ॐ↑ HACS ↑ αβγδφε
|文章標題：
Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1
|核心內容：
哺乳動物的雷帕黴素靶標(MTOR)是兩種不同複合物的一部分，mTORC1含有Raptor和mLST8，mTORC2含有Rictor，mLST8和SIN1。儘管人們已經對mTOR的功能和調控進行了大量的研究，但mTOR複合體的胞質核分布尚不清楚。在建立合適的實驗條件後，我們發現mTOR、mLST8、Rictor和SIN1在細胞核中的含量低於未轉化的、未永生化的二倍體人原代成纖維細胞胞漿中的mTOR、mLST8、Rictor和SIN1。雖然Raptor在細胞核中也很豐富，但mTOR/Raptor複合體主要是細胞質的，而mTOR/Rictor複合體在兩個隔室中都很豐富。雷帕黴素負性調節兩種mTOR複合體的形成，但其影響mTORC2的分子機制仍不清楚。我們描述了在原代細胞中，雷帕黴素短期處理只在胞漿內觸發Rictor和SIN1的去磷酸化，但不影響mTORC2的組裝。長期藥物治療會導致細胞核Rictor和SIN1的完全去磷酸化和胞漿易位，並伴隨mTORC2組裝的抑制。MTOR的胞漿和核上下遊效應因子與多種癌症和人類遺傳性疾病有關，如結節性硬化症、黑斑狼瘡症候群、von Hippel-Lindau病、1型神經纖維瘤病、多囊腎病、阿爾茨海默病、心肌肥厚、肥胖和糖尿病。因此，雷帕黴素的類似物目前正在許多不同的臨床試驗中進行測試。我們的數據使我們對病理生理條件下mTOR失調的分子後果有了新的見解，並應有助於優化雷帕黴素對人類疾病的治療。The mammalian target of rapamycin (mTOR) is part of two distinct complexes, mTORC1, containing raptor and mLST8, and mTORC2, containing rictor, mLST8 and sin1. Although great endeavors have already been made to elucidate the function and regulation of mTOR, the cytoplasmic nuclear distribution of the mTOR complexes is unknown. Upon establishment of the proper experimental conditions, we found mTOR, mLST8, rictor and sin1 to be less abundant in the nucleus than in the cytoplasm of non-transformed, non-immortalized, diploid human primary fibroblasts. Although raptor is also high abundant in the nucleus, the mTOR/raptor complex is predominantly cytoplasmic, whereas the mTOR/rictor complex is abundant in both compartments. Rapamycin negatively regulates the formation of both mTOR complexes, but the molecular mechanism of its effects on mTORC2 remained elusive. We describe that in primary cells short-term treatment with rapamycin triggers dephosphorylation of rictor and sin1 exclusively in the cytoplasm, but does not affect mTORC2 assembly. Prolonged drug treatment leads to complete dephosphorylation and cytoplasmic translocation of nuclear rictor and sin1 accompanied by inhibition of mTORC2 assembly. The distinct cytoplasmic and nuclear upstream and downstream effectors of mTOR are involved in many cancers and human genetic diseases, such as tuberous sclerosis, Peutz-Jeghers syndrome, von Hippel-Lindau disease, neurofibromatosis type 1, polycystic kidney disease, Alzheimer's disease, cardiac hypertrophy, obesity and diabetes. Accordingly, analogs of rapamycin are currently tested in many different clinical trials. Our data allow new insights into the molecular consequences of mTOR dysregulation under pathophysiological conditions and should help to optimize rapamycin treatment of human diseases.
參考文獻：https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/hmg/17/19/10.1093_hmg_ddn192/2/ddn192.pdf?Expires=1492580701&Key-Pair-Id=APKAIUCZBIA4LVPAVW3Q&Signature=UxyF5LS9Gl2GlXltXvx0SjQ44Lx~42ZNPV-ogDaRQbI6BCD6fGVy7dJa~HEwhW8PX4el9vkLcfQzxSgTyC9
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