The Phosphatase Cdc14 Triggers Mitotic Exit by Reversal of Cdk-Dependent Phosphorylation

Visintin, Rosella; Craig, Karen L.; Hwang, Ellen S.; Prinz, Susanne; Tyers, Mike; Amon, Angelika

doi:10.1016/s1097-2765(00)80286-5

Cited by 711 publications

(794 citation statements)

References 59 publications

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“…After MEN activation, Cdc14 is released into the nucleus so that Cdc14 is able to dephosphorylate its substrates and promote the inactivation of CDK (Visintin et al, 1998). Thus, the localization of Cdc14 has been used as a molecular marker for mitotic exit.…”

Section: Pp2a Regulates Cdc14 Localizationmentioning

confidence: 99%

“…Phosphatase Cdc14, the key player in the MEN pathway, dephosphorylates Cdh1, an activator for APC (anaphase promoting complex), and subsequently activates the degradation of a Btype cyclin, Clb2. Cdc14 also enhances the stability of Sic1 protein, which acts as a CDK inhibitor (Visintin et al, 1998). During most of the cell cycle, Cdc14 is localized in the nucleolus, but its translocation out of the nucleolus in anaphase and telophase allows it to encounter its substrates, such as Cdh1 and Sic1.…”

Section: Introductionmentioning

confidence: 99%

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Phosphatase 2A Negatively Regulates Mitotic Exit inSaccharomyces cerevisiae

Wang

2006

MBoC

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In budding yeast Saccharomyces cerevisiae, Cdc5 kinase is a component of mitotic exit network (MEN), which inactivates cyclin-dependent kinase (CDK) after chromosome segregation. cdc5-1 mutants arrest at telophase at the nonpermissive temperature due to the failure of CDK inactivation. To identify more negative regulators of MEN, we carried out a genetic screen for genes that are toxic to cdc5-1 mutants when overexpressed. Genes that encode the B-regulatory subunit (Cdc55) and the three catalytic subunits (Pph21, Pph22, and Pph3) of phosphatase 2A (PP2A) were isolated. In addition to cdc5-1, overexpression of CDC55, PPH21, or PPH22 is also toxic to other temperature-sensitive mutants that display defects in mitotic exit. Consistently, deletion of CDC55 partially suppresses the temperature sensitivity of these mutants. Moreover, in the presence of spindle damage, PP2A mutants display nuclear localized Cdc14, the key player in MEN pathway, indicative of MEN activation. All the evidence suggests the negative role of PP2A in mitotic exit. Finally, our genetic and biochemical data suggest that PP2A regulates the phosphorylation of Tem1, which acts at the very top of MEN pathway. INTRODUCTIONThe key driving force for cell division in all eukaryotic cells is the conserved cyclin-dependent kinase (CDK). CDK activity fluctuates during the cell cycle, peaking at the S and M phases and dropping at the G1 phase. Although the high CDK activity is required for DNA duplication and chromosome segregation, the low CDK activity at late M and G1 phase is essential for the loading of DNA replication complexes onto replication origins (Noton and Diffley, 2000;Lengronne and Schwob, 2002). Thus, cells have developed a signal transduction pathway, named the mitotic exit network (MEN), to inactivate CDK after mitosis (Morgan, 1999). The components of the MEN pathway include protein kinases Cdc5, Cdc15, Dbf2, a GTPase Tem1, a phosphatase Cdc14, and a Dbf2 binding protein Mob1 Luca and Winey, 1998;Lee et al., 2001a). Phosphatase Cdc14, the key player in the MEN pathway, dephosphorylates Cdh1, an activator for APC (anaphase promoting complex), and subsequently activates the degradation of a Btype cyclin, Clb2. Cdc14 also enhances the stability of Sic1 protein, which acts as a CDK inhibitor (Visintin et al., 1998). During most of the cell cycle, Cdc14 is localized in the nucleolus, but its translocation out of the nucleolus in anaphase and telophase allows it to encounter its substrates, such as Cdh1 and Sic1. All the components in the MEN pathway are required for the release of Cdc14 from the nucleolus, suggesting that Cdc14 acts downstream of MEN pathway (Shou et al., 1999;Visintin et al., 1999).The regulation of MEN activity is achieved through the multilayer control of Tem1, a small GTPase that localizes at the spindle pole body (SPB) and acts on the very top of the MEN pathway. Tem1's activator, the GTPase exchange factor (GEF) Lte1, exhibits daughter-cell specific localization. Thus, SPB-localized Tem1 is activated after it encounters...

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Section: Pp2a Regulates Cdc14 Localizationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phosphatase 2A Negatively Regulates Mitotic Exit inSaccharomyces cerevisiae

Wang

2006

MBoC

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“…The released Cdc14p dephosphorylates Cdh1p and promotes APC/C-Cdh1p degradation of cyclin B and mitotic exit [Visintin et al, 1998]. When the SAC is activated, the budding yeast homologue of the fission yeast Byr4p, Bfa1p (which binds to Bub2p, the budding yeast homologue of Cdc16p), is required to prevent release of Cdc14p from the nucleolus and subsequent mitotic exit [Wang et al, 2000].…”

Section: The Spindle Checkpoint Is a Branched Pathwaymentioning

confidence: 99%

SAC‐ing mitotic errors: How the spindle assembly checkpoint (SAC) plays defense against chromosome mis‐segregation

Kadura

Sazer

2005

Cell Motil. Cytoskeleton

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“…Lorsque les cellules entrent en mitose, l'activité Cdk1 favorise des niveaux élevés de Skp2 par deux mécanismes : la phosphorylation stabilisatrice de la Ser64 de Skp2 et la phosphorylation inactivatrice de Cdh1 [7]. À la sortie de la mitose, l'APC Cdh1 est activée et la Ser64 de Skp2 est déphospho-rylée par Cdc14B, favorisant l'interaction de Skp2 avec l'APC Cdh1 et sa dégradation.…”

Section: Régulation De Skp2 Par Des Phosphorylations Réversiblesunclassified

“…Par exemple, Cdc14B pourrait participer à l'activation de l'APC Cdh1 en fin de mitose et en G1, comme cela a été démontré chez la levure S. cerevisiae [7]. En accord avec cette idée, on a récemment observé que Cdc14B prend part à l'activation de Cdh1 en réponse au stress génotoxique [8].…”

Section: La Phosphatase Cdc14b : Un Nouveau Gène Suppresseur De Tumeuunclassified