TGF-β II型受体与乳腺癌转移:这么联系上了
  • TGF-β促进晚期乳腺癌转移,TGF-βⅡ型受体的调控仍不确定;
  • 研究发现FAF1通过招募VCP/E3连接酶复合体破坏TbRⅡ在细胞表面的稳定性,从而限制TGF-b反应过度;
  • 活化的AKT直接磷酸化FAF1,扰乱FAF1-VCP复合体并降低质膜上FAF1水平,进而导致细胞表面TbRⅡ增加并促进TGF-β诱导的SMAD和非SMAD信号通路;
  • 通过各种体外和体内模型实验发现FAF1的抑制转移作用;
  • TbRII受到严格调控,SMAD和AKT通路的相互作用导致TGF-β的致癌反应。
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FAF1 phosphorylation by AKT accumulates TGF-β type II receptor and drives breast cancer metastasis

通过AKT的FAF1磷酸化累积TGF-bⅡ型受体并促使乳腺癌转移

10.1038/ncomms15021

2017-04-26, Article

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TGF-β is pro-metastatic for the late-stage breast cancer cells. Despite recent progress, the regulation of TGF-β type II receptor remains uncertain. Here we report that FAF1 destabilizes TβRII on the cell surface by recruiting the VCP/E3 ligase complex, thereby limiting excessive TGF-β response. Importantly, activated AKT directly phosphorylates FAF1 at Ser 582, which disrupts the FAF1-VCP complex and reduces FAF1 at the plasma membrane. The latter results in an increase in TβRII at the cell surface that promotes both TGF-β-induced SMAD and non-SMAD signalling. We uncover a metastasis suppressing role for FAF1 through analyses of FAF1-knockout animals, various in vitro and in vivo models of epithelial-to-mesenchymal transition and metastasis, an MMTV-PyMT transgenic mouse model of mammary tumour progression and clinical breast cancer samples. These findings describe a previously uncharacterized mechanism by which TβRII is tightly controlled. Together, we reveal how SMAD and AKT pathways interact to confer pro-oncogenic responses to TGF-β.

First Authors:
Feng Xie,Ke Jin,Li Shao

Correspondence Authors:
Fangfang Zhou,Long Zhang

All Authors:
Feng Xie,Ke Jin,Li Shao,Yao Fan,Yifei Tu,Yihao Li,Bin Yang,Hans van Dam,Peter Ten Dijke,Honglei Weng,Steven Dooley,Shuai Wang,Junling Jia,Jin Jin,Fangfang Zhou,Long Zhang

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