Cross-talk between CDK and PKA signaling

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、应激反应通路或细胞周期机制。这些信号需要整合到协调的生理反应中。信号整合可以发生，例如，通过信号通路的串扰或通过目标蛋白的多点磷酸化。有证据表明，这两个激酶途径之间存在串扰，以协调新陈代谢、生长和分裂。通过结合生物化学、质谱学、遗传学、酵母生理学和活细胞成像，我们将从三个不同的方面研究CDK和PKA通路之间的串扰：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Nth1。

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.