Reversible smad-dependent signaling between tumor suppression and oncogenesis
Reversible smad-dependent signaling between tumor suppression and oncogenesis
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DOI：
10.1158/0008-5472.can-06-4629
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发表时间：
2007-06-01
期刊：
影响因子：
11.2
通讯作者：
Okazaki, Kazuichi
中科院分区：
文献类型：
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作者：
Sekimoto, Go;Matsuzaki, Koichi;Okazaki, Kazuichi
癌细胞通常通过降低转化生长因子-β (TGF-β) 的肿瘤抑制活性以及刺激其致癌活性（如 Ras 转化细胞中的情况）来获得优势；然而，分子机制仍然很大程度上未知。 TGF-β 激活其 I 型受体 (T beta RI) 和 c-Jun NH2 末端激酶 (JNK)，后者在 COOH 末端 (pSmad2/3C) 和接头区域 (pSmad2/3L) 磷酸化 Smad2 和 Smad3。在此，我们报告 Ras 转化抑制 T beta RI 介导的 pSmad3C 信号传导，该信号传导通过下调 c-Myc 来抑制生长。相反，过度活跃的 Ras 会持续刺激 JNK 介导的 pSmad2/3L 信号传导，从而通过上调纤溶酶原激活剂抑制剂-1 和基质金属蛋白酶-1 (MMP-1)、MMP-2 和 MMP-9 促进肿瘤侵袭。相反，缺乏 JNK 依赖性磷酸化位点的突变体 Smad3 选择性阻断接头磷酸化，可在 Ras 转化细胞中通过 pSmad3C 保留肿瘤抑制功能，同时消除 pSmad2/3L 介导的侵袭能力。因此，JNK/pSmad2/3L 通路的特异性抑制应该通过将 Smad 依赖性信号从肿瘤发生转变为肿瘤抑制来抑制癌症进展。
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 (T beta RI) 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 T beta RI-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.