S phase
Cdk2 is active during G1 and S phase of the cell cycle, and therefore acts as a G1-S phase checkpoint control. Prior to G1 phase, levels of Cdk4 and Cdk6 increase along with cyclin D. This allows for the partial phosphorylation of Rb, and partial activation of E2F at the beginning of G1 phase, which promotes cyclin E synthesis and increased Cdk2 activity. At the end of G1 phase, the Cdk2/Cyclin E complex reaches maximum activity and plays a significant role in the initiation of S phase. Other non-Cdk proteins also become active during the G1-S phase transition. For example, the retinoblastoma (Rb) and p27 proteins are phosphorylated by Cdk2 – cyclin A/E complexes, fully deactivating them. This allows E2F transcription factors to express genes that promote entry into S phase where DNA is replicated prior to division. Additionally, NPAT, a known substrate of the Cdk2-Cyclin E complex, functions to activate histone gene transcription when phosphorylated. This increases the synthesis of histone proteins (the major protein component of chromatin), and subsequently supports the DNA replication stage of the cell cycle. Finally, at the end of S phase, the ubiquitin proteasome degrades cyclin E.