Cross-talk between CDK and PKA signaling

CDK 和 PKA 信号传导之间的串扰

• 批准号: 426546316
• 负责人: Professorin Dr. Jennifer Christina Ewald, Ph.D.
• 金额: --
• 依托单位: Abteilung Molekulare Zellbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/426546316?language=en
• 关键词: Cross; talk; between; CDK; PKA

A cell is constantly receiving signals from its environment and from intracellular processes including nutrient sensors, stress response pathways, or the cell cycle machinery. These signals need to be integrated into coordinated physiological responses. Signal integration can occur for example through cross-talk of kinase pathways or through multi-site phosphorylation of target proteins. Two of the most important globally acting kinases in baker’s yeast are the cyclin-dependent kinase, which regulates the cell cycle, and the protein kinase A, which regulates carbon metabolism, growth, and general stress responses. Evidence suggests that there is cross-talk between these two kinase pathways to coordinate metabolism, growth, and division. However, the molecular mechanisms coordinating CDK and PKA signaling remain largely unexplored.Here, I propose to mechanistically determine how two of the yeast cell’s global signaling pathways are integrated to determine cellular physiology. By combining biochemistry, mass spectrometry, genetics, yeast physiology and live cell imaging, we will investigate the cross-talk between the CDK and PKA pathways in three different ways: Firstly, we will investigate how these kinases jointly regulate our model substrate, the trehalose degrading enzyme Nth1. This enzyme can be phosphorylated on at least four PKA and one CDK sites, but the function and interdependency of these site are still unclear. Secondly, using Nth1 and other models we will elucidate if and how PKA can generate docking motifs for CDK, and thus alter the binding of CDK to its substrates. Thirdly, we will determine if and how CDK regulates the PKA pathway during the cell cycle, based on evidence from a recently generated phosphoproteome data set. Unraveling the CDK-PKA interface from these different angles will further advance our understanding of how the cell coordinates different (potentially conflicting) aims during growth and the cell cycle in different environments.

细胞不断地接收来自其环境和细胞内过程的信号，包括营养传感器，应激反应途径或细胞周期机制。这些信号需要整合到协调的生理反应中。信号整合可以例如通过激酶途径的串扰或通过靶蛋白的多位点磷酸化而发生。面包酵母中两种最重要的全局作用激酶是调节细胞周期的细胞周期蛋白依赖性激酶和调节碳代谢、生长和一般应激反应的蛋白激酶A。有证据表明，这两种激酶途径之间存在相互作用，以协调代谢、生长和分裂。然而，协调CDK和PKA信号的分子机制仍然在很大程度上unexplored. In，我建议机械地确定如何整合酵母细胞的两个全球信号通路，以确定细胞生理学。通过结合生物化学，质谱，遗传学，酵母生理学和活细胞成像，我们将研究CDK和PKA途径之间的串扰在三个不同的方式：首先，我们将研究这些激酶如何共同调节我们的模型底物，海藻糖降解酶Nth 1。该酶至少在四个PKA和一个CDK位点上被磷酸化，但这些位点的功能和相互依赖性尚不清楚。其次，我们将使用Nth 1和其他模型阐明PKA是否以及如何产生CDK的对接基序，从而改变CDK与其底物的结合。第三，我们将确定是否以及如何CDK调节PKA通路在细胞周期中，根据最近产生的磷酸化蛋白质组数据集的证据。从这些不同的角度揭示CDK-PKA界面将进一步促进我们对细胞在不同环境中生长和细胞周期期间如何协调不同（可能冲突的）目标的理解。