TRAF2和OTUD7B控制一个依赖于ubiquitin的开关,该开关调节mTORC2信号
Bin Wang1,2, Zuliang Jie3, Donghyun Joo3
1Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Nature
|May 11, 2017
概括
G蛋白结合受体激酶2 (GRK2) 调节了G蛋白结合受体 (GPCR) 的信号传递. 这项研究显示GRK2
科学领域:
- 细胞信号传递和分子生物学
- 生物化学和酶学
- 癌症生物学和分子机制
背景情况:
- 拉巴胺素 (mTOR) 途径的机理性标对细胞生长和新陈代谢至关重要,它能够整合营养和生长因子的信号.
- mTOR在两个不同的复合体,mTORC1和mTORC2中起作用,其失调与癌症和代谢障碍等疾病有关.
- 控制mTORC1和mTORC2动态组装和功能切换的精确机制尚不完全理解.
研究的目的:
- 阐明GβL (也称为MLST8) 在调节mTORC2复合体形成和激活中的作用.
- 鉴定参与调节 GβL 泛酶的特定泛酶和泛酶酶.
- 调查改变的GβL无化对mTORC2活性,下游信号和瘤发生的影响.
主要方法:
- 在人类和小鼠细胞中研究了GβL泛化状态.
- 使用生物化学测试来评估蛋白质与蛋白质相互作用和复合物形成 (mTORC1与mTORC2).
- 使用基因操纵 (突变,删除) 和体内模型 (例如,Kras驱动的肺瘤发生) 来研究功能后果.
主要成果:
- 通过TRAF2 E3结合酶对GβL进行K63结合的多化,通过破坏GβL- SIN1相互作用来促进mTORC1的形成.
- 通过OTUD7B对GβL的去化促进了GβL-SIN1的相互作用,通过生长信号促进了mTORC2的组合和激活.
- 突变或GβL的切断损害了全方位化,增强了mTORC2的形成,导致AKT信号的增加和瘤形成.
- 在小鼠中Otud7b的遗传删除抑制了AKT激活和Kras驱动的肺癌.
结论:
- GβL无处不在状态作为控制mTORC2动态组装和激活的关键开关.
- TRAF2和OTUD7B对抗GβL无所不在的调节,从而微调mTORC1/mTORC2平衡.
- 这种依赖于无处不在的机制对于在生理条件和癌症发展中调节mTORC2活性至关重要.
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