基因敲除
内化
小窝蛋白1
SMAD公司
转化生长因子
Smad2蛋白
生物
上皮-间质转换
细胞生物学
下调和上调
小窝
波形蛋白
R-SMAD
受体
信号转导
癌症研究
细胞培养
免疫学
内皮糖蛋白
生物化学
干细胞
基因
免疫组织化学
遗传学
川地34
作者
Cheol Hwangbo,Nara Tae,S Lee,O Kim,Ok Kyu Park,Jinwoong Kim,S-H Kwon,Ju Hee Lee
出处
期刊:Oncogene
[Springer Nature]
日期:2015-04-20
卷期号:35 (3): 389-401
被引量:75
摘要
Syntenin, a tandem PDZ domain containing scaffold protein, functions as a positive regulator of cancer cell progression in several human cancers. We report here that syntenin positively regulates transforming growth factor (TGF)-β1-mediated Smad activation and the epithelial-to-mesenchymal transition (EMT) by preventing caveolin-1-mediated internalization of TGF-β type I receptor (TβRI). Knockdown of syntenin suppressed TGF-β1-mediated cell migration, transcriptional responses and Smad2/3 activation in various types of cells; however, overexpression of syntenin facilitated TGF-β1-mediated responses. In particular, syntenin knockdown abolished both the basal and TGF-β1-mediated repression of E-cadherin expression, as well as induction of vimentin expression along with Snail and Slug upregulation; thus, blocking the TGF-β1-induced EMT in A549 cells. In contrast, overexpression of syntenin exhibited the opposite effect. Knockdown of syntenin-induced ubiquitination and degradation of TβRI, but not TGF-β type II receptor, leading to decreased TβRI expression at the plasma membrane. Syntenin associated with TβRI at its C-terminal domain and a syntenin mutant lacking C-terminal domain failed to increase TGF-β1-induced responses. Biochemical analyzes revealed that syntenin inhibited the interaction between caveolin-1 and TβRI and knockdown of syntenin induced a massive internalization of TβRI and caveolin-1 from lipid rafts, indicating that syntenin may increase TGF-β signaling by inhibiting caveolin-1-dependent internalization of TβRI. Moreover, a positive correlation between syntenin expression and phospho-Smad2 levels is observed in human lung tumors. Taken together, these findings demonstrate that syntenin may act as an important positive regulator of TGF-β signaling by regulating caveolin-1-mediated internalization of TβRI; thus, providing a novel function for syntenin that is linked to cancer progression.
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