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• W2552631918 abstract "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 [1Solomon M.J. Glotzer M. Lee T.H. Philippe M. Kirschner M.W. Cyclin activation of p34cdc2.Cell. 1990; 63: 1013-1024Abstract Full Text PDF PubMed Scopus (504) Google Scholar, 2Novak B. Tyson J.J. Numerical analysis of a comprehensive model of M-phase control in Xenopus oocyte extracts and intact embryos.J. Cell Sci. 1993; 106: 1153-1168Crossref PubMed Google Scholar]. The positive feedback in Cdk1 activation creates a bistable switch that makes mitotic commitment irreversible [2Novak B. Tyson J.J. Numerical analysis of a comprehensive model of M-phase control in Xenopus oocyte extracts and intact embryos.J. Cell Sci. 1993; 106: 1153-1168Crossref PubMed Google Scholar, 3Sha W. Moore J. Chen K. Lassaletta A.D. Yi C.S. Tyson J.J. Sible J.C. Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts.Proc. Natl. Acad. Sci. USA. 2003; 100: 975-980Crossref PubMed Scopus (386) Google Scholar, 4Pomerening J.R. Sontag E.D. Ferrell Jr., J.E. Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2.Nat. Cell Biol. 2003; 5: 346-351Crossref PubMed Scopus (587) Google Scholar]. 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." @default.
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• W2552631918 date "2016-12-01" @default.
• W2552631918 modified "2023-09-25" @default.
• W2552631918 title "Two Bistable Switches Govern M Phase Entry" @default.
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• W2552631918 doi "https://doi.org/10.1016/j.cub.2016.10.022" @default.
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