title: Reversible Smad-dependent signaling between tumor suppression and oncogenesis.
abstract: Cancer cells often gain advantage by reducing the tumor-suppressive activity of transforming growth factor-beta (TGF-beta) together with stimulation of its oncogenic activity as in Ras-transformed cells; however, molecular mechanisms remain largely unknown. TGF-beta activates both its type I receptor (TbetaRI) 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 TbetaRI-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.
authors.affiliation: Department of Gastroenterology, Kansai Medical University, Osaka, Japan.
authors.forename: Go
authors.initials: G
authors.lastname: Sekimoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuzaki
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yoshida
authors.forename: Shigeo
authors.initials: S
authors.lastname: Mori
authors.forename: Miki
authors.initials: M
authors.lastname: Murata
authors.forename: Toshihito
authors.initials: T
authors.lastname: Seki
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Matsui
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Fujisawa
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Okazaki
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D011905:Genes, ras / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D016212:Transforming Growth Factor beta; D048670:MAP Kinase Kinase 4; D020782:Matrix Metalloproteinases; D018631:ras Proteins