PP2A<sup>Cdc55</sup>regulates G<sub>1</sub>cyclin stability

McCourt, Paula; Gallo-Ebert, Christina; Yan, Gonghong; Jiang, Yu; Nickels, Joseph T.

doi:10.4161/cc.24231

Cited by 9 publications

(11 citation statements)

References 72 publications

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“…Deletion of CDC55 in the tgl3 tgl4 background extended this delay further by ∼60 min, indicating additive effects. This is not surprising because Cdc55 has been reported to influence the stability of the G1 cyclin Cln2, thereby exhibiting a major impact on the timing of the G1/S transition (58). The swe1 cdc55 double mutant, on the other hand, behaved like wild type, confirming that Swe1 phosphorylation/activity is responsible for controlling the cell-cycle progression at G1/S.…”

Section: Lipolysis-defective Mutants Accumulate Saturated and Unsaturmentioning

confidence: 49%

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression

Chauhan

Visram

Cristobal-Sarramian

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cell growth and division requires the precise duplication of cellular DNA content but also of membranes and organelles. Knowledge about the cell-cycle-dependent regulation of membrane and storage lipid homeostasis is only rudimentary. Previous work from our laboratory has shown that the breakdown of triacylglycerols (TGs) is regulated in a cell-cycle-dependent manner, by activation of the Tgl4 lipase by the major cyclin-dependent kinase Cdc28. The lipases Tgl3 and Tgl4 are required for efficient cell-cycle progression during the G1/S (Gap1/replication phase) transition, at the onset of bud formation, and their absence leads to a cell-cycle delay. We now show that defective lipolysis activates the Swe1 morphogenesis checkpoint kinase that halts cell-cycle progression by phosphorylation of Cdc28 at tyrosine residue 19. Saturated longchain fatty acids and phytosphingosine supplementation rescue the cell-cycle delay in the Tgl3/Tgl4 lipase-deficient strain, suggesting that Swe1 activity responds to imbalanced sphingolipid metabolism, in the absence of TG degradation. We propose a model by which TG-derived sphingolipids are required to activate the protein phosphatase 2A (PP2A Cdc55 ) to attenuate Swe1 phosphorylation and its inhibitory effect on Cdc28 at the G1/S transition of the cell cycle.T he eukaryotic cell cycle is a highly coordinated and conserved process. In addition to DNA replication, one of the major requirements for the cell to progress through the cell cycle is the precise duplication of membrane-enclosed organelles and other cellular components before cell division. Knowledge about the mechanisms regulating (membrane) lipid homeostasis during the cell cycle is scarce (1), however several levels of evidence suggest regulation of key enzymes of lipid metabolism in a cell-cycledependent manner. The PAH1-encoded phosphatidic acid (PA) phosphatase (Pah1), a key enzyme of triacylglycerol (TG) synthesis that provides the TG precursor diacylglycerol (DG), is phosphorylated and inactivated by the cyclin-dependent kinases Cdc28 and Pho85-Pho80 (2, 3). Kurat et al. showed that Tgl4, next to Tgl3, one of the two major TG lipases in yeast and the ortholog of mammalian ATGL (4, 5), is also phosphorylated by Cdc28. In contrast to Pah1, however, Tgl4 is activated by Cdc28 (6). This inverse regulation of Pah1 and Tgl4 by Cdc28-dependent phosphorylation led to the model by which the TG content oscillates during the cell cycle: On the one hand, TG synthesis serves as a buffer for excess de novo generated fatty acids (FAs), and on the other hand, in times of increased demand-that is, at the onset of bud formation and bud growth-Tgl4-catalyzed lipolysis becomes active to provide TG-derived precursors for membrane lipid synthesis (6).TG and membrane phospholipids share the same intermediates, PA and DG; PA is generated by sequential acylation of glycerol-3-phosphate, reactions that mostly take place in the endoplasmic reticulum (ER) membrane (7). The dephosphorylation of PA to DG by the PAH1-encoded PA phosphatase Pah1 is ...

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Section: Lipolysis-defective Mutants Accumulate Saturated and Unsaturmentioning

confidence: 49%

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression

Chauhan

Visram

Cristobal-Sarramian

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…After S phase is initiated, B55β levels decline which de-protects cyclin E1 from phosphorylation thus triggers its recognition and ubiquitylation by SCF Fbxw7 . In support of a possible involvement of PP2A in cyclin E1 regulation, a recent report found that in yeast PP2A Cdc55 controls the stability of G 1 cyclin Cln2 through regulation of its phosphorylation state (27). In cancers, this regulation can be aberrant and augmented B55β expression functions to antagonize cyclin E1 degradation, leading to its hyperaccumulation especially in cells that overexpress CCNE1 .…”

Section: Discussionmentioning

confidence: 98%

PP2A-B55β Antagonizes Cyclin E1 Proteolysis and Promotes Its Dysregulation in Cancer

et al. 2014

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Cyclin E1 regulates the initiation of S phase in cellular division. However, in many cancers cyclin E1 is aberrantly overexpressed and this molecular phenotype correlates with increased tumor aggressiveness and poor patient survival. The molecular cause(s) of cyclin E1 abnormalities in cancers is poorly understood. Here, we show cyclin E1 overexpression in cancer is promoted by dysregulation of the protein phosphatase PP2A-B55β. PP2A-B55β targets the N- and C-terminal phosphodegrons of cyclin E1 for dephosphorylation, thus protecting it from degradation mediated by the SCFFbxw7 ubiquitin ligase. Augmented B55β expression stabilizes cyclin E1 and promotes its overexpression in cancer-derived cell lines and breast tumors. Conversely, B55β ablation enforces the degradation of cyclin E1 and inhibits cancer cell proliferation in vitro and tumor formation in vivo. Therefore, PP2A-B55β promotes cyclin E1 overexpression by antagonizing its degradation and its inhibition could represent a therapeutic mechanism for abrogating cyclin E1 function in cancers.

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“…We hypothesized that this could be counteracted by a phosphatase that dephosphorylates cyclin E's CPDs, thus preventing Fbw7 binding. Indeed, degron dephosphorylation regulates the stability of c-Myc, an Fbw7 substrate with a CPD highly related to the cyclin E T380 region (31,32), as well as that of Cln2, the cyclin E ortholog of budding yeast (33).…”

Section: Fig 1 Cyclin E Is Dephosphorylated Specifically At S384 Bothmentioning

confidence: 99%

The PP2A-B56 Phosphatase Opposes Cyclin E Autocatalytic Degradation via Site-Specific Dephosphorylation

Davis

Swanger

Hughes

et al. 2017

Molecular and Cellular Biology

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Cyclin E, in conjunction with its catalytic partner cyclin-dependent kinase 2 (CDK2), regulates cell cycle progression as cells exit quiescence and enter S-phase. Multiple mechanisms control cyclin E periodicity during the cell cycle, including phosphorylation-dependent cyclin E ubiquitylation by the SCF Fbw7 ubiquitin ligase. Serine 384 (S384) is the critical cyclin E phosphorylation site that stimulates Fbw7 binding and cyclin E ubiquitylation and degradation. Because S384 is autophosphorylated by bound CDK2, this presents a paradox as to how cyclin E can evade autocatalytically induced degradation in order to phosphorylate its other substrates. We found that S384 phosphorylation is dynamically regulated in cells and that cyclin E is specifically dephosphorylated at S384 by the PP2A-B56 phosphatase, thereby uncoupling cyclin E degradation from cyclin E-CDK2 activity. Furthermore, the rate of S384 dephosphorylation is high in interphase but low in mitosis. This provides a mechanism whereby interphase cells can oppose autocatalytic cyclin E degradation and maintain cyclin E-CDK2 activity while also enabling cyclin E destruction in mitosis, when inappropriate cyclin E expression is genotoxic.KEYWORDS cell cycle, cyclin-dependent kinases, cyclins, serine/threonine phosphatases, ubiquitination T he mammalian cell cycle is regulated by cyclin-dependent kinases (CDKs) and their associated cyclin regulatory subunits. Cyclin E-CDK2 has essential roles as cells exit quiescence and during endoreduplication. It also regulates numerous processes during the G 1 and S-phases of the cell cycle, including S-phase entry, DNA replication, and centrosome duplication (1-5).Cells must tightly regulate cyclin E-CDK2 activity, and this is accomplished through a variety of mechanisms, including E2F-dependent cyclin E transcription, binding of CDK inhibitor proteins (p27Kip1 and p21Cip1), activating and inhibitory phosphorylation of CDK2, and cyclin E degradation by the ubiquitin-proteasome system (1, 2). Abnormal cyclin E-CDK2 activity disrupts normal G 1 /S control and causes genomic instability (6-12). Importantly, cyclin E is oncogenic in multiple contexts: the cyclin E gene is amplified in human serous ovarian and basal breast cancers, and its deregulated activity promotes tumorigenesis in mice (13-16).The F-box protein Fbw7 is the substrate recognition component of an SCF ubiquitin ligase that targets cyclin E for degradation after cyclin E becomes phosphorylated within conserved motifs called Cdc4 phosphodegrons (CPDs) (17)(18)(19)(20)(21)(22). Fbw7 substrate CPDs contain two negative charges: a phosphorylated-Thr/Ser (pT/S) in the 0 position, and a second pT/S or an acidic amino acid in the ϩ4 position (23,24). Cyclin E contains two CPDs: a high-affinity C-terminal degron that is phosphorylated at T380 and S384 and is the primary determinant of Fbw7 binding and a low-affinity N-terminal degron that contains only one phosphorylation site, at T62 (Fig. 1A). Phosphorylation-

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PP2A^Cdc55regulates G₁cyclin stability

Cited by 9 publications

References 72 publications

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression

PP2A-B55β Antagonizes Cyclin E1 Proteolysis and Promotes Its Dysregulation in Cancer

The PP2A-B56 Phosphatase Opposes Cyclin E Autocatalytic Degradation via Site-Specific Dephosphorylation

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PP2ACdc55regulates G1cyclin stability

Cited by 9 publications

References 72 publications

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression

PP2A-B55β Antagonizes Cyclin E1 Proteolysis and Promotes Its Dysregulation in Cancer

The PP2A-B56 Phosphatase Opposes Cyclin E Autocatalytic Degradation via Site-Specific Dephosphorylation

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PP2A^Cdc55regulates G₁cyclin stability