Lre1 Directly Inhibits the NDR/Lats Kinase Cbk1 at the Cell Division Site in a Phosphorylation-Dependent Manner

Lombardi, Ilde Mancini; Palani, Saravanan; Meitinger, Franz; Darieva, Zoulfia; Hofmann, Astrid; Sharrocks, Andrew D.; Pereira, Gislene

doi:10.1016/j.cub.2013.07.032

Cited by 15 publications

(16 citation statements)

References 51 publications

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“…although our data suggest that it could act upstream of or in parallel to the Ace2 transcription factor. The RAM network is under precise regulatory control, with mitotic Cdk1 activity working through multiple mechanisms to prevent premature RAM activation and cell separation (3,29). Whether the MEN acts, like the SIN, to inhibit RAM activity until cytokinesis is complete is not known.…”

Section: Discussionmentioning

confidence: 99%

Cross Talk between NDR Kinase Pathways Coordinates Cytokinesis with Cell Separation in Schizosaccharomyces pombe

2014

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NDR (nuclear Dbf-2-related) kinases constitute key regulatory nodes in signaling networks that control multiple biological processes such as growth, proliferation, mitotic exit, morphogenesis, and apoptosis. Two NDR pathways called the septation initiation network (SIN) and the morphogenesis Orb6 network (MOR) exist in the fission yeast Schizosaccharomyces pombe. The SIN promotes cytokinesis, and the MOR drives cell separation at the end of cytokinesis and polarized growth during interphase. We showed previously that cross talk exists between these two pathways, with the SIN inhibiting the MOR during cytokinesis through phosphorylation of the MOR component Nak1 by the SIN Sid2 kinase. The reason for this inhibition remained uncertain. We show here that failure to inhibit MOR signaling during cytokinesis results in cell lysis at the site of septum formation. Time-lapse analysis revealed that MOR signaling during cytokinesis causes cells to prematurely initiate septum degradation/cell separation. The cell lysis phenotype is due to premature initiation of cell separation because it can be rescued by mutations in genes required for cell separation/septum degradation. We also shed further light on how the SIN inhibits the MOR. Sid2 phosphorylation of the MOR proteins Sog2 and Nak1 is required to prevent cell lysis during cytokinesis. Together, these results show that SIN inhibition of the MOR enforces proper temporal ordering of cytokinetic events. In the fission yeast Schizosaccharomyces pombe, cytokinesis and other late mitotic events are regulated by the septation initiation network (SIN) pathway, an NDR (nuclear Dbf-2-related) kinase signaling network analogous to the hippo pathway in mammalian cells and the mitotic exit network (MEN) in the budding yeast Saccharomyces cerevisiae (1-4). SIN signaling is essential for actomyosin ring assembly and constriction as well as for septum formation. The SIN also regulates mitotic entry, spindle checkpoint inactivation, spindle elongation, telophase nuclear positioning, and inhibition of polarized growth during cytokinesis (5-9). Recent work has begun to identify targets of the SIN, which include cytoskeletal and signaling proteins (5,8,(10)(11)(12)(13). SIN signaling is under precise temporal control; the SIN is activated in the anaphase of mitosis and inactivated upon completion of actomyosin ring constriction and septum formation (14). Regulation of other cell cycle signaling networks by the SIN may be important for properly coordinating cell cycle events. For example, the SIN inhibits a second conserved NDR kinase pathway called the morphogenesis Orb6 network (MOR) (9), which is analogous to the RAM (regulation of Ace2 and morphogenesis) network in budding yeast (3). The MOR normally drives septum degradation and cell separation following actomyosin ring constriction as well as polarized growth during the interphase by promoting localization of the actin cytoskeleton to cell tips (15). In mitosis, the SIN and other proteins cause actin to reorganize at the cell divisio...

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Section: Discussionmentioning

confidence: 99%

Cross Talk between NDR Kinase Pathways Coordinates Cytokinesis with Cell Separation in Schizosaccharomyces pombe

2014

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“…We note that Lre1 has recently shown to be an inhibitor of the Cbk1 kinase that is required for nuclear entry by Ace2 (22). Lre1 is phosphorylated, and it is a substrate of the Cdk1 kinase and the Cdc14 phosphatase (22). Lre1 phosphorylation is also regulated by the Rts1 phosphatase, either directly or indirectly, as an rts1 mutation affects Lre1 phosphorylation (17).…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, Ace2 localization could be controlled by other proteins whose activity is controlled by dephosphorylation by Rts1. We note that Lre1 has recently shown to be an inhibitor of the Cbk1 kinase that is required for nuclear entry by Ace2 (22). Lre1 is phosphorylated, and it is a substrate of the Cdk1 kinase and the Cdc14 phosphatase (22).…”

Section: Discussionmentioning

confidence: 99%

The Rts1 Regulatory Subunit of PP2A Phosphatase Controls Expression of the HO Endonuclease via Localization of the Ace2 Transcription Factor

Parnell

Lucena

et al. 2014

Journal of Biological Chemistry

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Background:The yeast HO gene is tightly repressed and expressed only in mother cells. Results: Mutation of the PP2ARts1 phosphatase results in decreased HO expression due to altered localization of the Ace2 transcription factor. Conclusion: Altered Ace2 localization results in inappropriate Ash1 repressor expression in mothers. Significance: Changes in transcription factor phosphorylation can affect localization and cause inappropriate expression of a repressor.

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“…Furthermore, localization of Cdc14 at the bud neck occurs before splitting of the septin ring and actomyosin ring contraction, and it is important for the dephosphorylation of Inn1, a protein that is required for coupling primary septum formation with actomyosin ring contraction and membrane ingression [110,111]. Besides Inn1, many other Cdc14 substrates that also participate in the coordination of the different stages of the cytokinesis process, such as Aip1, Ede1, Lre1, and Vhs2, have been identified [112][113][114]. Similarly, the guanine exchange factor Bud3, which is necessary to mark the site for bud emergence during the next cell cycle and to direct Clb2 to the bud neck to regulate cytokinesis [115][116][117], is also another Cdc14 phosphatase substrate [54].…”

Section: Cytokinesis Is Regulated By Cdc14 Activity and Its Subcellulmentioning

confidence: 99%

The Multiple Roles of the Cdc14 Phosphatase in Cell Cycle Control

Manzano-López

Monje-Casas

2020

IJMS

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The Cdc14 phosphatase is a key regulator of mitosis in the budding yeast Saccharomyces cerevisiae. Cdc14 was initially described as playing an essential role in the control of cell cycle progression by promoting mitotic exit on the basis of its capacity to counteract the activity of the cyclin-dependent kinase Cdc28/Cdk1. A compiling body of evidence, however, has later demonstrated that this phosphatase plays other multiple roles in the regulation of mitosis at different cell cycle stages. Here, we summarize our current knowledge about the pivotal role of Cdc14 in cell cycle control, with a special focus in the most recently uncovered functions of the phosphatase.

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Lre1 Directly Inhibits the NDR/Lats Kinase Cbk1 at the Cell Division Site in a Phosphorylation-Dependent Manner

Abstract: We established Lre1 as a direct inhibitor of the NDR kinase Cbk1-Mob2, which is regulated in a cell-cycle-dependent manner. We propose that similar inhibitory proteins may also provide fine tuning for the activity of NDR kinases in other organisms.

Cited by 15 publications

References 51 publications

Cross Talk between NDR Kinase Pathways Coordinates Cytokinesis with Cell Separation in Schizosaccharomyces pombe

Cross Talk between NDR Kinase Pathways Coordinates Cytokinesis with Cell Separation in Schizosaccharomyces pombe

The Rts1 Regulatory Subunit of PP2A Phosphatase Controls Expression of the HO Endonuclease via Localization of the Ace2 Transcription Factor

The Multiple Roles of the Cdc14 Phosphatase in Cell Cycle Control

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