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 Wehle1,2, Carter S Bass2, Josef Sulc2
1Graduate Program in Neuroscience, University of Washington, Seattle, WA, USA.
bioRxiv : the preprint server for biology
|August 14, 2023
概括
猛素 (mTOR) 蛋白相互作用网络 (PIN) 的哺乳动物标显示了模块化组织,具有不同的相互作用组,对特定的抑制剂作出反应. 这揭示了超越线性模型的复杂信号.
科学领域:
- 细胞信号传递和分子生物学.
- 在复杂的生物途径中研究蛋白质-蛋白质相互作用.
背景情况:
- 哺乳动物的目标拉巴胺素 (mTOR) 途径对于细胞生长,转化至关重要,并且与癌症和发育障碍有关.
- 现有的mTOR信号传输模型无法完全捕捉其复杂的系统行为.
研究的目的:
- 量化地绘制mTOR相关蛋白质的蛋白相互作用网络 (PIN).
- 了解mTOR PIN的模块化组织和动态改造,以应对刺激和抑制剂.
主要方法:
- 量化多重共免疫沉被用来监测mTOR相关蛋白质之间的300多个二进制相互作用.
- 实验涉及不同介质条件下的小鼠3T3纤维细胞和用激酶抑制剂 (PI3K,AKT,mTOR,MEK,ERK) 的治疗.
- 分析了由于PIK3CA或MTOR变异导致过度生长障碍的患者的原发性纤维细胞.
主要成果:
- 在一个小时内观察到mTOR PIN (27+相互作用) 的广泛重塑,以应对血清变化,先前的酸化变化.
- 在PIN中确定了不同的"模块",显示了对特定激酶抑制剂的差异性反应.
- 患者衍生的纤维细胞中mTOR通路组件的过度活化与过度活性的PIN相关.
结论:
- mTOR PIN 呈现出一个模块化组织,协调的交互组对不同的路径节点做出反应.
- 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.
- 这种模块化网络视角提供了对mTOR路径调节和失调的更细致的理解.
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