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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]

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