PP2A Cdc55 Phosphatase Imposes Ordered Cell-Cycle Phosphorylation by Opposing Threonine Phosphorylation

Godfrey, Molly; Touati, Sandra A.; Kataria, Meghna; Jones, Andrew W.; Snijders, Ambrosius P.; Uhlmann, Frank

doi:10.1016/j.molcel.2016.12.018

Cited by 91 publications

(132 citation statements)

References 52 publications

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“… Comparison of phosphosites in common between this study and Godfrey et al (). Phosphosites were grouped by their dephosphorylation timing.…”

Section: Resultsmentioning

confidence: 51%

“…The major budding yeast mitotic exit phosphatase Cdc14 shows selectivity for phosphoserine residues (Bremmer et al , ; Eissler et al , ). In contrast, the PP2A Cdc55 phosphatase preferentially counteracts threonine phosphorylation (Godfrey et al , ). The human PP2A Cdc55 ortholog, PP2A B55 , is also thought to prefer phosphothreonine substrates during mitotic exit (Cundell et al , ; Hein et al , ).…”

Section: Resultsmentioning

confidence: 99%

“…The G1 cyclin Cln2 in budding yeast uses a hydrophobic patch to interact with substrate LLPP sequences, whereas the S phase cyclin Clb5 recognizes RxL motifs (Bhaduri & Pryciak, 2011;Kõivomägi et al, 2013;Bhaduri et al, 2015). Budding yeast PP2A Cdc55 and mammalian PP2A B55 phosphatases both show a preference for threonine over serine dephosphorylation (Cundell et al, 2016;Godfrey et al, 2017;Hein et al, 2017). In addition, PP2A B55 interacts with a polybasic patch, while the PP2A B56 isoform recognizes an LxxIxE motif (Hertz et al, 2016;Wang et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Phosphoproteome dynamics during mitotic exit in budding yeast

et al. 2018

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The cell division cycle culminates in mitosis when two daughter cells are born. As cyclin‐dependent kinase (Cdk) activity reaches its peak, the anaphase‐promoting complex/cyclosome (APC/C) is activated to trigger sister chromatid separation and mitotic spindle elongation, followed by spindle disassembly and cytokinesis. Degradation of mitotic cyclins and activation of Cdk‐counteracting phosphatases are thought to cause protein dephosphorylation to control these sequential events. Here, we use budding yeast to analyze phosphorylation dynamics of 3,456 phosphosites on 1,101 proteins with high temporal resolution as cells progress synchronously through mitosis. This reveals that successive inactivation of S and M phase Cdks and of the mitotic kinase Polo contributes to order these dephosphorylation events. Unexpectedly, we detect as many new phosphorylation events as there are dephosphorylation events. These correlate with late mitotic kinase activation and identify numerous candidate targets of these kinases. These findings revise our view of mitotic exit and portray it as a dynamic process in which a range of mitotic kinases contribute to order both protein dephosphorylation and phosphorylation.

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“… Comparison of phosphosites in common between this study and Godfrey et al (). Phosphosites were grouped by their dephosphorylation timing.…”

Section: Resultsmentioning

confidence: 51%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phosphoproteome dynamics during mitotic exit in budding yeast

et al. 2018

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“…Subsequent events could then be triggered, once PP2A:B55 itself is inactivated. A similar mechanism of different catalytic activity of PP2A:B55 towards early and late substrates has been demonstrated to control the timing of cell cycle transition in yeast and during mitotic exit . However, mitotic entry and exit are not mere mirror images of the same sequence of events but involve markedly different processes.…”

Section: Organising Mitosis: Open Questions In the Mitotic Entry Fieldmentioning

confidence: 88%

Triggering mitosis

Crncec

Hochegger

2019

FEBS Letters

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Entry into mitosis is triggered by the activation of cyclin‐dependent kinase 1 (Cdk1). This simple reaction rapidly and irreversibly sets the cell up for division. Even though the core step in triggering mitosis is so simple, the regulation of this cellular switch is highly complex, involving a large number of interconnected signalling cascades. We do have a detailed knowledge of most of the components of this network, but only a poor understanding of how they work together to create a precise and robust system that ensures that mitosis is triggered at the right time and in an orderly fashion. In this review, we will give an overview of the literature that describes the Cdk1 activation network and then address questions relating to the systems biology of this switch. How is the timing of the trigger controlled? How is mitosis insulated from interphase? What determines the sequence of events, following the initial trigger of Cdk1 activation? Which elements ensure robustness in the timing and execution of the switch? How has this system been adapted to the high levels of replication stress in cancer cells?

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“…The order of CDK substrate phosphorylation depends on rising CDK activity, coupled with variations in substrate affinities for different CDK-cyclin complexes and the opposing phosphatases [1–4]. Here we address the ordering of substrate phosphorylation by a second major cell-cycle kinase, Cdc7-Dbf4 or Dbf4-dependent kinase (DDK).…”

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confidence: 99%

Firing of Replication Origins Frees Dbf4-Cdc7 to Target Eco1 for Destruction

Seoane

Morgan

2017

Current Biology

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Summary Robust progression through the cell-division cycle depends on the precisely ordered phosphorylation of hundreds of different proteins by cyclin-dependent kinases (CDKs) and other kinases. The order of CDK substrate phosphorylation depends on rising CDK activity, coupled with variations in substrate affinities for different CDK-cyclin complexes and the opposing phosphatases [1–4]. Here we address the ordering of substrate phosphorylation by a second major cell-cycle kinase, Cdc7-Dbf4 or Dbf4-dependent kinase (DDK). The primary function of DDK is to initiate DNA replication by phosphorylating the Mcm2-7 replicative helicase [5–7]. DDK also phosphorylates the cohesin acetyltransferase, Eco1 [8]. Sequential phosphorylations of Eco1 by CDK, DDK, and Mck1 create a phosphodegron that is recognized by the ubiquitin ligase SCFCdc4. DDK, despite being activated in early S phase, does not phosphorylate Eco1 to trigger its degradation until late S phase [8]. DDK associates with docking sites on loaded Mcm double hexamers at unfired replication origins [9, 10]. We hypothesized that these docking interactions sequester limiting amounts of DDK, delaying Eco1 phosphorylation by DDK until replication is complete. Consistent with this hypothesis, we find that overproduction of DDK leads to premature Eco1 degradation. Eco1 degradation also occurs prematurely if Mcm complex loading at origins is prevented by depletion of Cdc6, and Eco1 is stabilized if loaded Mcm complexes are prevented from firing by a Cdc45 mutant. We propose that the timing of Eco1 phosphorylation, and potentially that of other DDK substrates, is determined in part by sequestration of DDK at unfired replication origins during S phase.

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PP2A Cdc55 Phosphatase Imposes Ordered Cell-Cycle Phosphorylation by Opposing Threonine Phosphorylation

Cited by 91 publications

References 52 publications

Phosphoproteome dynamics during mitotic exit in budding yeast

Phosphoproteome dynamics during mitotic exit in budding yeast

Triggering mitosis

Firing of Replication Origins Frees Dbf4-Cdc7 to Target Eco1 for Destruction

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