A link between mitotic entry and membrane growth suggests a novel model for cell size control

Anastasia, Steph D.; Nguyen, Duy Linh; Thai, Vu; Meloy, Melissa; MacDonough, Tracy; Kellogg, Douglas R.

doi:10.1083/jcb.201108108

Cited by 62 publications

(106 citation statements)

References 85 publications

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“…Of note, Mih1 activity was previously implicated in regulating cell-cycle progression in response to altered secretion, which is also required for delivery of membrane lipids to the expanding plasma membrane in the growing bud. A block in secretion in a sec6-4 temperature-sensitive mutant also triggers a Swe1-dependent checkpoint but during early mitosis (60). Thus, Swe1 may indeed function as a lipid-dependent checkpoint at multiple stages of the cell cycle; here, we show that it operates as a lipolysis-regulated checkpoint kinase at the G1/S transition of the cell cycle and that its activity is regulated by the PP2A Cdc55 phosphatase in a lipid-dependent manner.…”

Section: Lipolysis-defective Mutants Accumulate Saturated and Unsaturmentioning

confidence: 66%

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: 66%

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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“…An interesting modified version of the "actin-sensing" hypothesis is that progression through the Swe1p checkpoint merely requires an actin-dependent process, such as polarized exocytosis, rather than the checkpoint acting as an intrinsic actin sensor. An intriguing recent study by Kellogg and colleagues, 88 63 while at the same time priming Swe1p for degradation by the Cdc5p-and Cla4p-dependent mechanism just described. 60,64,65 The function of this dual regulatory effect, in which Cdc28p both activates and inhibits its own inhibitor, is still not fully understood.…”

Section: G 2 /M Checkpoint In S Pombe and Vertebratesmentioning

confidence: 92%

“…102,103 In S. cerevisiae, Protein Kinase C (Pkc1p) activates the Zds proteins. 88 It appears, therefore, that Gwl and Pkc1p are functional homologs with respect to PP2A inhibitor activation. As a third commonality, the PP2A inhibitors in each mechanism (i.e., Arpp19/Ensa or Zds) appear to be signaling nodes that integrate multiple upstream signaling pathways.…”

Section: The Other Side Of the Coin: Phosphatase Inhibition For G 2 Tmentioning

confidence: 98%

Cell cycle checkpoint regulators reach a zillion

Yasutis

Kozminski

2013

Cell Cycle

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Entry into mitosis is regulated by a checkpoint at the boundary between the G2 and M phases of the cell cycle (G2/M). In many organisms, this checkpoint surveys DNA damage and cell size and is controlled by both the activation of mitotic cyclin-dependent kinases (Cdks) and the inhibition of an opposing phosphatase, protein phosphatase 2A (PP2A). Misregulation of mitotic entry can often lead to oncogenesis or cell death. Recent research has focused on discovering the signaling pathways that feed into the core checkpoint control mechanisms dependent on Cdk and PP2A. Herein, we review the conserved mechanisms of the G2/M transition, including recently discovered upstream signaling pathways that link cell growth and DNA replication to cell cycle progression. Critical consideration of the human, frog and yeast models of mitotic entry frame unresolved and emerging questions in this field, providing a prediction of signaling molecules and pathways yet to be discovered.

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“…In agreement with this idea, Cdc55 and Zds1/Zds2 are known to regulate polarized growth and cell wall biogenesis. 35,36 Identification of the molecular targets and functions of Cdc55 in the cytoplasm requires further investigation.…”

Section: Zds1 Is Not Necessarily An Inhibitor Of Pp2a-cdc55mentioning

confidence: 99%

Comparative genetic analysis of PP2A-Cdc55 regulators in budding yeast

et al. 2014

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A link between mitotic entry and membrane growth suggests a novel model for cell size control

Abstract: The strength of a signal generated by membrane growth could indicate when sufficient cell growth has occurred for mitotic entry.

Cited by 62 publications

References 85 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

Cell cycle checkpoint regulators reach a zillion

Comparative genetic analysis of PP2A-Cdc55 regulators in budding yeast

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