Pathway crosstalk enables cells to interpret TGF-β duration.
Pathway crosstalk enables cells to interpret TGF-β duration.
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DOI：
10.1038/s41540-018-0060-5
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发表时间：
2018
影响因子：
4
通讯作者：
Xing J
中科院分区：
文献类型：
--
作者：
Zhang J;Tian XJ;Chen YJ;Wang W;Watkins S;Xing J
细胞内和细胞外信号的时间质量的检测和传递是一个重要的细胞机制。细胞如何解释刺激的持续时间信息在很大程度上仍未被探索。在本文中，我们对TGF-β诱导的SNAIL1激活进行了综合定量和计算分析，SNAIL1是一个关键的转录因子，调节随后的几个细胞命运决定，如凋亡和上皮到间质转化。我们证明了多种TGF-β激活通路之间的串扰形成了从SMAD到GLI1的中继，分别初始化和维持snail表达。SNAIL1是TGF-β信号通过上游发散途径分布的信息的关键整合者。交织的网络作为一个时间检查点，因此细胞可以根据TGF-β持续时间产生短暂或持续的SNAIL1表达。此外，我们观察到TGF-β处理导致GSK3分子意外地在高尔基体和内质网中以酶活性酪氨酸磷酸化形式积累，随后在细胞核中以酶抑制丝氨酸磷酸化形式积累。随后的模型分析和抑制实验表明，GSK3酶活性的初始局部升高与底物Gli1的正反馈回路偶联，形成一个具有多目标功能的网络基序。也就是说，基序对随机波动具有鲁棒性，并且响应时间分布窄，对初始条件不敏感。特别是对于TGF-β信号，该基序通过调节SNAIL1的表达，确保从SMAD到GLI1的平稳传递。细胞能够可靠地接收、解码、整合和传输细胞外信号的持续时间和强度等信息。美国匹兹堡大学邢建华领导的团队重建了TGF-β处理下人类乳腺细胞的早期反应信号转导网络，该网络由多个相互关联的信号通路组成。该网络包含由桥接模块连接的瞬态和持续信号响应模块。TGF-β以特定的时间顺序激活这些模块，不同的TGF-β持续时间产生不同的下游基因表达时间谱。也就是说，细胞使用网络作为信号持续时间和不同细胞反应的时间检查点。因此，网络就像一个计算机芯片，利用多个单元的组合状态来扩大其编码信号持续时间信息的能力。
The detection and transmission of the temporal quality of intracellular and extracellular signals is an essential cellular mechanism. It remains largely unexplored how cells interpret the duration information of a stimulus. In this paper, we performed an integrated quantitative and computational analysis on TGF-β induced activation of SNAIL1, a key transcription factor that regulates several subsequent cell fate decisions such as apoptosis and epithelial-to-mesenchymal transition. We demonstrate that crosstalk among multiple TGF-β activated pathways forms a relay from SMAD to GLI1 that initializes and maintains SNAILl expression, respectively. SNAIL1 functions as a key integrator of information from TGF-β signaling distributed through upstream divergent pathways. The intertwined network serves as a temporal checkpoint, so that cells can generate a transient or sustained expression of SNAIL1 depending on TGF-β duration. Furthermore, we observed that TGF-β treatment leads to an unexpected accumulation of GSK3 molecules in an enzymatically active tyrosine phosphorylation form in Golgi apparatus and ER, followed by accumulation of GSK3 molecules in an enzymatically inhibitive serine phosphorylation in the nucleus. Subsequent model analysis and inhibition experiments revealed that the initial localized increase of GSK3 enzymatic activity couples to the positive feedback loop of the substrate Gli1 to form a network motif with multi-objective functions. That is, the motif is robust against stochastic fluctuations, and has a narrow distribution of response time that is insensitive to initial conditions. Specifically for TGF-β signaling, the motif ensures a smooth relay from SMAD to GLI1 on regulating SNAIL1 expression. Cells can reliably receive, decode, integrate and transmit the information of duration and strength of extracellular signals. A team led by Jianhua Xing at USA’s University of Pittsburgh reconstructed the early response signal transduction network of human mammary cells subject to TGF-β treatment, which is composed of multiple interconnected signaling pathways. The network contains transient and sustained signal response modules connected by a bridging module. TGF-β activates these modules in a specific temporal order, and different duration of TGF-β generates different temporal profiles of downstream gene expression. That is, cells use the network as a temporal checkpoint for the signal duration and differential cellular responses. Therefore the network resembles a computer chip that uses combinatorial states of multiple units to enlarge its capacity of coding the information of signal duration.
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影响因子：
4
作者：
Behar, Marcelo;Hoffmann, Alexander
通讯作者：
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影响因子：
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通讯作者：
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影响因子：
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作者：
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