title: Protein phosphatase 2A controls the order and dynamics of cell-cycle transitions.
abstract: Bistability of the Cdk1-Wee1-Cdc25 mitotic control network underlies the switch-like transitions between interphase and mitosis. Here, we show by mathematical modeling and experiments in Xenopus egg extracts that protein phosphatase 2A (PP2A), which can dephosphorylate Cdk1 substrates, is essential for this bistability. PP2A inhibition in early interphase abolishes the switch-like response of the system to Cdk1 activity, promoting mitotic onset even with very low levels of Cyclin, Cdk1, and Cdc25, while simultaneously inhibiting DNA replication. Furthermore, even if replication has already initiated, it cannot continue in mitosis. Exclusivity of S and M phases does not depend on bistability only, since partial PP2A inhibition prevents replication without inducing mitotic onset. In these conditions, interphase-level mitotic kinases inhibit Cyclin E-Cdk2 chromatin loading, blocking initiation complex formation. Therefore, by counteracting both Cdk1 activation and activity of mitotic kinases, PP2A ensures robust separation of S phase and mitosis and dynamic transitions between the two states.
authors: Institute of Molecular Genetics, CNRS, UMR5535, University of Montpellier I and II, 34293 Montpellier, France.
authors: Liliana
authors: L
authors: Krasinska
authors: Maria Rosa
authors: MR
authors: Domingo-Sananes
authors: Orsolya
authors: O
authors: Kapuy
authors: Nikolaos
authors: N
authors: Parisis
authors: Bethany
authors: B
authors: Harker
authors: Gregory
authors: G
authors: Moorhead
authors: Michel
authors: M
authors: Rossignol
authors: Béla
authors: B
authors: Novák
authors: Daniel
authors: D
authors: Fisher
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D003198:Computer Simulation; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004261:DNA Replication; D004791:Enzyme Inhibitors / Q000494:pharmacology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008954:Models, Biological; D009716:Numerical Analysis, Computer-Assisted; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D013997:Time Factors; D014981:Xenopus; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D019927:Cyclin E; D004791:Enzyme Inhibitors; D029867:Xenopus Proteins; C530005:WEE1 protein, Xenopus; D011505:Protein-Tyrosine Kinases; D016203:CDC2 Protein Kinase; C495891:Cdk2 protein, Xenopus; D051357:Cyclin-Dependent Kinase 2; D054648:Protein Phosphatase 2; D020687:cdc25 Phosphatases