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Phosphatase specificity influences the phosphorylation timing of CDK substrates during the cell cycle

ABSTRACT: Cell cycle events are ordered by cyclin-dependent kinases (CDKs), which phosphorylate hundreds of substrates. Multiple phosphatases oppose these CDK substrates, yet their collective role in regulating phosphorylation timing in vivo remains unclear. Here, we show that four phosphatases (PP2A-B55, PP2A-B56, CDC14, and PP1) each target distinct subsets of CDK substrate sites in vivo in fission yeast, influencing when phosphorylation occurs during G2 and mitosis. On average, sites dephosphorylated by CDC14 and PP2A-B56 are phosphorylated earlier during G2, followed by sites dephosphorylated by PP1 and PP2A-B55. This suggests that these phosphatases set different phosphorylation thresholds at the G2/M transition. Consistent with this, depleting PP2A-B55 or CDC14 accelerates mitotic onset, likely by advancing phosphorylation of their respective CDK substrates, suggesting these phosphorylation thresholds are important for regulating mitotic onset. Our findings establish in vivo phosphatase substrate specificity as a key factor regulating the timing of CDK substrate phosphorylation throughout the cell cycle.

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ORGANISM(S): Schizosaccharomyces Pombe 927

SUBMITTER: Theresa Zeisner

LAB HEAD: Paul Nurse

PROVIDER: PXD060298 | Pride | 2025-10-05

REPOSITORIES: Pride

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Phosphatase specificity influences phosphorylation timing of CDK substrates during the cell cycle.

Zeisner Theresa U TU Auchynnikava Tania T Roberts Emma L EL Nurse Paul P

Nature communications 20251124 1

Cell cycle events are ordered by cyclin-dependent kinases (CDKs), which phosphorylate hundreds of substrates. Multiple phosphatases oppose these CDK substrates, yet their collective role in regulating phosphorylation timing in vivo remains unclear. Here, we show that four phosphatases (PP2A-B55, PP2A-B56, CDC14, and PP1) each target distinct subsets of CDK substrate sites in vivo in fission yeast, influencing when phosphorylation occurs during G2 and mitosis. On average, sites dephosphorylated b ...[more]

PMID: 41285957

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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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