A Dynamic Network Model of mTOR Signaling Reveals TSC-Independent mTORC2 Regulation
A Dynamic Network Model of mTOR Signaling Reveals TSC-Independent mTORC2 Regulation
复制标题
DOI：
10.1126/scisignal.2002469
复制
发表时间：
2012-03-27
影响因子：
7.3
通讯作者：
Thedieck, Kathrin
中科院分区：
文献类型：
--
作者：
Pezze, Piero Dalle;Sonntag, Annika G.;Thedieck, Kathrin
雷帕霉素激酶哺乳动物靶蛋白（mTOR）存在于两种多蛋白复合物（mTORC 1和mTORC 2）中，是生长和代谢的中心调节因子。mTORC 1的胰岛素激活由磷酸肌醇3-激酶（PI 3 K）、Akt和抑制性结节性硬化症复合物1/2（TSC 1-TSC 2）介导，启动了最终抑制PI 3 K的负反馈回路。我们提出了一个数据驱动的动态胰岛素-mTOR网络模型，该模型集成了整个核心网络，并使用该模型来研究胰岛素调节mTORC 2的机制。通过计算机模拟和实验分析针对网络内几个水平的扰动的影响，我们发现，与当前的假设相反，TSC 1-TSC 2复合物不是mTORC 2的直接或间接（通过负反馈回路起作用）调节剂。虽然mTORC 2激活需要活性PI 3 K，但这不受负反馈回路的影响。因此，我们提出了一种通过PI 3 K变体的mTORC 2激活途径，该变体对调节mTORC 1的负反馈回路不敏感。这种推定的途径预测mTORC 2将对抑制TSC 1-TSC 2的Akt不敏感，并且实际上，我们发现mTORC 2在几种细胞类型中对组成性Akt活化不敏感。我们的研究结果表明，一个以前未知的网络结构连接mTORC 2的上游线索，并澄清哪些分子连接器有助于mTORC 2激活。
The kinase mammalian target of rapamycin (mTOR) exists in two multiprotein complexes (mTORC1 and mTORC2) and is a central regulator of growth and metabolism. Insulin activation of mTORC1, mediated by phosphoinositide 3-kinase (PI3K), Akt, and the inhibitory tuberous sclerosis complex 1/2 (TSC1-TSC2), initiates a negative feedback loop that ultimately inhibits PI3K. We present a data-driven dynamic insulin-mTOR network model that integrates the entire core network and used this model to investigate the less well understood mechanisms by which insulin regulates mTORC2. By analyzing the effects of perturbations targeting several levels within the network in silico and experimentally, we found that, in contrast to current hypotheses, the TSC1-TSC2 complex was not a direct or indirect (acting through the negative feedback loop) regulator of mTORC2. Although mTORC2 activation required active PI3K, this was not affected by the negative feedback loop. Therefore, we propose an mTORC2 activation pathway through a PI3K variant that is insensitive to the negative feedback loop that regulates mTORC1. This putative pathway predicts that mTORC2 would be refractory to Akt, which inhibits TSC1-TSC2, and, indeed, we found that mTORC2 was insensitive to constitutive Akt activation in several cell types. Our results suggest that a previously unknown network structure connects mTORC2 to its upstream cues and clarifies which molecular connectors contribute to mTORC2 activation.