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Two interlinked bistable switches govern mitotic control in mammalian cells
journal contribution
posted on 2023-06-09, 16:09 authored by Scott Rata, Maria Fernanda Suarez Peredo Rodriguez, Stephy Joseph, Nisha Peter, Fabio Rodrigo Echegaray Iturra, Fengwei Yang, Anotida Madzvamuse, Jan G Ruppert, Kumiko Samejima, Melpomeni Platani, Monica Alvarez-Fernandez, Marcos Malumbres, William C Earnshaw, Bela Novak, Helfrid HocheggerHelfrid HocheggerDistinct protein phosphorylation levels in interphase and M phase require tight regulation of Cdk1 activity [1, 2]. A bistable switch, based on positive feedback in the Cdk1 activation loop, has been proposed to generate different thresholds for transitions between these cell-cycle states [3, 4, 5]. Recently, the activity of the major Cdk1-counteracting phosphatase, PP2A:B55, has also been found to be bistable due to Greatwall kinase-dependent regulation [6]. However, the interplay of the regulation of Cdk1 and PP2A:B55 in vivo remains unexplored. Here, we combine quantitative cell biology assays with mathematical modeling to explore the interplay of mitotic kinase activation and phosphatase inactivation in human cells. By measuring mitotic entry and exit thresholds using ATP-analog-sensitive Cdk1 mutants, we find evidence that the mitotic switch displays hysteresis and bistability, responding differentially to Cdk1 inhibition in the mitotic and interphase states. Cdk1 activation by Wee1/Cdc25 feedback loops and PP2A:B55 inactivation by Greatwall independently contributes to this hysteretic switch system. However, elimination of both Cdk1 and PP2A:B55 inactivation fully abrogates bistability, suggesting that hysteresis is an emergent property of mutual inhibition between the Cdk1 and PP2A:B55 feedback loops. Our model of the two interlinked feedback systems predicts an intermediate but hidden steady state between interphase and M phase. This could be verified experimentally by Cdk1 inhibition during mitotic entry, supporting the predictive value of our model. Furthermore, we demonstrate that dual inhibition of Wee1 and Gwl kinases causes loss of cell-cycle memory and synthetic lethality, which could be further exploited therapeutically.
Funding
EPSRC; EP/G03706X/1
New predictive mathematical and computational models in experimental sciences; G1949; ROYAL SOCIETY; WM160017
Exploiting chemical genetics to investigate the control of microtubule dynamics by mitotic kinases; G0900; CANCER RESEARCH UK; C28206/A14499
InCeM: Research Training Network on Integrated Component Cycling in Epithelial Cell Motility; G1546; EUROPEAN UNION; 642866 - InCeM
The Wellcome Trust; 107022
Mexico CONACyT scholarship; 409236
Systems-level characterization of mammalian cell cycle transitions (sLoLa Oxford lead); G1488; BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCIL; BB/MM00354X/1
Unravelling new mathematics for 3D cell migration; G1438; LEVERHULME TRUST; RPG-2014-149
EU FP7 PloidyNet ITN; 607722
History
Publication status
- Published
File Version
- Published version
Journal
Current BiologyISSN
0960-9822Publisher
ElsevierExternal DOI
Issue
23Volume
28Page range
3824-3832.e6Department affiliated with
- Biochemistry Publications
Research groups affiliated with
- Genome Damage and Stability Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-12-06First Open Access (FOA) Date
2018-12-06First Compliant Deposit (FCD) Date
2018-12-05Usage metrics
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