Faculty Opinions recommendation of Re-examining the role of Cdc14 phosphatase in reversal of Cdk phosphorylation during mitotic exit.

2017 ◽  
Author(s):  
Christopher McInerny
Keyword(s):  
Mitotic Exit ◽  
Cdk Phosphorylation

scholarly journals Computational modelling of mitotic exit in budding yeast: the role of separase and Cdc14 endocycles

2011 ◽  
Vol 8 (61) ◽  
pp. 1128-1141 ◽  
Author(s):  
P. K. Vinod ◽  
Paula Freire ◽  
Ahmed Rattani ◽  
Andrea Ciliberto ◽  
Frank Uhlmann ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Budding Yeast ◽  
Cell Cycle Control ◽  
Computational Modelling ◽  
Eukaryotic Cell ◽  
Mitotic Exit ◽  
Intuitive Reasoning ◽  
Systematic Analysis ◽  
Systems View

The operating principles of complex regulatory networks are best understood with the help of mathematical modelling rather than by intuitive reasoning. Hereby, we study the dynamics of the mitotic exit (ME) control system in budding yeast by further developing the Queralt's model. A comprehensive systems view of the network regulating ME is provided based on classical experiments in the literature. In this picture, Cdc20–APC is a critical node controlling both cyclin (Clb2 and Clb5) and phosphatase (Cdc14) branches of the regulatory network. On the basis of experimental situations ranging from single to quintuple mutants, the kinetic parameters of the network are estimated. Numerical analysis of the model quantifies the dependence of ME control on the proteolytic and non-proteolytic functions of separase. We show that the requirement of the non-proteolytic function of separase for ME depends on cyclin-dependent kinase activity. The model is also used for the systematic analysis of the recently discovered Cdc14 endocycles. The significance of Cdc14 endocycles in eukaryotic cell cycle control is discussed as well.

scholarly journals LATS1/WARTS phosphorylates MYPT1 to counteract PLK1 and regulate mammalian mitotic progression

2012 ◽  
Vol 197 (5) ◽  
pp. 625-641 ◽  
Author(s):  
Tatsuyuki Chiyoda ◽  
Naoyuki Sugiyama ◽  
Takatsune Shimizu ◽  
Hideaki Naoe ◽  
Yusuke Kobayashi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Deoxyribonucleic Acid ◽  
Mitotic Exit ◽  
Dna Damage Checkpoint ◽  
Mitotic Progression ◽  
Myosin Phosphatase ◽  
G2 Checkpoint ◽  
Mitotic Exit Network ◽  
Kinase Screening

In the mitotic exit network of budding yeast, Dbf2 kinase phosphorylates and regulates Cdc14 phosphatase. In contrast, no phosphatase substrates of LATS1/WARTS kinase, the mammalian equivalent of Dbf2, has been reported. To address this discrepancy, we performed phosphoproteomic screening using LATS1 kinase. Screening identified MYPT1 (myosin phosphatase–targeting subunit 1) as a new substrate for LATS1. LATS1 directly and preferentially phosphorylated serine 445 (S445) of MYPT1. An MYPT1 mutant (S445A) failed to dephosphorylate Thr 210 of PLK1 (pololike kinase 1), thereby activating PLK1. This suggests that LATS1 promotes MYPT1 to antagonize PLK1 activity. Consistent with this, LATS1-depleted HeLa cells or fibroblasts from LATS1 knockout mice showed increased PLK1 activity. We also found deoxyribonucleic acid (DNA) damage–induced LATS1 activation caused PLK1 suppression via the phosphorylation of MYPT1 S445. Furthermore, LATS1 knockdown cells showed reduced G2 checkpoint arrest after DNA damage. These results indicate that LATS1 phosphorylates a phosphatase as does the yeast Dbf2 and demonstrate a novel role of LATS1 in controlling PLK1 at the G2 DNA damage checkpoint.

scholarly journals Loss of Cdc20 Causes a Securin-Dependent Metaphase Arrest in Two-Cell Mouse Embryos

2007 ◽  
Vol 27 (9) ◽  
pp. 3481-3488 ◽  
Author(s):  
Min Li ◽  
J. Philippe York ◽  
Pumin Zhang
Keyword(s):  
Ubiquitin Ligase ◽  
Cyclin B1 ◽  
Mitotic Exit ◽  
Adapter Proteins ◽  
Anaphase Promoting Complex ◽  
Metaphase Arrest ◽  
Cell Stage ◽  
Gene Trapping ◽  
Protein Substrates

ABSTRACT The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase mediating targeted proteolysis through ubiquitination of protein substrates to control the progression of mitosis. The APC/C recognizes its substrates through two adapter proteins, Cdc20 and Cdh1, which contain similar C-terminal domains composed of seven WD-40 repeats believed to be involved in interacting with their substrates. During the transition from metaphase to anaphase, APC/C-Cdc20 mediates the ubiquitination of securin and cyclin B1, allowing the activation of separase and the onset of anaphase and mitotic exit. APC/C-Cdc20 and APC/C-Cdh1 have overlapping substrates. It is unclear whether they are redundant for mitosis. Using a gene-trapping approach, we have obtained mice which lack Cdc20 function. These mice show failed embryogenesis. The embryos were arrested in metaphase at the two-cell stage with high levels of cyclin B1, indicating an essential role of Cdc20 in mitosis that is not redundant with that of Cdh1. Interestingly, Cdc20 and securin double mutant embryos could not maintain the metaphase arrest, suggesting a role of securin in preventing mitotic exit.

scholarly journals A Mathematical Model of Mitotic Exit in Budding Yeast: The Role of Polo Kinase

PLoS ONE ◽  
2012 ◽  
Vol 7 (2) ◽  
pp. e30810 ◽  
Author(s):  
Baris Hancioglu ◽  
John J. Tyson
Keyword(s):  
Mathematical Model ◽  
Budding Yeast ◽  
Mitotic Exit ◽  
Polo Kinase

scholarly journals Role of Inn1 and its interactions with Hof1 and Cyk3 in promoting cleavage furrow and septum formation in S. cerevisiae

2009 ◽  
Vol 185 (6) ◽  
pp. 995-1012 ◽  
Author(s):  
Ryuichi Nishihama ◽  
Jennifer H. Schreiter ◽  
Masayuki Onishi ◽  
Elizabeth A. Vallen ◽  
Julia Hanna ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mitotic Exit ◽  
Chitin Synthase ◽  
Cleavage Furrow ◽  
Sh3 Domains ◽  
C2 Domains ◽  
Division Site ◽  
Primary Septum ◽  
N Terminus

Cytokinesis requires coordination of actomyosin ring (AMR) contraction with rearrangements of the plasma membrane and extracellular matrix. In Saccharomyces cerevisiae, new membrane, the chitin synthase Chs2 (which forms the primary septum [PS]), and the protein Inn1 are all delivered to the division site upon mitotic exit even when the AMR is absent. Inn1 is essential for PS formation but not for Chs2 localization. The Inn1 C-terminal region is necessary for localization, and distinct PXXP motifs in this region mediate functionally important interactions with SH3 domains in the cytokinesis proteins Hof1 (an F-BAR protein) and Cyk3 (whose overexpression can restore PS formation in inn1Δ cells). The Inn1 N terminus resembles C2 domains but does not appear to bind phospholipids; nonetheless, when overexpressed or fused to Hof1, it can provide Inn1 function even in the absence of the AMR. Thus, Inn1 and Cyk3 appear to cooperate in activating Chs2 for PS formation, which allows coordination of AMR contraction with ingression of the cleavage furrow.

scholarly journals The Role of Cdc55 in the Spindle Checkpoint Is through Regulation of Mitotic Exit in Saccharomyces cerevisiae

2006 ◽  
Vol 17 (2) ◽  
pp. 658-666 ◽  
Author(s):  
Christopher M. Yellman ◽  
Daniel J. Burke
Keyword(s):  
Sister Chromatid ◽  
Spindle Checkpoint ◽  
Sister Chromatid Cohesion ◽  
Mitotic Exit ◽  
Negative Regulator ◽  
Regulatory Subunit ◽  
Checkpoint Activation ◽  
Chromatid Cohesion ◽  
Phosphatase 2A

Cdc55, a B-type regulatory subunit of protein phosphatase 2A, has been implicated in mitotic spindle checkpoint activity and maintenance of sister chromatid cohesion during metaphase. The spindle checkpoint is composed of two independent pathways, one leading to inhibition of the metaphase-to-anaphase transition by checkpoint proteins, including Mad2, and the other to inhibition of mitotic exit by Bub2. We show that Cdc55 is a negative regulator of mitotic exit. A cdc55 mutant, like a bub2 mutant, prematurely releases Cdc14 phosphatase from the nucleolus during spindle checkpoint activation, and premature exit from mitosis indirectly leads to loss of sister chromatid cohesion and inviability in nocodazole. The role of Cdc55 is separable from Bub2 and inhibits release of Cdc14 through a mechanism independent of the known negative regulators of mitotic exit. Epistasis experiments indicate Cdc55 acts either downstream or independent of the mitotic exit network kinase Cdc15. Interestingly, the B-type cyclin Clb2 is partially stable during premature activation of mitotic exit in a cdc55 mutant, indicating mitotic exit is incomplete.

Proteomic Analysis of Acute Promyelocytic Leukemia Reveals That PML-RARalpha Induces Cell Cycle Progression and Mitotic Exit by Increased Expression and Decreased Ser63 Phosphorylation of OP18.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2028-2028
Author(s):  
A. PeerZada ◽  
M. Geletu ◽  
J. Pullikan ◽  
V. Reddy ◽  
W. Hiddemann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Promyelocytic Leukemia ◽  
Cell Cycle Progression ◽  
Promyelocytic Leukemia ◽  
Mitotic Exit ◽  
Cycle Progression ◽  
2D Gel ◽  
First Time ◽  
Common Cell

Abstract We applied a mass spectrometry based approach to explore the proteins differentially regulated by PML-RARalpha, a translocation characteristic of acute promyelocytic leukemia (APL). Bioinformatic pathway analysis placed the 46 identified PML-RARalpha regulated proteins into three major networks, OP18-MAPK1, HSP-STAT3 and CCT-MYC. Using this approach, we were able to generate a common cell cycle network of the proteins in these pathways. Further analysis indicated that mRNA expression of OP18, which belonged to this network, was elevated in APL patients and the increased OP18 protein expression upon PML-RARalpha induction was overcome by retinoic acid treatment. Here we also report, for the first time a novel role of PML-RARalpha in cell cycle progression and mitotic exit. RNA interference experiments revealed that siRNA against OP18 overcomes PML-RARalpha effects on cell cycle progression. In addition to increased OP18 expression by PML-RARalpha, 2D gel electrophoresis revealed an isomer of OP18, subsequently confirmed by 2D-western as ser63 phosphomer to be downregulated by PML-RARalpha. Based on these findings, point mutation experiments indicated that decreased phosphorylation of ser63 in OP18 is important for PML-RARalpha mediated cell cycle and mitotic index effects since a constitutive phosphorylated mutant (ser63/asp) of OP18 overcame the PML-RARalpha effects in U9/PR cells, NB4 and APL patients. In summary, our results demonstrate that the effect of PML-RARalpha on cell cycle progression and mitotic exit is via two mechanisms: increasing the expression of OP18 and decreasing the phosphorylation of OP18 at ser63.

scholarly journals Phosphatase 2A Negatively Regulates Mitotic Exit in Saccharomyces cerevisiae

2006 ◽  
Vol 17 (1) ◽  
pp. 80-89 ◽  
Author(s):  
Yanchang Wang ◽  
Tuen-Yung Ng
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mitotic Exit ◽  
Regulatory Subunit ◽  
Temperature Sensitive ◽  
Cyclin Dependent Kinase ◽  
Yeast Saccharomyces Cerevisiae ◽  
Catalytic Subunits ◽  
Phosphatase 2A ◽  
Negative Role

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.

scholarly journals Inhibition of Cdc42 during mitotic exit is required for cytokinesis

2013 ◽  
Vol 202 (2) ◽  
pp. 231-240 ◽  
Author(s):  
Benjamin D. Atkins ◽  
Satoshi Yoshida ◽  
Koji Saito ◽  
Chi-Fang Wu ◽  
Daniel J. Lew ◽  
...  
Keyword(s):  
Cell Cycle ◽  
General Feature ◽  
Budding Yeast ◽  
Mitotic Exit ◽  
Division Site ◽  
Polo Kinase ◽  
Cell Cycle Regulator ◽  
P21 Activated Kinase

The role of Cdc42 and its regulation during cytokinesis is not well understood. Using biochemical and imaging approaches in budding yeast, we demonstrate that Cdc42 activation peaks during the G1/S transition and during anaphase but drops during mitotic exit and cytokinesis. Cdc5/Polo kinase is an important upstream cell cycle regulator that suppresses Cdc42 activity. Failure to down-regulate Cdc42 during mitotic exit impairs the normal localization of key cytokinesis regulators—Iqg1 and Inn1—at the division site, and results in an abnormal septum. The effects of Cdc42 hyperactivation are largely mediated by the Cdc42 effector p21-activated kinase Ste20. Inhibition of Cdc42 and related Rho guanosine triphosphatases may be a general feature of cytokinesis in eukaryotes.

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