拉格拉特-拉格复合体将mTORC1定位到 lysosomal 表面,并且是通过氨基酸激活mTORC1的必要条件
Yasemin Sancak1, Liron Bar-Peled, Roberto Zoncu
1Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Cell
|April 13, 2010
概括
氨基酸通过诱导其转移到溶酶体膜向mTORC1通路发出信号. 这种运动由Rag GTPases和Ragulator复合体介导,对于生长调节至关重要,并且在疾病中经常受到干扰.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 拉巴胺素复合物1 (mTORC1) 激酶的机械性标调节细胞生长,以应对营养和生长因子.
- mTORC1信号的失调与各种疾病有关,包括癌症和代谢障碍.
- 已知Rag GTPases与mTORC1相互作用,并被建议调解氨基酸信号传递.
研究的目的:
- 阐明氨基酸激活mTORC1.1.的机制.
- 确定参与氨基酸感应和mTORC1调节的分子参与者.
- 为了研究 lysosomal 局部化在 mTORC1 激活中的作用.
主要方法:
- 免疫光显微镜来追踪mTORC1的定位.
- 同免疫沉试验用于研究蛋白质相互作用.
- 基因操纵 (基因淘汰/淘汰) 以评估Rag GTPases和Ragulator组件的功能.
- 生物化学试验测量mTORC1激酶活性.
主要成果:
- 氨基酸刺激诱导mTORC1的转移到溶酶体膜.
- 一个名为Ragulator (MAPKSP1,ROBLD3,c11orf59) 的新型综合体与Rag GTPases相互作用,并将它们招募到 lysosomes.
- 拉格勒对氨基酸诱导的mTORC1激活至关重要.
- mTORC1的构成性定位到溶酶体膜使该通路对氨基酸可用性不敏感,并且独立于Rag/Ragulator功能.
结论:
- 拉格调节器介导的mTORC1对溶酶体膜的招募是氨基酸向mTORC1.1.信号的关键步骤.
- 这种机制突出了溶解体作为营养感知和生长控制的中心枢纽.
- 了解这种途径为与mTORC1失调相关的疾病提供了潜在的治疗点.
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