This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sekimoto, G. Articles by Okazaki, K. Search for Related Content PubMed PubMed Citation Articles by Sekimoto, G. Articles by Okazaki, K.

Reversible Smad-Dependent Signaling between Tumor Suppression and Oncogenesis

Departments of ¹ Gastroenterology and Hepatology and ² Microbiology, Kansai Medical University, Osaka, Japan; ³ Division of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba; and ⁴ RIKEN Cell Bank, The Institute of Chemistry and Physics, Tsukuba, Japan

Requests for reprints: Koichi Matsuzaki, Department of Gastroenterology and Hepatology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka, Japan. Phone: 81-6-6992-1001; Fax: 81-6-6996-4874; E-mail: matsuzak{at}takii.kmu.ac.jp.

Cancer cells often gain advantage by reducing the tumor-suppressive activity of transforming growth factor-ß (TGF-ß) together with stimulation of its oncogenic activity as in Ras-transformed cells; however, molecular mechanisms remain largely unknown. TGF-ß activates both its type I receptor (TßRI) and c-Jun NH₂-terminal kinase (JNK), which phosphorylate Smad2 and Smad3 at the COOH-terminal (pSmad2/3C) and linker regions (pSmad2/3L). Here, we report that Ras transformation suppresses TßRI-mediated pSmad3C signaling, which involves growth inhibition by down-regulating c-Myc. Instead, hyperactive Ras constitutively stimulates JNK-mediated pSmad2/3L signaling, which fosters tumor invasion by up-regulating plasminogen activator inhibitor-1 and matrix metalloproteinase-1 (MMP-1), MMP-2, and MMP-9. Conversely, selective blockade of linker phosphorylation by a mutant Smad3 lacking JNK-dependent phosphorylation sites results in preserved tumor-suppressive function via pSmad3C in Ras-transformed cells while eliminating pSmad2/3L–mediated invasive capacity. Thus, specific inhibition of the JNK/pSmad2/3L pathway should suppress cancer progression by shifting Smad-dependent signaling from oncogenesis to tumor suppression. [Cancer Res 2007;67(11):5090–6]

This article has been cited by other articles:

				K. A. Harradine, K. Ridd, E. F. Saunier, F. F. Clermont, J. Perez-Losada, D. H. Moore, E. H. Epstein Jr., B. C. Bastian, and R. J. Akhurst Elevated Cutaneous Smad Activation Associates with Enhanced Skin Tumor Susceptibility in Organ Transplant Recipients Clin. Cancer Res., August 15, 2009; 15(16): 5101 - 5107. [Abstract] [Full Text] [PDF]

				J. Dzwonek, O. Preobrazhenska, S. Cazzola, A. Conidi, A. Schellens, M. van Dinther, A. Stubbs, A. Klippel, D. Huylebroeck, P. ten Dijke, et al. Smad3 Is a Key Nonredundant Mediator of Transforming Growth Factor {beta} Signaling in Nme Mouse Mammary Epithelial Cells Mol. Cancer Res., August 1, 2009; 7(8): 1342 - 1353. [Abstract] [Full Text] [PDF]

				K. Matsuzaki, C. Kitano, M. Murata, G. Sekimoto, K. Yoshida, Y. Uemura, T. Seki, S. Taketani, J.-i. Fujisawa, and K. Okazaki Smad2 and Smad3 Phosphorylated at Both Linker and COOH-Terminal Regions Transmit Malignant TGF-{beta} Signal in Later Stages of Human Colorectal Cancer Cancer Res., July 1, 2009; 69(13): 5321 - 5330. [Abstract] [Full Text] [PDF]

				K. Horiguchi, T. Shirakihara, A. Nakano, T. Imamura, K. Miyazono, and M. Saitoh Role of Ras Signaling in the Induction of Snail by Transforming Growth Factor-{beta} J. Biol. Chem., January 2, 2009; 284(1): 245 - 253. [Abstract] [Full Text] [PDF]

				L. Valle, T. Serena-Acedo, S. Liyanarachchi, H. Hampel, I. Comeras, Z. Li, Q. Zeng, H.-T. Zhang, M. J. Pennison, M. Sadim, et al. Germline Allele-Specific Expression of TGFBR1 Confers an Increased Risk of Colorectal Cancer Science, September 5, 2008; 321(5894): 1361 - 1365. [Abstract] [Full Text] [PDF]

				M. Erdogan, A. Pozzi, N. Bhowmick, H. L. Moses, and R. Zent Transforming Growth Factor-{beta} (TGF-{beta}) and TGF-{beta}-Associated Kinase 1 Are Required for R-Ras-Mediated Transformation of Mammary Epithelial Cells Cancer Res., August 1, 2008; 68(15): 6224 - 6231. [Abstract] [Full Text] [PDF]

				M. Erdogan, A. Pozzi, N. Bhowmick, H. L Moses, and R. Zent Signaling Pathways Regulating TC21-induced Tumorigenesis J. Biol. Chem., September 21, 2007; 282(38): 27713 - 27720. [Abstract] [Full Text] [PDF]