Model scenarios for switch-like mitotic transitions

To facilitate rapid accumulation of Cdk1-phosphorylated substrate proteins, the Cdk1 counter-acting phosphatase, PP2A-B55 is inhibited during M phase by stoichiometric inhibitors (ENSA and Arpp19). These inhibitors are activated when phosphorylated by Cdk1-activated Greatwall-kinase. Recent experiments show that ENSA is dephosphorylated and inactivated by the PP2A-B55 itself, and acts as an unfair substrate inhibiting PP2A-B55 activity towards other Cdk1 substrates. Mathematical modelling shows that this mutual antagonism between the phosphatase and its inhibitor is insufficient to explain the switch-like characteristics of mitotic entry and exit. We show that the feedback regulation of Greatwall activating kinase and/or inactivating phosphatase can explain the abruptness of these cell cycle transitions.