Reversible Smad-Dependent Signaling between Tumor Suppression and Oncogenesis

Go Sekimoto,Kazuichi Okazaki,Toshihito Seki,Shigeo Mori,Jun-Ichi Fujisawa,Miki Murata,Koichi Matsuzaki,Hirofumi Matsui,Katsunori Yoshida

doi:10.1158/0008-5472.can-06-4629

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.

Highlights

Smads are central mediators of signals from the receptors for transforming growth factor-h (TGF-h) superfamily members to the nucleus [1]
Jun NH2-terminal kinase (JNK) activated by TGF-h or hepatocyte growth factor (HGF) signals could directly phosphorylate Smad2 and Smad3 at linker regions in vitro (Fig. 1D)
We conclude from these findings that the JNK/pSmad2/ 3L pathway can be activated in response to TGF-h or HGF signal in the immortalized epithelial cells

Summary

Introduction

Smads are central mediators of signals from the receptors for transforming growth factor-h (TGF-h) superfamily members to the nucleus [1]. Smads are modular proteins with conserved Madhomology 1 (MH1), intermediate linker, and MH2 domains [2]. The catalytically active ThRI phosphorylates the COOH-terminal serine residues of receptor-activated Smads [3], which are Smad and the highly related protein Smad. The linker domain can undergo regulatory phosphorylation by other kinases, including mitogenactivated protein kinases such as extracellular signal-regulated kinase (Erk), c-Jun NH2-terminal kinase (JNK) and p38, or cyclindependent kinases [4,5,6,7]. Phosphorylated Smad and Smad rapidly oligomerize with Smad, forming functional trimeric protein complexes [2]. Monomeric Smad proteins constantly shuttle in and out of the nucleus, formation of the activated Smad complex favors their nuclear accumulation [2].

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Conclusion