Journal
CURRENT BIOLOGY
Volume 26, Issue 24, Pages 3361-3367Publisher
CELL PRESS
DOI: 10.1016/j.cub.2016.10.022
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Funding
- BBSRC Strategic LoLa grant [BB/MM00354X/1]
- JST-PRESTO program
- JSPS-KAKENHI [24687025]
- Takeda Science Foundation
- EPSRC [EP/G03706X/1]
- Grants-in-Aid for Scientific Research [24687025] Funding Source: KAKEN
- Biotechnology and Biological Sciences Research Council [BB/M00354X/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [1364264] Funding Source: researchfish
- BBSRC [BB/M00354X/1] Funding Source: UKRI
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The abrupt and irreversible transition from interphase to M phase is essential to separate DNA replication from chromosome segregation. This transition requires the switch-like phosphorylation of hundreds of proteins by the cyclin-dependent kinase 1 (Cdk1): cyclin B (CycB) complex. Previous studies have ascribed these switch-like phosphorylations to the auto-activation of Cdk1: CycB through the removal of inhibitory phosphorylations on Cdk1-Tyr15 [1, 2]. The positive feedback in Cdk1 activation creates a bistable switch that makes mitotic commitment irreversible [2-4]. Here, we surprisingly find that Cdk1 auto-activation is dispensable for irreversible, switch-like mitotic entry due to a second mechanism, whereby Cdk1: CycB inhibits its counteracting phosphatase (PP2A: B55). We show that the PP2A: B55-inhibiting Greatwall (Gwl)-endosulfine (ENSA) pathway is both necessary and sufficient for switch-like phosphorylations of mitotic substrates. Using purified components of the Gwl-ENSA pathway in a reconstituted system, we found a sharp Cdk1 threshold for phosphorylation of a luminescent mitotic substrate. The Cdk1 threshold to induce mitotic phosphorylation is distinctly higher than the Cdk1 threshold required to maintain these phosphorylations-evidence for bistability. A combination of mathematical modeling and biochemical reconstitution show that the bistable behavior of the Gwl-ENSA pathway emerges from its mutual antagonism with PP2A: B55. Our results demonstrate that two interlinked bistable mechanisms provide a robust solution for irreversible and switch-like mitotic entry.
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