Cdc25 – eine Verbindung zwischen dem Zellzyklus und der Regulation des Stoffwechsels

01.11.2025 bis 31.10.2028

Cells must coordinate metabolism, growth, and the cell division cycle to survive and maintain a healthy physiology. This coordination requires cross-talk between the cell cycle machinery and metabolic regulators. We and others have observed oscillations in the activity of the metabolic regulator PKA during cell cycle progression, which could be part of such cross-talk. However, how PKA activity during the cell cycle is regulated is so far unknown.

We previously found that several upstream regulators of the PKA pathway are phosphorylated after a release from a G1 arrest. After detailed analysis of sequences and structures of these regulators, the guanine-nucleotide-exchange-factor (GEF) Cdc25 particularly caught our attention. Cdc25 has a large middle region of unknown function, which appears to be mostly intrinsically disordered and highly phosphorylated. We have shown in vitro, that these phosphorylations are at least in part from the cell cycle kinase Cdk1. In addition to phosphorylation sites, we find putative docking motifs for cyclins, the CDK adaptor protein Cks1, and the anaphase-promoting complex. We therefore hypothesize that Cdc25 could be the receiver of cell cycle-dependent signals to coordinate PKA activity with cell cycle progression. In line with this hypothesis, mutating three putative Cdk1 targets sites on Cdc25 in vivo led to a growth defect.

Here, we propose to investigate the role of the GEF Cdc25 in coordinating metabolism, growth and division using a combination of in vivo and in vitro biochemistry, genetics and live cell imaging. Specifically, we will determine the abundance and localization of Cdc25 during the cell cycle and investigate which sites contribute to this. We will then explore the effect of this regulation on downstream components of the pathway and the physiology of the cell. With this project, we will likely close an important gap in understanding the coordination of metabolism with cell cycle progression in yeast. Furthermore, we can contribute to a more general understanding of how GEFs, such as those regulating the oncogene Ras in mammals, interact with other signalling pathways.