PP2ARts1 is a master regulator of pathways that control cell size

Zapata, Jessica; Dephoure, Noah; MacDonough, Tracy; Yu, Yan; Parnell, Emily J.; Mooring, Meghan; Gygi, Steven P.; Stillman, David J.; Kellogg, Douglas R.

doi:10.1083/jcb.201309119

Cited by 67 publications

(101 citation statements)

References 82 publications

(168 reference statements)

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Section: Ptp1 Regulates Cdk1 Tyrosine Dephosphorylationmentioning

confidence: 95%

“…In addition, the temperature sensitivity of rts1D is partially suppressed by swe1D ( Figure S1A). The increase in Cdk1-Y19 phosphorylation in these mutants and their interaction with mih1D can at least be partially attributed to upregulation of Swe1 protein in both cdc55D and rts1D cells (Minshull et al 1996;Harvey et al 2011;Zapata et al 2014) and downregulation of Mih1 in cdc55D cells (Pal et al 2008), but it also may be caused by other functions of PP2A.To test whether PP2A regulates Cdk1-Y19 phosphorylation independently of its function regulating Swe1 and Mih1, we developed an in vivo phosphatase assay in which we monitor Cdk1-Y19 dephosphorylation in mitotically arrested cells that first induce high levels of Swe1 and Cdk1-Y19 phosphorylation using galactose induction of a GAL-SWE1-AID gene, then rapidly repress SWE1 transcription with glucose, and degrade the Swe1-AID protein with the addition of auxin (Figure 2). This experimental design allows us to assess the role of PP2A independently of its function regulating Swe1 and in the absence of Swe1-dependent rephosphorylation of Cdk1.…”

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confidence: 98%

“…We hypothesize that an unidentified mechanism reduces Cdk1 activity in nocodazole-arrested cells and may be used to control the increase in total Cdk1 activity as Clb2 protein rises during the arrest. Mutation of the B-regulatory subunits of PP2A, CDC55 and RTS1, also causes an increase in Cdk1-Y19 phosphorylation (Minshull et al 1996;Zapata et al 2014) ( Figure 1A). cdc55D and rts1D are also synthetically lethal or result in sickness, respectively, in combination with mih1D, and these interactions are completely suppressed by deletion of SWE1 (Pal et al 2008;Costanzo et al 2010) ( Figure 1E).…”

mentioning

confidence: 99%

“…PP2A is a heterotrimeric complex composed of a catalytic subunit, a scaffolding subunit, and one of two B-regulatory subunits, Cdc55 (homologous to B55/B) or Rts1 (homologous to B56/B9) (Healy et al 1991;Stark 1996;Shu et al 1997;Zhao et al 1997). Deletion of CDC55 or RTS1 elevates Cdk1-Y19 phosphorylation (Minshull et al 1996;Zapata et al 2014), and both mutants display synthetic interactions when combined with mih1D (Pal et al 2008;Costanzo et al 2010), suggesting that PP2A may function with Mih1. However, these synthetic interactions instead may be explained by negative regulation of Swe1 by PP2A Cdc55 and PP2A Rts1 (Harvey et al 2011).…”

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confidence: 99%

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Redundant Regulation of Cdk1 Tyrosine Dephosphorylation in Saccharomyces cerevisiae

et al. 2015

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Cdk1 activity drives both mitotic entry and the metaphase-to-anaphase transition in all eukaryotes. The kinase Wee1 and the phosphatase Cdc25 regulate the mitotic activity of Cdk1 by the reversible phosphorylation of a conserved tyrosine residue. Mutation of cdc25 in Schizosaccharomyces pombe blocks Cdk1 dephosphorylation and causes cell cycle arrest. In contrast, deletion of MIH1, the cdc25 homolog in Saccharomyces cerevisiae, is viable. Although Cdk1-Y19 phosphorylation is elevated during mitosis in mih1D cells, Cdk1 is dephosphorylated as cells progress into G 1 , suggesting that additional phosphatases regulate Cdk1 dephosphorylation. Here we show that the phosphatase Ptp1 also regulates Cdk1 dephosphorylation in vivo and can directly dephosphorylate Cdk1 in vitro. Using a novel in vivo phosphatase assay, we also show that PP2A bound to Rts1, the budding yeast B56-regulatory subunit, regulates dephosphorylation of Cdk1 independently of a function regulating Swe1, Mih1, or Ptp1, suggesting that PP2A Rts1 either directly dephosphorylates Cdk1-Y19 or regulates an unidentified phosphatase.KEYWORDS Cdc25/Mih1; Cdk1; PP2A; Wee1/Swe1; mitosis M ITOTIC onset is regulated in all eukaryotes by an increase in Cdk1 activity caused by the dephosphorylation of Cdk1 on a conserved inhibitory tyrosine (tyrosine 19 in budding yeast) (Nurse 1990). The Wee1 kinase phosphorylates and inhibits Cdk1 (Gould and Nurse 1989; Parker et al. 1992), and the Cdc25 phosphatase acts as a mitotic inducer by dephosphorylating and activating Cdk1 (Dunphy and Kumagai 1991;Gautier et al. 1991). wee1 mutants in fission yeast shorten G 2 by prematurely activating Cdk1 (Nurse 1975;Russell and Nurse 1987), whereas cdc25 mutants cannot accumulate sufficient Cdk1 activity to enter mitosis and arrest (Russell and Nurse 1986). Both Wee1 and Cdc25 are the targets of numerous cell-cycle checkpoints, all of which delay mitotic entry by activating Wee1 or inhibiting Cdc25 (Kellogg 2003). In budding yeast, Swe1 (the Wee1 homolog) and Mih1 (the Cdc25 homolog) also function prior to mitosis (Russell et al. 1989;Harvey and Kellogg 2003;Pal et al. 2008), but our recent work revealed that overexpression of Swe1 or activation of a Swe1-dependent checkpoint arrests cells in metaphase .Deletion of cdc25 in fission yeast is lethal and arrests cells in G 2 , indicating the essential role of Cdk1-Y15 dephosphorylation in fission yeast (Russell and Nurse 1986). In contrast, although deletion of MIH1 exhibits high Cdk1-Y19 phosphorylation during mitosis, these cells have only mild delays in mitotic entry and anaphase onset and initiate Cdk1-Y19 dephosphorylation at anaphase onset (Russell et al. 1989;Pal et al. 2008;. This behavior argues that at least one additional phosphatase functions redundantly with Mih1.Russell and colleagues (Millar et al. 1992) identified the fission yeast Pyp3 as a phosphatase that functions redundantly with Cdc25. Increased expression of pyp3 or the budding yeast and mammalian homologs PTP1, PTP1B and TC-PTP1, respectively, suppress...

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Section: Ptp1 Regulates Cdk1 Tyrosine Dephosphorylationmentioning

confidence: 95%

mentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Redundant Regulation of Cdk1 Tyrosine Dephosphorylation in Saccharomyces cerevisiae

et al. 2015

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“…For example, proteomewide mass spectrometry studies have found that all three of the Gin4-related kinases are strongly hyperphosphorylated on multiple sites in rts1∆ cells, and that synthesis of ceramides influences Gin4 phosphorylation (Zapata et al 2014;Lebesgue et al 2017).…”

Section: Elm1 and The Gin4-related Kinases Do Not Influence Torc2 Sigmentioning

confidence: 99%

Modulation of TORC2 Signaling by a Conserved Lkb1 Signaling Axis in Budding Yeast

et al. 2018

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Nutrient availability, growth rate and cell size are closely linked. For example, in budding yeast, the rate of cell growth is proportional to nutrient availability, cell size is proportional to growth rate, and growth rate is proportional to cell size. Thus, cells grow slowly in poor nutrients and are nearly half the size of cells growing in rich nutrients. Moreover, large cells grow faster than small cells. A signaling network that surrounds Tor kinase complex 2 (TORC2) plays an important role in enforcing these proportional relationships. Cells that lack components of the TORC2 network fail to modulate their growth rate or size in response to changes in nutrient availability. Here, we show that budding yeast homologs of the Lkb1 tumor suppressor kinase are required for normal modulation of TORC2 signaling in response to changes in carbon source. Lkb1 kinases activate Snf1/AMPK to initiate transcription of genes required for utilization of poor carbon sources. However, Lkb1 influences TORC2 signaling via a novel pathway that is independent of Snf1/AMPK. Of the three Lkb1 homologs in budding yeast, Elm1 plays the most important role in modulating TORC2. Elm1 activates a pair of related kinases called Gin4 and Hsl1. Previous work found that loss of Gin4 and Hsl1 causes cells to undergo unrestrained growth during a prolonged mitotic arrest, which suggests that they play a role in linking cell cycle progression to cell growth. We found that Gin4 and Hsl1 also control the TORC2 network. In addition, Gin4 and Hsl1 are themselves influenced by signals from the TORC2 network, consistent with previous work showing that the TORC2 network constitutes a feedback loop. Together, the data suggest a model in which the TORC2 network sets growth rate in response to carbon source, while also relaying signals via Gin4 and Hsl1 that set the critical amount of growth required for cell cycle progression. This kind of close linkage between control of cell growth and size would suggest a simple mechanistic explanation for the proportional relationship between cell size and growth rate.3

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Organelle size scaling over embryonic development

Wesley

Mishra

Levy

2020

WIREs Developmental Biology

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PP2ARts1 is a master regulator of pathways that control cell size

Abstract: PP2ARts1 controls diverse pathways that influence cell size and may link cell cycle entry to cell growth via the transcription factor Ace2.

Cited by 67 publications

References 82 publications

Redundant Regulation of Cdk1 Tyrosine Dephosphorylation in Saccharomyces cerevisiae

Redundant Regulation of Cdk1 Tyrosine Dephosphorylation in Saccharomyces cerevisiae

Modulation of TORC2 Signaling by a Conserved Lkb1 Signaling Axis in Budding Yeast

Organelle size scaling over embryonic development

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