CDC25C

CDC25C is a human protein tyrosine phosphatase of the Cdc25 family and a dual-specificity phosphatase that activates cyclin-dependent kinase 1 (CDK1) to promote entry into mitosis. It primarily acts at the G2/M transition by removing inhibitory phosphates from CDK1 in complex with cyclin B, enabling CDK1/cyclin B to drive mitotic events. The catalytic activity relies on a conserved active-site motif found in dual-specificity phosphatases.

Regulation: CDC25C activity is tightly controlled by the cell cycle and DNA damage signaling. In response to DNA damage, ATM/ATR activate the checkpoint kinases Chk1/Chk2 to phosphorylate CDC25C at a key regulatory site (Ser216 in humans). This phosphorylation promotes binding to 14-3-3 proteins, leading to cytoplasmic sequestration and prevention of CDK1 activation, enforcing G2 arrest. Additional phosphorylation and proteolytic mechanisms can modulate stability and localization. In normal conditions, CDC25C is regulated by phosphorylation and protein-protein interactions that permit its accumulation in the nucleus and activation of CDK1.

Family and domains: The CDC25 family in humans includes CDC25A, CDC25B, and CDC25C. CDC25C contains the HCX5R catalytic motif typical of dual-specificity phosphatases and acts mainly during G2/M to activate CDK1.

Clinical significance: Deregulation of CDC25C has been linked to genomic instability and tumorigenesis in various cancers. Overexpression or mislocalization can contribute to unchecked mitotic entry, while loss-of-function can trigger cell cycle arrest. Because of its central role, components of the CDC25 pathway are investigated as potential cancer therapeutic targets.