scholarly journals Control of the mitotic exit network during meiosis

2012 ◽  
Vol 23 (16) ◽  
pp. 3122-3132 ◽  
Author(s):  
Michelle A. Attner ◽  
Angelika Amon
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Signaling Pathway ◽  
Vegetative Growth ◽  
Spindle Pole ◽  
Mitotic Exit ◽  
Regulatory Pathways ◽  
Spindle Pole Bodies ◽  
Mitotic Exit Network ◽  
Meiosis I

The mitotic exit network (MEN) is an essential GTPase signaling pathway that triggers exit from mitosis in budding yeast. We show here that during meiosis, the MEN is dispensable for exit from meiosis I but contributes to the timely exit from meiosis II. Consistent with a role for the MEN during meiosis II, we find that the signaling pathway is active only during meiosis II. Our analysis further shows that MEN signaling is modulated during meiosis in several key ways. Whereas binding of MEN components to spindle pole bodies (SPBs) is necessary for MEN signaling during mitosis, during meiosis MEN signaling occurs off SPBs and does not require the SPB recruitment factor Nud1. Furthermore, unlike during mitosis, MEN signaling is controlled through the regulated interaction between the MEN kinase Dbf20 and its activating subunit Mob1. Our data lead to the conclusion that a pathway essential for vegetative growth is largely dispensable for the specialized meiotic divisions and provide insights into how cell cycle regulatory pathways are modulated to accommodate different modes of cell division.

scholarly journals A Novel Hyperactive Nud1 Mitotic Exit Network Scaffold Causes Spindle Position Checkpoint Bypass in Budding Yeast

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 46
Author(s):  
Michael Vannini ◽  
Victoria R. Mingione ◽  
Ashleigh Meyer ◽  
Courtney Sniffen ◽  
Jenna Whalen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Budding Yeast ◽  
Signal Transduction Pathway ◽  
Spindle Pole ◽  
Mitotic Exit ◽  
Independent Manner ◽  
Spindle Pole Bodies ◽  
Mitotic Exit Network ◽  
Cell Cycle Transition ◽  
Spindle Position

Mitotic exit is a critical cell cycle transition that requires the careful coordination of nuclear positioning and cyclin B destruction in budding yeast for the maintenance of genome integrity. The mitotic exit network (MEN) is a Ras-like signal transduction pathway that promotes this process during anaphase. A crucial step in MEN activation occurs when the Dbf2-Mob1 protein kinase complex associates with the Nud1 scaffold protein at the yeast spindle pole bodies (SPBs; centrosome equivalents) and thereby becomes activated. This requires prior priming phosphorylation of Nud1 by Cdc15 at SPBs. Cdc15 activation, in turn, requires both the Tem1 GTPase and the Polo kinase Cdc5, but how Cdc15 associates with SPBs is not well understood. We have identified a hyperactive allele of NUD1, nud1-A308T, that recruits Cdc15 to SPBs in all stages of the cell cycle in a CDC5-independent manner. This allele leads to early recruitment of Dbf2-Mob1 during metaphase and requires known Cdc15 phospho-sites on Nud1. The presence of nud1-A308T leads to loss of coupling between nuclear position and mitotic exit in cells with mispositioned spindles. Our findings highlight the importance of scaffold regulation in signaling pathways to prevent improper activation.

scholarly journals Spatial signals link exit from mitosis to spindle position

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Jill Elaine Falk ◽  
Dai Tsuchiya ◽  
Jolien Verdaasdonk ◽  
Soni Lacefield ◽  
Kerry Bloom ◽  
...  
Keyword(s):  
Spindle Pole ◽  
Mitotic Exit ◽  
Zone Model ◽  
Cytoplasmic Microtubule ◽  
Binucleate Cells ◽  
Spindle Pole Bodies ◽  
Mitotic Exit Network ◽  
Bud Neck ◽  
Competing Models ◽  
Spindle Position

In budding yeast, if the spindle becomes mispositioned, cells prevent exit from mitosis by inhibiting the mitotic exit network (MEN). The MEN is a signaling cascade that localizes to spindle pole bodies (SPBs) and activates the phosphatase Cdc14. There are two competing models that explain MEN regulation by spindle position. In the 'zone model', exit from mitosis occurs when a MEN-bearing SPB enters the bud. The 'cMT-bud neck model' posits that cytoplasmic microtubule (cMT)-bud neck interactions prevent MEN activity. Here we find that 1) eliminating cMT– bud neck interactions does not trigger exit from mitosis and 2) loss of these interactions does not precede Cdc14 activation. Furthermore, using binucleate cells, we show that exit from mitosis occurs when one SPB enters the bud despite the presence of a mispositioned spindle. We conclude that exit from mitosis is triggered by a correctly positioned spindle rather than inhibited by improper spindle position.

scholarly journals Spindle Pole Bodies Exploit the Mitotic Exit Network in Metaphase to Drive Their Age-Dependent Segregation

Cell ◽  
2012 ◽  
Vol 148 (5) ◽  
pp. 958-972 ◽  
Author(s):  
Manuel Hotz ◽  
Christian Leisner ◽  
Daici Chen ◽  
Cristina Manatschal ◽  
Thomas Wegleiter ◽  
...  
Keyword(s):  
Spindle Pole ◽  
Mitotic Exit ◽  
Spindle Pole Bodies ◽  
Mitotic Exit Network ◽  
Age Dependent

scholarly journals Downregulation of the Tem1 GTPase by Amn1 after cytokinesis involves both nuclear import and SCF-mediated degradation

2021 ◽  
Vol 134 (19) ◽  
Author(s):  
Alain Devault ◽  
Simonetta Piatti
Keyword(s):  
Cell Cycle ◽  
Daughter Cell ◽  
Spindle Pole ◽  
Mitotic Exit ◽  
Spindle Pole Bodies ◽  
Origin Licensing ◽  
Kinase Cascade ◽  
Scf Ubiquitin Ligase ◽  
Dual Mechanism ◽  
Dependent Processes

ABSTRACT At mitotic exit the cell cycle engine is reset to allow crucial processes, such as cytokinesis and replication origin licensing, to take place before a new cell cycle begins. In budding yeast, the cell cycle clock is reset by a Hippo-like kinase cascade called the mitotic exit network (MEN), whose activation is triggered at spindle pole bodies (SPBs) by the Tem1 GTPase. Yet, MEN activity must be extinguished once MEN-dependent processes have been accomplished. One factor contributing to switching off the MEN is the Amn1 protein, which binds Tem1 and inhibits it through an unknown mechanism. Here, we show that Amn1 downregulates Tem1 through a dual mode of action. On one side, it evicts Tem1 from SPBs and escorts it into the nucleus. On the other, it promotes Tem1 degradation as part of a Skp, Cullin and F-box-containing (SCF) ubiquitin ligase. Tem1 inhibition by Amn1 takes place after cytokinesis in the bud-derived daughter cell, consistent with its asymmetric appearance in the daughter cell versus the mother cell. This dual mechanism of Tem1 inhibition by Amn1 may contribute to the rapid extinguishing of MEN activity once it has fulfilled its functions.

scholarly journals Mitotic Exit Regulation through Distinct Domains within the Protein Kinase Cdc15

2003 ◽  
Vol 23 (14) ◽  
pp. 5018-5030 ◽  
Author(s):  
Allison J. Bardin ◽  
Monica G. Boselli ◽  
Angelika Amon
Keyword(s):  
Protein Kinase ◽  
Protein Phosphatase ◽  
Kinase Domain ◽  
Spindle Pole ◽  
Mitotic Exit ◽  
Spindle Pole Bodies ◽  
Mitotic Exit Network ◽  
Self Association ◽  
Premature Release

ABSTRACT The mitotic exit network (MEN), a Ras-like signaling cascade, promotes the release of the protein phosphatase Cdc14 from the nucleolus and is essential for cells to exit from mitosis in Saccharomyces cerevisiae. We have characterized the functional domains of one of the MEN components, the protein kinase Cdc15, and investigated the role of these domains in mitotic exit. We show that a region adjacent to Cdc15's kinase domain is required for self-association and for binding to spindle pole bodies and that this domain is essential for CDC15 function. Furthermore, we find that overexpression of CDC15 lacking the C-terminal 224 amino acids results in hyperactivation of MEN and premature release of Cdc14 from the nucleolus, suggesting that this domain within Cdc15 functions to inhibit MEN signaling. Our findings indicate that multiple modes of MEN regulation occur through the protein kinase Cdc15.

scholarly journals LTE1 promotes exit from mitosis by multiple mechanisms

2016 ◽  
Vol 27 (25) ◽  
pp. 3991-4001 ◽  
Author(s):  
Jill E. Falk ◽  
Ian W. Campbell ◽  
Kelsey Joyce ◽  
Jenna Whalen ◽  
Anupama Seshan ◽  
...  
Keyword(s):  
Mother Cell ◽  
Regulatory Elements ◽  
Spindle Pole ◽  
Mitotic Exit ◽  
Genome Integrity ◽  
Cell Compartment ◽  
Activating Function ◽  
Spindle Pole Bodies ◽  
Mitotic Exit Network ◽  
Spindle Position

In budding yeast, alignment of the anaphase spindle along the mother–bud axis is crucial for maintaining genome integrity. If the anaphase spindle becomes misaligned in the mother cell compartment, cells arrest in anaphase because the mitotic exit network (MEN), an essential Ras-like GTPase signaling cascade, is inhibited by the spindle position checkpoint (SPoC). Distinct localization patterns of MEN and SPoC components mediate MEN inhibition. Most components of the MEN localize to spindle pole bodies. If the spindle becomes mispositioned in the mother cell compartment, cells arrest in anaphase due to inhibition of the MEN by the mother cell–restricted SPoC kinase Kin4. Here we show that a bud-localized activating signal is necessary for full MEN activation. We identify Lte1 as this signal and show that Lte1 activates the MEN in at least two ways. It inhibits small amounts of Kin4 that are present in the bud via its central domain. An additional MEN-activating function of Lte1 is mediated by its N- and C-terminal GEF domains, which, we propose, directly activate the MEN GTPase Tem1. We conclude that control of the MEN by spindle position is exerted by both negative and positive regulatory elements that control the pathway’s GTPase activity.

scholarly journals Inactivation of Mitotic Kinase Triggers Translocation of MEN Components to Mother-Daughter Neck in Yeast

2003 ◽  
Vol 14 (11) ◽  
pp. 4734-4743 ◽  
Author(s):  
Hong Hwa Lim ◽  
Foong May Yeong ◽  
Uttam Surana
Keyword(s):  
Chromosome Segregation ◽  
Spindle Pole Body ◽  
Spindle Pole ◽  
Mitotic Exit ◽  
Mitotic Kinase ◽  
Division Site ◽  
Pole Body ◽  
Spindle Pole Bodies ◽  
Mitotic Exit Network ◽  
Mutant Cells

Chromosome segregation, mitotic exit, and cytokinesis are executed in this order during mitosis. Although a scheme coordinating sister chromatid separation and initiation of mitotic exit has been proposed, the mechanism that temporally links the onset of cytokinesis to mitotic exit is not known. Exit from mitosis is regulated by the mitotic exit network (MEN), which includes a GTPase (Tem1) and various kinases (Cdc15, Cdc5, Dbf2, and Dbf20). Here, we show that Dbf2 and Dbf20 functions are necessary for the execution of cytokinesis. Relocalization of these proteins from spindle pole bodies to mother daughter neck seems to be necessary for this role because cdc15-2 mutant cells, though capable of exiting mitosis at semipermissive temperature, are unable to localize Dbf2 (and Dbf20) to the “neck” and fail to undergo cytokinesis. These cells can assemble and constrict the actomyosin ring normally but are incapable of forming a septum, suggesting that MEN components are critical for the initiation of septum formation. Interestingly, the spindle pole body to neck translocation of Dbf2 and Dbf20 is triggered by the inactivation of mitotic kinase. The requirement of kinase inactivation for translocation of MEN components to the division site thus provides a mechanism that renders mitotic exit a prerequisite for cytokinesis.

scholarly journals Regulation of the Mitotic Exit Protein Kinases Cdc15 and Dbf2

2001 ◽  
Vol 12 (10) ◽  
pp. 2961-2974 ◽  
Author(s):  
Rosella Visintin ◽  
Angelika Amon
Keyword(s):  
Cell Cycle ◽  
Protein Kinases ◽  
Protein Complex ◽  
Protein Phosphatase ◽  
Kinase Activity ◽  
Spindle Pole ◽  
Mitotic Exit ◽  
Gtpase Activating Protein ◽  
Gtp Binding ◽  
Spindle Pole Bodies

In budding yeast, the release of the protein phosphatase Cdc14 from its inhibitor Cfi1/Net1 in the nucleolus during anaphase triggers the inactivation of Clb CDKs that leads to exit from mitosis. The mitotic exit pathway controls the association between Cdc14 and Cfi1/Net1. It is comprised of the RAS-like GTP binding protein Tem1, the exchange factor Lte1, the GTPase activating protein complex Bub2-Bfa1/Byr4, and several protein kinases including Cdc15 and Dbf2. Here we investigate the regulation of the protein kinases Dbf2 and Cdc15. We find that Cdc15 is recruited to both spindle pole bodies (SPBs) during anaphase. This recruitment depends on TEM1 but notDBF2 or CDC14 and is inhibited byBUB2. Dbf2 also localizes to SPBs during anaphase, which coincides with activation of Dbf2 kinase activity. Both events depend on the mitotic exit pathway components TEM1 andCDC15. In cells lacking BUB2, Dbf2 localized to SPBs in cell cycle stages other than anaphase and telophase and Dbf2 kinase was prematurely active during metaphase. Our results suggest an order of function of mitotic exit pathway components with respect to SPB localization of Cdc15 and Dbf2 and activation of Dbf2 kinase. BUB2 negatively regulates all 3 events. Loading of Cdc15 on SPBs depends on TEM1, whereas loading of Dbf2 on SPBs and activation of Dbf2 kinase depend onTEM1 and CDC15.

scholarly journals Cross-compartment signal propagation in the mitotic exit network

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Xiaoxue Zhou ◽  
Wenxue Li ◽  
Yansheng Liu ◽  
Angelika Amon
Keyword(s):  
Signal Propagation ◽  
Spindle Pole ◽  
Mitotic Exit ◽  
Signaling Cascades ◽  
Effector Protein ◽  
Signal Integration ◽  
Temporal Cues ◽  
Spindle Pole Bodies ◽  
Cytoplasmic Face ◽  
Mitotic Exit Network

In budding yeast, the mitotic exit network (MEN), a GTPase signaling cascade, integrates spatial and temporal cues to promote exit from mitosis. This signal integration requires transmission of a signal generated on the cytoplasmic face of spindle pole bodies (SPBs; yeast equivalent of centrosomes) to the nucleolus, where the MEN effector protein Cdc14 resides. Here, we show that the MEN activating signal at SPBs is relayed to Cdc14 in the nucleolus through the dynamic localization of its terminal kinase complex Dbf2-Mob1. Cdc15, the protein kinase that activates Dbf2-Mob1 at SPBs, also regulates its nuclear access. Once in the nucleus, priming phosphorylation of Cfi1/Net1, the nucleolar anchor of Cdc14, by the Polo-like kinase Cdc5 targets Dbf2-Mob1 to the nucleolus. Nucleolar Dbf2-Mob1 then phosphorylates Cfi1/Net1 and Cdc14, activating Cdc14. The kinase-primed transmission of the MEN signal from the cytoplasm to the nucleolus exemplifies how signaling cascades can bridge distant inputs and responses.

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