A Quantitative Model for Ordered Cdk Substrate Dephosphorylation during Mitotic Exit

SummaryAfter sister chromatid splitting at anaphase onset, exit from mitosis comprises an ordered series of events. Dephosphorylation of numerous mitotic substrates, which were phosphorylated by cyclin-dependent kinase (Cdk), is thought to bring about mitotic exit, but how temporal ordering of mitotic exit events is achieved is poorly understood. Here, we show, using budding yeast, that dephosphorylation of Cdk substrates involved in sequential mitotic exit events occurs with ordered timing. We test different models of how ordering might be achieved by modulating Cdk and Cdk-counteracting phosphatase Cdc14 activities in vivo, as well as by kinetic analysis of Cdk substrate phosphorylation and dephosphorylation in vitro. Our results suggest that the gradual change of the phosphatase to kinase ratio over the course of mitotic exit is read out by Cdk substrates that respond by dephosphorylation at distinct thresholds. This provides an example and a mechanistic explanation for a quantitative model of cell-cycle progression.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (219 K)Download as PowerPoint slideHighlights► Cdk substrates are sequentially dephosphorylated during mitotic exit ► The Cdk/Cdc14 phosphatase ratio determines the substrate phosphorylation status ► Catalytic efficiency of Cdc14 is highest for its early dephosphorylated substrates ► The gradual change of the Cdk/Cdc14 ratio instructs sequential dephosphorylation