Schaber2012 - Hog pathway in yeast

Schaber2012 - Hog pathway in yeast
The high osmolarity glycerol (HOG) pathway in the yeast Saccharomyces cerevisiae is one of the best-studied mitogen-activated protein kinase (MAPK) pathways and serves as a prototype signalling system for eukaryotes. This pathway is necessary and sufficient to adapt to high external osmolarity. A key component of this pathway is the stress-activated protein kinase (SAPK) Hog1, which is rapidly phosphorylated by the SAPK kinase Pbs2 upon hyper-osmotic shock, and which is the terminal kinase of two parallel signalling pathways, subsequently called the Sho1 branch and the Sln1 branch, respectively. Ensemble modelling (192 models) is used to study the yeast HOG pathway, a prototype for eukaryotic mitogen-activated kinase signalling systems. The best fit model (Model Nr.22: described here) provides new insights into the function of this system, some of which are then experimentally validated.

This model is described in the article:
Modelling reveals novel roles of two parallel signalling pathways and homeostatic feedbacks in yeast.

Schaber J, Baltanas R, Bush A, Klipp E, Colman-Lerner A.
Mol Syst Biol. 2012 Nov 13;8:622.
Abstract:
The high osmolarity glycerol (HOG) pathway in yeast serves as a prototype signalling system for eukaryotes. We used an unprecedented amount of data to parameterise 192 models capturing different hypotheses about molecular mechanisms underlying osmo-adaptation and selected a best approximating model. This model implied novel mechanisms regulating osmo-adaptation in yeast. The model suggested that (i) the main mechanism for osmo-adaptation is a fast and transient non-transcriptional Hog1-mediated activation of glycerol production, (ii) the transcriptional response serves to maintain an increased steady-state glycerol production with low steady-state Hog1 activity, and (iii) fast negative feedbacks of activated Hog1 on upstream signalling branches serves to stabilise adaptation response. The best approximating model also indicated that homoeostatic adaptive systems with two parallel redundant signalling branches show a more robust and faster response than single-branch systems. We corroborated this notion to a large extent by dedicated measurements of volume recovery in single cells. Our study also demonstrates that systematically testing a model ensemble against data has the potential to achieve a better and unbiased understanding of molecular mechanisms.

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Schaber等人2012年研究——酿酒酵母高渗甘油（HOG）通路

酿酒酵母（Saccharomyces cerevisiae）中的高渗甘油（HOG）通路是目前研究最为深入的丝裂原活化蛋白激酶（MAPK）通路之一，同时也是真核生物信号传导系统的经典原型。该通路是酵母适应外界高渗环境的必要且充分条件。此通路的关键组分为应激活化蛋白激酶（SAPK）Hog1：在高渗胁迫下，它会被SAPK激酶Pbs2快速磷酸化；同时它也是两条平行信号通路的末端激酶，这两条通路分别被命名为Sho1分支与Sln1分支。研究团队采用集成建模策略（共构建192个模型）解析酵母HOG通路——这一真核丝裂原活化蛋白激酶信号系统的原型。其中拟合度最优的模型（第22号模型，即本文所述模型）为该系统的功能提供了全新见解，其中部分结论已通过实验验证。

本模型对应的发表文章为：
《Modelling reveals novel roles of two parallel signalling pathways and homeostatic feedbacks in yeast》（《建模揭示酵母两条平行信号通路与稳态反馈的全新功能》）
作者：Schaber J、Baltanas R、Bush A、Klipp E、Colman-Lerner A.
发表于《分子系统生物学（Mol Syst Biol）》，2012年11月13日；8卷：622页。

**摘要**
酵母高渗甘油（HOG）通路是真核生物信号传导系统的经典原型。本研究使用前所未有的海量数据对192个模型进行参数化，这些模型涵盖了关于渗透适应分子机制的各类假说，并筛选出最优拟合模型。该模型揭示了调控酵母渗透适应的全新机制：① 渗透适应的核心机制是由Hog1介导的、快速且瞬时的非转录依赖型甘油合成激活；② 转录应答的作用是在维持甘油合成稳态升高的同时，使Hog1活性维持在较低水平；③ 活化的Hog1对上游信号分支的快速负反馈，可稳定适应应答过程。最优拟合模型同时表明，拥有两条平行冗余信号分支的稳态适应系统，相比单分支系统展现出更稳健且更快速的应答效果。研究团队通过对单细胞体积恢复过程的专属测量，在很大程度上佐证了这一结论。本研究同时证实，通过系统性地针对实验数据对模型集合进行检验，有望实现对分子机制更全面且无偏的解析。

本模型已收录于BioModels数据库（BioModels Database），其编号为MODEL1209110001。
如需引用BioModels数据库，请参考文献：《BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models》（《BioModels数据库：面向已发表定量动力学模型的增强、精选与注释资源》）。

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