGF-β superfamily signaling,” Cell Research, vol. 19, no. 1, pp. 8–20, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  9. H. Ikushima and K. Miyazono, “TGFβ signalling: a complex web in cancer progression,” Nature Reviews Cancer, vol. 10, no. 6, pp. 415–424, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. R. Derynck and X. H. Feng, “TGF-β receptor signaling,” Biochimica et Biophysica Acta, vol. 1333, no. 2, pp. F105–F150, 1997. View at Publisher · View at Google Scholar · View at Scopus
  11. X. H. Feng and R. Derynck, “A kinase subdomain of transforming growth factor-β (TGF-β) type I receptor determines the TGF-β intracellular signaling specificity,” EMBO Journal, vol. 16, no. 13, pp. 3912–3923, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  12. D. Javelaud and A. Mauviel, “Transforming growth factor-betas: smad signaling and roles in physiopathology,” Pathologie Biologie, vol. 52, no. 1, pp. 50–54, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. P. Ten Dijke and C. S. Hill, “New insights into TGF-β-Smad signalling,” Trends in Biochemical Sciences, vol. 29, no. 5, pp. 265–273, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. C. H. Heldin, K. Miyazono, and P. Ten Dijke, “TGF-β signalling from cell membrane to nucleus through SMAD proteins,” Nature, vol. 390, no. 6659, pp. 465–471, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. X. H. Feng and R. Derynck, “Specificity and versatility in TGF-β signaling through smads,” Annual Review of Cell and Developmental Biology, vol. 21, pp. 659–693, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. R. Derynck, Y. Zhang, and X. H. Feng, “Smads: transcriptional activators of TGF-β responses,” Cell, vol. 95, no. 6, pp. 737–740, 1998. View at Publisher · View at Google Scholar · View at Scopus
  17. K. Miyazono, P. Ten Dijke, and C. H. Heldin, “TGF-β signaling by Smad proteins,” Advances in Immunology, vol. 75, pp. 115–157, 2000. View at Google Scholar · View at Scopus
  18. Y. Shi and J. Massagué, “Mechanisms of TGF-β signaling from cell membrane to the nucleus,” Cell, vol. 113, no. 6, pp. 685–700, 2003. View at Publisher · View at Google Scholar · View at Scopus
  19. M. Schiller, D. Javelaud, and A. Mauviel, “TGF-β-induced SMAD signaling and gene regulation: consequences for extracellular matrix remodeling and wound healing,” Journal of Dermatological Science, vol. 35, no. 2, pp. 83–92, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  20. C. M. Zimmerman and R. W. Padgett, “Transforming growth factor β signaling mediators and modulators,” Gene, vol. 249, no. 1-2, pp. 17–30, 2000. View at Publisher · View at Google Scholar · View at Scopus
  21. J. Massagué, S. W. Blain, and R. S. Lo, “TGFβ signaling in growth control, cancer, and heritable disorders,” Cell, vol. 103, no. 2, pp. 295–309, 2000. View at Google Scholar · View at Scopus
  22. N. A. Ali, M. J. McKay, and M. P. Molloy, “Proteomics of Smad4 regulated transforming growth factor-beta signalling in colon cancer cells,” Molecular BioSystems, vol. 6, no. 11, pp. 2332–2338, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. A. Nakao, M. Afrakhte, A. Morén et al., “Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling,” Nature, vol. 389, no. 6651, pp. 631–635, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  24. Y. Zhang, C. Chang, D. J. Gehling, A. Hemmati-Brivanlou, and R. Derynck, “Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 3, pp. 974–979, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  25. T. Ebisawa, M. Fukuchi, G. Murakami et al., “Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation,” Journal of Biological Chemistry, vol. 276, no. 16, pp. 12477–12480, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  26. W. Shi, C. Sun, B. He et al., “GADD34-PP1c recruited by Smad7 dephosphorylates TGFβ type I receptor,” Journal of Cell Biology, vol. 164, no. 2, pp. 291–300, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. J. Massagué, “How cells read TGF-β signals,” Nature Reviews Molecular Cell Biology, vol. 1, no. 3, pp. 169–178, 2000. View at Google Scholar
  28. R. Derynck and Y. E. Zhang, “Smad-dependent and Smad-independent pathways in TGF-β family signalling,” Nature, vol. 425, no. 6958, pp. 577–584, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. M. Lutz and P. Knaus, “Integration of the TGF-β pathway into the cellular signalling network,” Cellular Signalling, vol. 14, no. 12, pp. 977–988, 2002. View at Publisher · View at Google Scholar · View at Scopus
  30. J. P. Thiery, H. Acloque, R. Y. J. Huang, and M. A. Nieto, “Epithelial-mesenchymal transitions in development and disease,” Cell, vol. 139, no. 5, pp. 871–890, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  31. L. S. Aroeira, A. Aguilera, J. A. Sánchez-Tomero et al., “Epithelial to mesenchymal transition and peritoneal membrane failure in peritoneal dialysis patients: pathologic significance and potential therapeutic interventions,” Journal of the American Society of Nephrology, vol. 18, no. 7, pp. 2004–2013, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  32. R. Kalluri and R. A. Weinberg, “The basics of epithelial-mesenchymal transition,” Journal of Clinical Investigation, vol. 119, no. 6, pp. 1420–1428, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  33. J. M. Pérez-Pomares, A. Phelps, M. Sedmerova et al., “Experimental studies on the spatiotemporal expression of WT1 and RALDH2 in the embryonic avian heart: a model for the regulation of myocardial and valvuloseptal development by epicardially derived cells (EPDCs),” Developmental Biology, vol. 247, no. 2, pp. 307–326, 2002. View at Publisher · View at Google Scholar · View at Scopus
  34. J. P. Thiery and J. P. Sleeman, “Complex networks orchestrate epithelial-mesenchymal transitions,” Nature Reviews Molecular Cell Biology, vol. 7, no. 2, pp. 131–142, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  35. S. Thomson, F. Petti, I. Sujka-Kwok et al., “A systems view of epithelial-mesenchymal transition signaling states,” Clinical and Experimental Metastasis, vol. 28, no. 2, pp. 137–155, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. A. Moustakas and C. H. Heldin, “Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression,” Cancer Science, vol. 98, no. 10, pp. 1512–1520, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  37. A. J. Whitmarsh and R. J. Davis, “Signal transduction by MAP kinases: regulation by phosphorylation-dependent switches,” Sciences STKE, vol. 1999, no. 1, p. PE1, 1999. View at Google Scholar · View at Scopus
  38. X. Wang and C. Tournier, “Regulation of cellular functions by the ERK5 signalling pathway,” Cellular Signalling, vol. 18, no. 6, pp. 753–760, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  39. G. Zhou, Z. Q. Bao, and J. E. Dixon, “Components of a new human protein kinase signal transduction pathway,” Journal of Biological Chemistry, vol. 270, no. 21, pp. 12665–12669, 1995. View at Google Scholar · View at Scopus
  40. P. Rafiee, J. K. Lee, C. C. Leung, and T. A. Raffin, “TNF-α induces tyrosine phosphorylation of mitogen-activated protein kinase in adherent human neutrophils,” Journal of Immunology, vol. 154, no. 9, pp. 4785–4792, 1995. View at Google Scholar · View at Scopus
  41. V. L. Lowes, N. Y. Ip, and Y. H. Wong, “Integration of signals from receptor tyrosine kinases and G protein-coupled receptors,” NeuroSignals, vol. 11, no. 1, pp. 5–19, 2002. View at Publisher · View at Google Scholar · View at Scopus
  42. T. Joneson, J. A. Fulton, D. J. Volle, O. V. Chaika, D. Bar-Sagi, and R. E. Lewis, “Kinase suppressor of Ras inhibits the activation of extracellular ligand-regulated (ERK) mitogen-activated Protein (MAP) kinase by growth factors, activated Ras, and Ras effectors,” Journal of Biological Chemistry, vol. 273, no. 13, pp. 7743–7748, 1998. View at Publisher · View at Google Scholar · View at Scopus
  43. Y. T. Ip and R. J. Davis, “Signal transduction by the c-Jun N-terminal kinase (JNK)—from inflammation to development,” Current Opinion in Cell Biology, vol. 10, no. 2, pp. 205–219, 1998. View at Publisher · View at Google Scholar · View at Scopus
  44. S. Davis, P. Vanhoutte, C. Pagès, J. Caboche, and S. Laroche, “The MAPK/ERK cascade targets both Elk-1 and cAMP response element- binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo,” Journal of Neuroscience, vol. 20, no. 12, pp. 4563–4572, 2000. View at Google Scholar · View at Scopus
  45. R. Eferl and E. F. Wagner, “AP-1: a double-edged sword in tumorigenesis,” Nature Reviews Cancer, vol. 3, no. 11, pp. 859–868, 2003. View at Google Scholar · View at Scopus
  46. R. Zenz, H. Scheuch, P. Martin et al., “c-Jun regulates eyelid closure and skin tumor development through EGFR signaling,” Developmental Cell, vol. 4, no. 6, pp. 879–889, 2003. View at Publisher · View at Google Scholar · View at Scopus
  47. W. Sun, K. Kesavan, B. C. Schaefer et al., “MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway,” Journal of Biological Chemistry, vol. 276, no. 7, pp. 5093–5100, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  48. S. Pelet, F. Rudolf, M. Nadal-Ribelles, E. De Nadal, F. Posas, and M. Peter, “Transient activation of the HOG MAPK pathway regulates bimodal gene expression,” Science, vol. 332, no. 6030, pp. 732–735, 2011. View at Publisher · View at Google Scholar · View at PubMed
  49. R. Treisman, “Regulation of transcription by MAP kinase cascades,” Current Opinion in Cell Biology, vol. 8, no. 2, pp. 205–215, 1996. View at Publisher · View at Google Scholar · View at Scopus
  50. D. Javelaud and A. Mauviel, “Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-β: implications for carcinogenesis,” Oncogene, vol. 24, no. 37, pp. 5742–5750, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  51. M. Karin, Z. G. Liu, and E. Zandi, “AP-1 function and regulation,” Current Opinion in Cell Biology, vol. 9, no. 2, pp. 240–246, 1997. View at Publisher · View at Google Scholar · View at Scopus
  52. E. Shaulian and M. Karin, “AP-1 as a regulator of cell life and death,” Nature Cell Biology, vol. 4, no. 5, pp. E131–E136, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  53. C. Hauge and M. Frödin, “RSK aand MSK in MAP kinase signalling,” Journal of Cell Science, vol. 119, no. 15, pp. 3021–3023, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  54. M. D. Godeny and P. P. Sayeski, “ERK1/2 regulates ANG II-dependent cell proliferation via cytoplasmic activation of RSK2 and nuclear activation of elk1,” American Journal of Physiology, vol. 291, no. 6, pp. C1308–C1317, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  55. C. A. Hazzalin and L. C. Mahadevan, “MAPK-regulated transcription: a continuously variable gene switch?” Nature Reviews Molecular Cell Biology, vol. 3, no. 1, pp. 30–40, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. D. Hao, P. Gao, P. Liu et al., “AC3-33, a novel secretory protein, inhibits Elk1 transcriptional activity via ERK pathway,” Molecular Biology Reports, vol. 38, no. 2, pp. 1375–1378, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  57. P. Angel and M. Karin, “The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation,” Biochimica et Biophysica Acta, vol. 1072, no. 2-3, pp. 129–157, 1991. View at Google Scholar · View at Scopus
  58. T. Smeal, M. Hibi, and M. Karin, “Altering the specificity of signal transduction cascades: positive regulation of c-Jun transcriptional activity by protein kinase A,” EMBO Journal, vol. 13, no. 24, pp. 6006–6010, 1994. View at Google Scholar · View at Scopus
  59. T. Hai and T. Curran, “Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 9, pp. 3720–3724, 1991. View at Google Scholar · View at Scopus
  60. S. Kamakura, T. Moriguchi, and E. Nishida, “Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus,” Journal of Biological Chemistry, vol. 274, no. 37, pp. 26563–26571, 1999. View at Publisher · View at Google Scholar · View at Scopus
  61. S. Bailey, A. G. Hall, A. D. J. Pearson, and C. P. F. Redfern, “The role of AP-1 in glucocorticoid resistance in leukaemia,” Leukemia, vol. 15, no. 3, pp. 391–397, 2001. View at Publisher · View at Google Scholar · View at Scopus
  62. L. M. Wakefield and A. B. Roberts, “TGF-β signaling: positive and negative effects on tumorigenesis,” Current Opinion in Genetics and Development, vol. 12, no. 1, pp. 22–29, 2002. View at Publisher · View at Google Scholar · View at Scopus
  63. J. Li, Z. Zhao, J. Liu et al., “MEK/ERK and p38 MAPK regulate chondrogenesis of rat bone marrow mesenchymal stem cells through delicate interaction with TGF-β1/Smads pathway,” Cell Proliferation, vol. 43, no. 4, pp. 333–343, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  64. M. L. Burch, S. N. Y. Yang, M. L. Ballinger, R. Getachew, N. Osman, and P. J. Little, “TGF-β stimulates biglycan synthesis via p38 and ERK phosphorylation of the linker region of Smad2,” Cellular and Molecular Life Sciences, vol. 67, no. 12, pp. 2077–2090, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  65. R. Mao, Y. Fan, Y. Mou, H. Zhang, S. Fu, and J. Yang, “TAK1 lysine 158 is required for TGF-β-induced TRAF6-mediated Smad-independent IKK/NF-κB and JNK/AP-1 activation,” Cellular Signalling, vol. 23, no. 1, pp. 222–227, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  66. M. Guma, D. Stepniak, H. Shaked et al., “Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation,” The Journal of Experimental Medicine, vol. 208, no. 9, pp. 1889–1900, 2011. View at Publisher · View at Google Scholar · View at PubMed
  67. S. Holland, O. Coste, D. D. Zhang, S. C. Pierre, G. Geisslinger, and K. Scholich, “The ubiquitin ligase MYCBP2 regulates transient receptor potential vanilloid receptor 1 (TRPV1) internalization through inhibition of p38 MAPK signaling,” Journal of Biological Chemistry, vol. 286, no. 5, pp. 3671–3680, 2011. View at Publisher · View at Google Scholar · View at PubMed
  68. M. C. Lawrence, B. Naziruddin, M. F. Levy, A. Jackson, and K. McGlynn, “Calcineurin/nuclear factor of activated T cells and MAPK signaling induce TNF-α gene expression in pancreatic islet endocrine cells,” Journal of Biological Chemistry, vol. 286, no. 2, pp. 1025–1036, 2011. View at Publisher · View at Google Scholar · View at PubMed
  69. M. E. Engel, M. A. McDonnell, B. K. Law, and H. L. Moses, “Interdependent SMAD and JNK signaling in transforming growth factor-β- mediated transcription,” Journal of Biological Chemistry, vol. 274, no. 52, pp. 37413–37420, 1999. View at Publisher · View at Google Scholar · View at Scopus
  70. L. Yu, M. C. Hébert, and Y. E. Zhang, “TGF-β receptor-activated p38 MAP kinase mediates smad-independent TGF-β responses,” EMBO Journal, vol. 21, no. 14, pp. 3749–3759, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  71. M. M. Martin, J. A. Buckenberger, J. Jiang et al., “TGF-β1 stimulates human at1 receptor expression in lung fibroblasts by cross talk between the Smad, p38 MAPK, JNK, and PI3K signaling pathways,” American Journal of Physiology, vol. 293, no. 3, pp. L790–L799, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  72. K. M. Mulder and S. L. Morris, “Activation of p21(ras) by transforming growth factor β in epithelial cells,” Journal of Biological Chemistry, vol. 267, no. 8, pp. 5029–5031, 1992. View at Google Scholar · View at Scopus
  73. A. Wong, B. Lamothe, A. Lee, J. Schlessinger, and I. Lax, “FRS2α attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 10, pp. 6684–6689, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  74. C. Reardon and D. M. McKay, “TGF-β suppresses IFN-γ-STAT1-dependent gene transcription by enhancing STAT1-PIAS1 interactions in epithelia but not monocytes/macrophages,” Journal of Immunology, vol. 178, no. 7, pp. 4284–4295, 2007. View at Google Scholar · View at Scopus
  75. M. K. Lee, C. Pardoux, M. C. Hall et al., “TGF-β activates Erk MAP kinase signalling through direct phosphorylation of ShcA,” EMBO Journal, vol. 26, no. 17, pp. 3957–3967, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  76. J. Yue and K. M. Mulder, “Requirement of Ras/MAPK pathway activation by transforming growth factor β for transforming growth factor β1 production in a Smad-dependent pathway,” Journal of Biological Chemistry, vol. 275, no. 40, pp. 30765–30773, 2000. View at Google Scholar · View at Scopus
  77. K. Yamaguchi, K. Shirakabe, H. Shibuya et al., “Identification of a member of the MAPKKK family as a potential Mediator of TGF-β signal transduction,” Science, vol. 270, no. 5244, pp. 2008–2011, 1995. View at Google Scholar · View at Scopus
  78. M. Takekawa, K. Tatebayashi, F. Itoh, M. Adachi, K. Imai, and H. Saito, “Smad-dependent GADD45β expression mediates delayed activation of p38 MAP kinase by TGF-β,” EMBO Journal, vol. 21, no. 23, pp. 6473–6482, 2002. View at Publisher · View at Google Scholar · View at Scopus
  79. P. G. Santamaria and A. R. Nebreda, “Deconstructing ERK signaling in tumorigenesis,” Molecular Cell, vol. 38, no. 1, pp. 3–5, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  80. J. H. Zuo, W. Zhu, M. Y. Li et al., “Activation of EGFR promotes squamous carcinoma SCC10A cell migration and invasion via inducing EMT-like phenotype change and MMP-9-mediated degradation of E-cadherin,” Journal of Cellular Biochemistry, vol. 112, no. 9, pp. 2508–2517, 2011. View at Google Scholar
  81. J. P. Thiery, “Cell adhesion in development: a complex signaling network,” Current Opinion in Genetics and Development, vol. 13, no. 4, pp. 365–371, 2003. View at Publisher · View at Google Scholar · View at Scopus
  82. J. Zavadil, M. Bitzer, D. Liang et al., “Genetic programs of epithelial cell plasticity directed by transforming growth factor-β,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 12, pp. 6686–6691, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  83. M. Davies, M. Robinson, E. Smith, S. Huntley, S. Prime, and I. Paterson, “Induction of an epithelial to mesenchymal transition in human immortal and malignant keratinocytes by TGF-β1 involves MAPK, Smad and AP-1 signalling pathways,” Journal of Cellular Biochemistry, vol. 95, no. 5, pp. 918–931, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  84. R. U. De Iongh, E. Wederell, F. J. Lovicu, and J. W. McAvoy, “Transforming growth factor-β-induced epithelial-mesenchymal transition in the lens: a model for cataract formation,” Cells Tissues Organs, vol. 179, no. 1-2, pp. 43–55, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  85. J. Zavadil and E. P. Böttinger, “TGF-β and epithelial-to-mesenchymal transitions,” Oncogene, vol. 24, no. 37, pp. 5764–5774, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  86. L. Xie, B. K. Law, A. M. Chytil, K. A. Brown, M. E. Aakre, and H. L. Moses, “Activation of the Erk pathway is required for TGF-β1-induced EMT in vitro,” Neoplasia, vol. 6, no. 5, pp. 603–610, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  87. R. Strippoli, I. Benedicto, M. L. P. Lozano, A. Cerezo, M. López-Cabrera, and M. A. Del Pozo, “Epithelial-to-mesenchymal transition of peritoneal mesothelial cells is regulated by an ERK/NF-κB/Snail1 pathway,” Disease Models and Mechanisms, vol. 1, no. 4-5, pp. 264–274, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  88. A. Cano, M. A. Pérez-Moreno, I. Rodrigo et al., “The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression,” Nature Cell Biology, vol. 2, no. 2, pp. 76–83, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  89. P. A. Pérez-Mancera, I. González-Herrero, M. Pérez-Caro et al., “SLUG in cancer development,” Oncogene, vol. 24, no. 19, pp. 3073–3082, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  90. J. Choi, S. Y. Park, and C. K. Joo, “Transforming growth factor-β1 represses E-cadherin production via Slug expression in lens epithelial cells,” Investigative Ophthalmology and Visual Science, vol. 48, no. 6, pp. 2708–2718, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  91. K. Lehmann, E. Janda, C. E. Pierreux et al., “Raf induces TGFβ production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells,” Genes and Development, vol. 14, no. 20, pp. 2610–2622, 2000. View at Publisher · View at Google Scholar · View at Scopus
  92. L. Xie, B. K. Law, M. E. Aakre et al., “Transforming growth factor beta-regulated gene expression in a mouse mammary gland epithelial cell line,” Breast Cancer Research, vol. 5, no. 6, pp. R187–R198, 2003. View at Google Scholar · View at Scopus
  93. R. S. Frey and K. M. Mulder, “Involvement of extracellular signal-regulated kinase 2 and stress- activated protein kinase/Jun N-terminal kinase activation by transforming growth factor β in the negative growth control of breast cancer cells,” Cancer Research, vol. 57, no. 4, pp. 628–633, 1997. View at Google Scholar · View at Scopus
  94. N. A. Bhowmick, R. Zent, M. Ghiassi, M. McDonnell, and H. L. Moses, “Integrin β1 signaling is necessary for transforming growtn factor-β activation of p38MAPK and epithelial plasticity,” Journal of Biological Chemistry, vol. 276, no. 50, pp. 46707–46713, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  95. J. H. Shim, C. Xiao, A. E. Paschal et al., “TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo,” Genes and Development, vol. 19, no. 22, pp. 2668–2681, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  96. R. Strippoli, I. Benedicto, M. Foronda et al., “p38 maintains E-cadherin expression by modulating TAK1-NF-κB during epithelial-to-mesenchymal transition,” Journal of Cell Science, vol. 123, no. 24, pp. 4321–4331, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  97. A. Sorrentino, N. Thakur, S. Grimsby et al., “The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner,” Nature Cell Biology, vol. 10, no. 10, pp. 1199–1207, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  98. M. Yamashita, K. Fatyol, C. Jin, X. Wang, Z. Liu, and Y. E. Zhang, “TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-β,” Molecular Cell, vol. 31, no. 6, pp. 918–924, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  99. A. V. Bakin, C. Rinehart, A. K. Tomlinson, and C. L. Arteaga, “p38 mitogen-activated protein kinase is required for TGFβ-mediated fibroblastic transdifferentiation and cell migration,” Journal of Cell Science, vol. 115, no. 15, pp. 3193–3206, 2002. View at Google Scholar · View at Scopus
  100. I. E. Zohn, Y. Li, E. Y. Skolnik, K. V. Anderson, J. Han, and L. Niswander, “p38 and a p38-interacting protein are critical for downregulation of E-cadherin during mouse gastrulation,” Cell, vol. 125, no. 5, pp. 957–969, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  101. Y. Liu, S. El-Naggar, D. S. Darling, Y. Higashi, and D. C. Dean, “Zeb1 links epithelial-mesenchymal transition and cellular senescence,” Development, vol. 135, no. 3, pp. 579–588, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  102. J. C. Hedges, M. A. Dechert, I. A. Yamboliev et al., “A role for p38(MAPK)/HSP27 pathway in smooth muscle cell migration,” Journal of Biological Chemistry, vol. 274, no. 34, pp. 24211–24219, 1999. View at Publisher · View at Google Scholar · View at Scopus
  103. S. Edlund, M. Landström, C. H. Heldin, and P. Aspenström, “Transforming growth factor-β-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA,” Molecular Biology of the Cell, vol. 13, no. 3, pp. 902–914, 2002. View at Publisher · View at Google Scholar · View at PubMed
  104. B. R. Hu, C. L. Liu, and D. J. Park, “Alteration of MAP kinase pathways after transient forebrain ischemia,” Journal of Cerebral Blood Flow and Metabolism, vol. 20, no. 7, pp. 1089–1095, 2000. View at Google Scholar
  105. Z. -M. Lv, Q. Wang, Q. Wan et al., “The role of the p38 MAPK signaling pathway in high glucose-induced epithelial-mesenchymal transition of cultured human renal tubular epithelial cells,” PLoS One, vol. 6, no. 7, Article ID e22806, 2011. View at Publisher · View at Google Scholar · View at PubMed
  106. M. Mariasegaram, G. H. Tesch, S. Verhardt, L. Hurst, H. Y. Lan, and D. J. Nikolic-Paterson, “Lefty antagonises TGF-β1 induced epithelial-mesenchymal transition in tubular epithelial cells,” Biochemical and Biophysical Research Communications, vol. 393, no. 4, pp. 855–859, 2010. View at Publisher · View at Google Scholar · View at PubMed
  107. B. Herrera, M. Fernández, C. Roncero et al., “Activation of p38MAPK by TGF-β in fetal rat hepatocytes requires radical oxygen production, but is dispensable for cell death,” FEBS Letters, vol. 499, no. 3, pp. 225–229, 2001. View at Publisher · View at Google Scholar · View at Scopus
  108. D. Y. Rhyu, Y. Yang, H. Ha et al., “Role of reactive oxygen species in TGF-β1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells,” Journal of the American Society of Nephrology, vol. 16, no. 3, pp. 667–675, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  109. H. Wu, X. Wang, S. Liu et al., “Sema4C participates in myogenic differentiation in vivo and in vitro through the p38 MAPK pathway,” European Journal of Cell Biology, vol. 86, no. 6, pp. 331–344, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  110. R. P. Kruger, J. Aurandt, and K. L. Guan, “Semaphorins command cells to move,” Nature Reviews Molecular Cell Biology, vol. 6, no. 10, pp. 789–800, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  111. J. R. Basile, A. Barac, T. Zhu, K. L. Guan, and J. S. Gutkind, “Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B,” Cancer Research, vol. 64, no. 15, pp. 5212–5224, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  112. R. J. Pasterkamp, J. J. Peschon, M. K. Spriggs, and A. L. Kolodkin, “Semaphorin 7A promotes axon outgrowth through integrins and MAPKs,” Nature, vol. 424, no. 6947, pp. 398–405, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  113. K. Suzuki, A. Kumanogoh, and H. Kikutani, “Semaphorins and their receptors in immune cell interactions,” Nature Immunology, vol. 9, no. 1, pp. 17–23, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  114. R. Zeng, M. Han, Y. Luo et al., “Role of Sema4C in TGF-β1-induced mitogen-activated protein kinase activation and epithelialmesenchymal transition in renal tubular epithelial cells,” Nephrology Dialysis Transplantation, vol. 26, no. 4, pp. 1149–1156, 2011. View at Publisher · View at Google Scholar · View at PubMed
  115. P. Momeni, G. Glöckner, O. Schmidt et al., “Mutations in a new gene, encoding a zinc-finger protein, cause tricho- rhino-phalangeal syndrome type I,” Nature Genetics, vol. 24, no. 1, pp. 71–74, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  116. Z. Gai, G. Zhou, S. Itoh et al., “Trps1 functions downstream of Bmp7 in kidney development,” Journal of the American Society of Nephrology, vol. 20, no. 11, pp. 2403–2411, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  117. R. Derynck, R. J. Akhurst, and A. Balmain, “TGF-β signaling in tumor suppression and cancer progression,” Nature Genetics, vol. 29, no. 2, pp. 117–129, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  118. P. M. Siegel and J. Massagué, “Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer,” Nature Reviews Cancer, vol. 3, no. 11, pp. 807–821, 2003. View at Google Scholar · View at Scopus
  119. M. P. De Caestecker, E. Piek, and A. B. Roberts, “Role of transforming growth factor-β signaling in cancer,” Journal of the National Cancer Institute, vol. 92, no. 17, pp. 1388–1402, 2000. View at Google Scholar · View at Scopus
  120. R. C. Bates and A. M. Mercurio, “Tumor necrosis factor-α stimulates the epithelial-tomesenchymal transition of human colonic organoids,” Molecular Biology of the Cell, vol. 14, no. 5, pp. 1790–1800, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  121. R. J. Orton, O. E. Sturm, V. Vyshemirsky, M. Calder, D. R. Gilbert, and W. Kolch, “Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway,” Biochemical Journal, vol. 392, no. 2, pp. 249–261, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus