Dataset Information

PP21Cdc55 phosphatase imposes phosphothreonine-specific ordering of cell cycle phosphorylation

ABSTRACT: In the quantitative model for cell cycle control, progression from G1 through S phase and into mitosis is ordered by thresholds of increasing cyclin-dependent kinase (Cdk) activity. How such thresholds are read out by substrates, that respond with the correct phosphorylation timing, if not known. In budding yeast, Cdk phosphorylates its many substrates with widely varying efficiencies, but there is no obvious correlation between phosphorylation efficiency and timing. Instead, we explore here whether Cdk-counteracting phosphatases impose Cdk thresholds. We find that the abundant PP2ACdc55 phosphatase counteracts Cdk phosphorylation in interphase and delays phosphorylation of late Cdk substrates, an effect that is independent of its known impact on the Cdk tyrosine phosphorylation status. Strikingly, PP2ACdc55 specifically counteracts phosphorylation of threonine residues. Consequently, we find that threonine-directed phosphorylation occurs late in the cell cycle, compared to serine phosphorylation. Late phosphorylation of Ndd1, a model substrate, depends on threonine identity. Our results support a model in which phosphatases contribute to ordering cell cycle progression by directly counteracting Cdk phosphorylation and unveil a principle of cell cycle control based on the phosphoacceptor amino acid.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

SUBMITTER: Andrew Jones

LAB HEAD: Ambrosius Snijders

PROVIDER: PXD004461 | Pride | 2017-01-23

REPOSITORIES: Pride

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PP2A<sup>Cdc55</sup> Phosphatase Imposes Ordered Cell-Cycle Phosphorylation by Opposing Threonine Phosphorylation.

Godfrey Molly M Touati Sandra A SA Kataria Meghna M Jones Andrew A Snijders Ambrosius P AP Uhlmann Frank F

Molecular cell 20170126 3

In the quantitative model of cell-cycle control, progression from G1 through S phase and into mitosis is ordered by thresholds of increasing cyclin-dependent kinase (Cdk) activity. How such thresholds are read out by substrates that respond with the correct phosphorylation timing is not known. Here, using the budding yeast model, we show that the abundant PP2A<sup>Cdc55</sup> phosphatase counteracts Cdk phosphorylation during interphase and delays phosphorylation of late Cdk substrates. PP2A<sup ...[more]

PMID: 28132839

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Project description:This model is from the article: Downregulation of PP2A(Cdc55) phosphatase by separase initiates mitotic exit in budding yeast. Queralt E, Lehane C, Novak B, Uhlmann F. Cell. 2006 May 19;125(4):719-32. 16713564 , Abstract: After anaphase, the high mitotic cyclin-dependent kinase (Cdk) activity is downregulated to promote exit from mitosis. To this end, in the budding yeast S. cerevisiae, the Cdk counteracting phosphatase Cdc14 is activated. In metaphase, Cdc14 is kept inactive in the nucleolus by its inhibitor Net1. During anaphase, Cdk- and Polo-dependent phosphorylation of Net1 is thought to release active Cdc14. How Net1 is phosphorylated specifically in anaphase, when mitotic kinase activity starts to decline, has remained unexplained. Here, we show that PP2A(Cdc55) phosphatase keeps Net1 underphosphorylated in metaphase. The sister chromatid-separating protease separase, activated at anaphase onset, interacts with and downregulates PP2A(Cdc55), thereby facilitating Cdk-dependent Net1 phosphorylation. PP2A(Cdc55) downregulation also promotes phosphorylation of Bfa1, contributing to activation of the "mitotic exit network" that sustains Cdc14 as Cdk activity declines. These findings allow us to present a new quantitative model for mitotic exit in budding yeast. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2012 The BioModels.net Team. For more information see the terms of use . To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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