The study by Holt et al. (2009) aimed to explore the mechanisms and evolution of cell-cycle control by analyzing the position and conservation of phosphorylation sites for the cyclin-dependent kinase Cdk1 in *Saccharomyces cerevisiae*. Using specific chemical inhibition of Cdk1 and quantitative mass spectrometry, they identified 547 phosphorylation sites on 308 Cdk1 substrates in vivo. The analysis revealed that most phosphorylation sites are not conserved in evolution but tend to cluster in rapidly evolving disordered regions. This suggests that regulation of protein function by phosphorylation often depends on simple, nonspecific mechanisms that disrupt or enhance protein-protein interactions. The gain or loss of phosphorylation sites in these regions could facilitate the evolution of kinase signaling circuits. The study also found that Cdk1 substrates are enriched in cell cycle-related functional categories and are involved in processes beyond traditional cell-cycle control, such as translation, chromatin remodeling, and protein secretion. Additionally, the structural context and conservation of Cdk1-dependent phosphorylation sites were analyzed, showing that many sites are predicted to be in loops and disordered regions. The evolution of these sites was examined across 32 fungal species, revealing that while some sites exhibit strong evolutionary conservation of their precise position, others show significant conservation of consensus sites throughout the lineage. The findings highlight the flexibility in phosphorylation site positioning and the potential for combinatorial control by multiple kinases, which can adapt rapidly to developmental challenges and opportunities.The study by Holt et al. (2009) aimed to explore the mechanisms and evolution of cell-cycle control by analyzing the position and conservation of phosphorylation sites for the cyclin-dependent kinase Cdk1 in *Saccharomyces cerevisiae*. Using specific chemical inhibition of Cdk1 and quantitative mass spectrometry, they identified 547 phosphorylation sites on 308 Cdk1 substrates in vivo. The analysis revealed that most phosphorylation sites are not conserved in evolution but tend to cluster in rapidly evolving disordered regions. This suggests that regulation of protein function by phosphorylation often depends on simple, nonspecific mechanisms that disrupt or enhance protein-protein interactions. The gain or loss of phosphorylation sites in these regions could facilitate the evolution of kinase signaling circuits. The study also found that Cdk1 substrates are enriched in cell cycle-related functional categories and are involved in processes beyond traditional cell-cycle control, such as translation, chromatin remodeling, and protein secretion. Additionally, the structural context and conservation of Cdk1-dependent phosphorylation sites were analyzed, showing that many sites are predicted to be in loops and disordered regions. The evolution of these sites was examined across 32 fungal species, revealing that while some sites exhibit strong evolutionary conservation of their precise position, others show significant conservation of consensus sites throughout the lineage. The findings highlight the flexibility in phosphorylation site positioning and the potential for combinatorial control by multiple kinases, which can adapt rapidly to developmental challenges and opportunities.