对mTOR信号的蛋白相互作用网络分析揭示了模块化组织
Devin T Wehle1, Carter S Bass2, Josef Sulc2
1Graduate Program in Neuroscience, University of Washington, Seattle, Washington, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.
The Journal of biological chemistry
|September 23, 2023
概括
猛素 (mTOR) 蛋白相互作用网络 (PIN) 的哺乳动物目标显示了模块化组织. 这个网络进行了广泛的改造,揭示了对路径调节器的协调反应,并提供了对健康和疾病中的mTOR信号的新见解.
科学领域:
- 细胞生物学 细胞生物学
- 分子信号传输的方法
- 系统生物学 系统生物学
背景情况:
- 哺乳动物的目标拉巴胺素 (mTOR) 是细胞生长,翻译和突触可塑性的关键调节剂.
- 现有的mTOR信号传输模型无法完全捕捉其复杂的系统行为.
- 了解mTOR的蛋白相互作用网络 (PIN) 对于破译其多种角色至关重要.
研究的目的:
- 量化地绘制mTOR相关的蛋白相互作用网络 (PIN).
- 为了研究mTOR PIN对刺激和抑制剂的反应的动态重塑.
- 探索mTOR PIN的模块化组织及其对疾病的影响.
主要方法:
- 定量多重共免疫沉用于监测300多种二进制蛋白相互作用.
- 在不同的血清条件下利用小鼠3T3纤维细胞.
- 采用小分子抑制剂,向酸3-酶/AKT/mTOR通路和MAPK通路 (MEK,ERK) 中的关键节点.
主要成果:
- 观察到广泛的PIN重塑,超过27个相互作用在1小时内发生变化,在显著的酸化变化之前发生变化.
- 在PIN中定义了不同的"模块",对特定的激酶抑制剂表现出不同的反应.
- 证明过度生长障碍中mTOR途径组件的过度激活与过度活跃的PIN相关.
结论:
- mTOR PIN 显示了一个模块化组织,协调的交互组响应不同的信号节点.
- 激酶抑制剂以复杂的方式影响模块化网络架构,挑战简单的线性信号传导模型.
- 这种模块化PIN框架提供了对mTOR通路调节及其在疾病中的失调的更全面的理解.
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