Definition of smad3 phosphorylation events that affect malignant and metastatic behaviors in breast cancer cells.
Definition of smad3 phosphorylation events that affect malignant and metastatic behaviors in breast cancer cells.
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DOI：
10.1158/0008-5472.can-14-0803
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发表时间：
2014-11-01
期刊：
影响因子：
11.2
通讯作者：
Ooshima A
中科院分区：
文献类型：
--
作者：
Bae E;Sato M;Kim RJ;Kwak MK;Naka K;Gim J;Kadota M;Tang B;Flanders KC;Kim TA;Leem SH;Park T;Liu F;Wakefield LM;Kim SJ;Ooshima A
Smad3是tgf - β信号传导的主要细胞内介质，在癌变过程中作为正、负调节因子发挥作用。在对TGFβ的响应中，TGFβ受体磷酸化Smad3 c尾部的丝氨酸残基。癌细胞通常含有高水平的MAPK和CDK活性，这可能导致Smad3连接体区域高度磷酸化。在这里，我们首次报道了Smad3连接子磷酸化位点的突变显著抑制原发肿瘤的生长，但显著增加乳腺癌细胞系的肺转移。相反，Smad3 c -尾磷酸化位点的突变具有相反的效果。我们发现Smad3连接子磷酸化位点的突变极大地增强了tgf β诱导的所有反应，包括生长停滞、细胞凋亡、推定的癌症干细胞群大小的减少、上皮-间质转化和侵袭性活动。此外，在Smad3 c -尾磷酸化位点突变时，所有tgf - β反应完全消失。我们的研究结果表明Smad3 C-tail和连接子磷酸化之间的平衡在肿瘤发生和转移中起着关键作用。我们的发现对乳腺癌的治疗干预具有重要意义。
Smad3, a major intracellular mediator of TGFβ signaling, functions as both a positive and negative regulator in carcinogenesis. In response to TGFβ, the TGFβ receptor phosphorylates serine residues at the Smad3 C-tail. Cancer cells often contain high levels of the MAPK and CDK activities, which can lead to the Smad3 linker region becoming highly phosphorylated. Here, we report, for the first time, that mutation of the Smad3 linker phosphorylation sites markedly inhibited primary tumor growth, but significantly increased lung metastasis of breast cancer cell lines. In contrast, mutation of the Smad3 C-tail phosphorylation sites had the opposite effect. We show that mutation of the Smad3 linker phosphorylation sites greatly intensifies all TGFβ-induced responses, including growth arrest, apoptosis, reduction in the size of putative cancer stem cell population, epithelial–mesenchymal transition, and invasive activity. Moreover, all TGFβ responses were completely lost on mutation of the Smad3 C-tail phosphorylation sites. Our results demonstrate a critical role of the counterbalance between the Smad3 C-tail and linker phosphorylation in tumorigenesis and metastasis. Our findings have important implications for therapeutic intervention of breast cancer.