Cell division cycle 25C–14-3-3 protein–protein interface (Cdc25C–14-3-3 PPI)

The Cell division cycle 25C (Cdc25C)–14-3-3 protein–protein interface is a pivotal regulatory mechanism that controls the G2/M transition of the cell cycle. This interaction is initiated when Cdc25C is phosphorylated at Serine 216 by checkpoint kinases such as Chk1 or Chk2 in response to DNA damage or during interphase (Peng et al., 1997, Science). The binding of 14-3-3 proteins to this phosphorylated site results in the cytoplasmic sequestration of Cdc25C, effectively preventing it from entering the nucleus to activate the Cyclin B1–Cdk1 complex (Dalal et al., 1999, Mol. Cell. Biol.). Because the activation of Cdk1 is essential for entry into mitosis, this interface serves as a critical gatekeeper for the G2 DNA damage checkpoint. In oncology, this interface is a target of interest because disrupting the interaction can force cancer cells with damaged DNA into premature mitosis, leading to mitotic catastrophe and cell death (Zhao et al., 2011, Expert Rev Mol Med). Small molecule inhibitors, such as FSC231, have been developed to specifically disrupt 14-3-3 protein-protein interactions, showing potential in sensitizing tumor cells to chemotherapy (Parthasarathy et al., 2015, Chem. Commun.). However, the primary challenge in targeting this interface lies in the functional diversity of 14-3-3 proteins, which interact with over 200 intracellular signaling partners, raising significant concerns regarding off-target toxicity and systemic safety (Mhawech, 2005, Cell Res.).

Other names

Cdc25C-YWHA interactionCdc25C-14-3-3 complexPhospho-Ser216-Cdc25C–14-3-3 interface

Disruption of the protein-protein interaction to prevent cytoplasmic sequestration of Cdc25C, thereby promoting Cdk1 activation and mitotic entry.