Reversible Smad-dependent signaling between tumor suppression and oncogenesis.
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.
Sekimoto
Go
G
Department of Gastroenterology, Kansai Medical University, Osaka, Japan.
Matsuzaki
Koichi
K
Yoshida
Katsunori
K
Mori
Shigeo
S
Murata
Miki
M
Seki
Toshihito
T
Matsui
Hirofumi
H
Fujisawa
Jun-ichi
J
Okazaki
Kazuichi
K
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
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