A mechanism of repression of TGFβ/Smad signaling by oncogenic Ras
A mechanism of repression of TGFβ/Smad signaling by oncogenic Ras
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DOI：
10.1101/gad.13.7.804
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发表时间：
1999-04-01
影响因子：
10.5
通讯作者：
Massagué, J
中科院分区：
文献类型：
--
作者：
Kretzschmar, M;Doody, J;Massagué, J
转化生长因子β可以抑制EGF和其他PAS激活的丝裂原对正常上皮细胞的增殖作用。然而，携带致癌PAS突变的上皮细胞通常表现出转化生长因子β抗分裂反应的缺失。在此，我们报道了致癌的PAS通过负调控转化生长因子β介体Smad2和Smad3来抑制乳腺和肺上皮细胞的转化生长因子β信号转导。癌基因激活的RAS抑制转化生长因子β诱导的Smad2和Smad3的核积聚和Smad依赖的转录。RAS通过Erk MAP激酶作用，导致Smad2和Smad3在连接DNA结合区和转录激活区的特定位置发生磷酸化。这些位点与激活Smad核转位的转化生长因子β受体磷酸化位点是分开的。Smad3中这些MAP激酶位点的突变产生了一种PAS抗性形式，可以挽救RAS转化细胞中对转化生长因子β的生长抑制反应。EGF在激活RNS方面比癌基因突变弱，导致Smad2和Smad3的磷酸化和细胞质保留较少。我们的结果提示，在正常细胞中，Smad2/Smad3被转化生长因子β信号和PAS信号平衡调节，而在癌细胞中，高活性PAS抑制抗增殖的转化生长因子β功能。
TGF beta can override the proliferative effects of EGF and other Pas-activating mitogens in normal epithelial cells. However, epithelial cells harboring oncogenic Pas mutations often show a loss of TGF beta antimitogenic responses. Here we report that oncogenic Pas inhibits TGF beta signaling in mammary and lung epithelial cells by negatively regulating the TGF beta mediators Smad2 and Smad3. Oncogenically activated Ras inhibits the TGF beta-induced nuclear accumulation of Smad2 and Smad3 and Smad-dependent transcription. Ras acting via Erk MAP kinases causes phosphorylation of Smad2 and Smad3 at specific sites in the region linking the DNA-binding domain and the transcriptional activation domain. These sites are separate from the TGF beta receptor phosphorylation sites that activate Smad nuclear translocation. Mutation of these MAP kinase sites in Smad3 yields a Pas-resistant form that can rescue the growth inhibitory response to TGF beta in Ras-transformed cells. EGF, which is weaker than oncogenic mutations at activating Rns, induces a less extensive phosphorylation and cytoplasmic retention of Smad2 and Smad3. Our results suggest a mechanism for the counterbalanced regulation of Smad2/Smad3 by TGF beta and Pas signals in normal cells, and for the silencing of antimitogenic TGF beta functions by hyperactive Pas in cancer cells.