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Two interlinked bistable switches govern mitotic control in mammalian cells

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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 MadzvamuseAnotida Madzvamuse, Jan G Ruppert, Kumiko Samejima, Melpomeni Platani, Monica Alvarez-Fernandez, Marcos Malumbres, William C Earnshaw, Bela Novak, Helfrid HocheggerHelfrid Hochegger
Distinct 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 Biology

ISSN

0960-9822

Publisher

Elsevier

Issue

23

Volume

28

Page range

3824-3832.e6

Department affiliated with

  • Biochemistry Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-12-06

First Open Access (FOA) Date

2018-12-06

First Compliant Deposit (FCD) Date

2018-12-05

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