Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, Republic of Korea.
Division of Bio-imaging, Chuncheon Center, Korea Basic Science Institute, Chuncheon, Gangwon-Do, Republic of Korea.
Oncogene. 2016 Jan 21;35(3):389-401. doi: 10.1038/onc.2015.100. Epub 2015 Apr 20.
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.
衔接蛋白（Syntenin）是一种含 PDZ 结构域的串联支架蛋白，在几种人类癌症中作为癌细胞进展的正向调节剂发挥作用。我们在此报告，衔接蛋白通过阻止小窝蛋白-1（caveolin-1）介导的 TGF-β Ⅰ型受体（TβRI）内化，正向调节转化生长因子（TGF）-β1 介导的 Smad 激活和上皮-间质转化（EMT）。衔接蛋白敲低抑制了各种类型细胞中 TGF-β1 介导的细胞迁移、转录应答和 Smad2/3 激活；然而，衔接蛋白过表达促进了 TGF-β1 介导的反应。具体而言，衔接蛋白敲低消除了 TGF-β1 对 E-钙黏蛋白表达的基础和 TGF-β1 介导的抑制作用，以及诱导波形蛋白表达，同时上调 Snail 和 Slug；从而阻断了 A549 细胞中的 TGF-β1 诱导的 EMT。相比之下，衔接蛋白过表达则表现出相反的效果。衔接蛋白敲低诱导 TβRI 的泛素化和降解，但不诱导 TGF-β Ⅱ型受体降解，导致质膜上 TβRI 表达减少。衔接蛋白与 TβRI 的 C 端结构域结合，并且缺乏 C 端结构域的衔接蛋白突变体不能增加 TGF-β1 诱导的反应。生化分析表明，衔接蛋白抑制了小窝蛋白-1 与 TβRI 的相互作用，衔接蛋白敲低诱导 TβRI 和小窝蛋白-1 从脂筏中大量内化，表明衔接蛋白可能通过抑制小窝蛋白-1 依赖性 TβRI 内化来增加 TGF-β 信号。此外，在人类肺癌肿瘤中观察到衔接蛋白表达与磷酸化 Smad2 水平之间存在正相关。综上所述，这些发现表明，衔接蛋白可能通过调节 TβRI 的小窝蛋白-1 介导内化来作为 TGF-β 信号的重要正向调节剂发挥作用；从而为衔接蛋白与癌症进展相关的提供了一个新的功能。
