Cdc15 integrates Tem1 GTPase-mediated spatial signals with Polo kinase-mediated temporal cues to activate mitotic exit

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Genes & development (Impact Factor: 10.8). 09/2011; 25(18):1943-54. DOI: 10.1101/gad.17257711
Source: PubMed


In budding yeast, a Ras-like GTPase signaling cascade known as the mitotic exit network (MEN) promotes exit from mitosis. To ensure the accurate execution of mitosis, MEN activity is coordinated with other cellular events and restricted to anaphase. The MEN GTPase Tem1 has been assumed to be the central switch in MEN regulation. We show here that during an unperturbed cell cycle, restricting MEN activity to anaphase can occur in a Tem1 GTPase-independent manner. We found that the anaphase-specific activation of the MEN in the absence of Tem1 is controlled by the Polo kinase Cdc5. We further show that both Tem1 and Cdc5 are required to recruit the MEN kinase Cdc15 to spindle pole bodies, which is both necessary and sufficient to induce MEN signaling. Thus, Cdc15 functions as a coincidence detector of two essential cell cycle oscillators: the Polo kinase Cdc5 synthesis/degradation cycle and the Tem1 G-protein cycle. The Cdc15-dependent integration of these temporal (Cdc5 and Tem1 activity) and spatial (Tem1 activity) signals ensures that exit from mitosis occurs only after proper genome partitioning.

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    • "The likely negative regulation of Cdc15 and/or Dbf2/Mob1 by mitotic CDK (Jaspersen and Morgan 2000) may be relieved by dephosphorylation of these proteins by Cdc14, after its release by the FEAR pathway prior to MEN activation (Konig et al. 2010). Tem1 appears to be the first MEN component loaded onto Nud1 at the SBP, and photobleaching analysis shows that it is initially highly dynamic in early anaphase (Cenamor et al. 1999; Bardin et al. 2000; Menssen et al. 2001; Visintin and Amon 2001; Molk et al. 2004; Rock and Amon 2011; Valerio-Santiago and Monje-Casas 2011). "
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    ABSTRACT: Productive cell proliferation involves efficient and accurate splitting of the dividing cell into two separate entities. This orderly process reflects coordination of diverse cytological events by regulatory systems that drive the cell from mitosis into G1. In the budding yeast Saccharomyces cerevisiae, separation of mother and daughter cells involves coordinated actomyosin ring contraction and septum synthesis, followed by septum destruction. These events occur in precise and rapid sequence once chromosomes are segregated and are linked with spindle organization and mitotic progress by intricate cell cycle control machinery. Additionally, critical paarts of the mother/daughter separation process are asymmetric, reflecting a form of fate specification that occurs in every cell division. This chapter describes central events of budding yeast cell separation, as well as the control pathways that integrate them and link them with the cell cycle.
    Genetics 12/2012; 192(4):1165-202. DOI:10.1534/genetics.112.145516 · 5.96 Impact Factor
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    • "During mitosis, association of MEN components with SPBs is essential for MEN activity (Rock and Amon, 2011; Valerio-Santiago and Monje-Casas, 2011). The MEN components Bub2-Bfa1, Tem1, Cdc15, and Dbf2-Mob1 localize to SPBs in a manner that depends on the spindle pole body component Nud1 (Bardin et al., 2000; Gruneberg et al., 2000; Visintin and Amon, 2001). "
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    ABSTRACT: 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.
    Molecular biology of the cell 06/2012; 23(16):3122-32. DOI:10.1091/mbc.E12-03-0235 · 4.47 Impact Factor
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    • "One factor is the activation of Tem1, the homologue of Spg1, and the other factor is the protein kinase activity of Cdc5, the homologue of Plo1. Interestingly , it was speculated that Nud1, the S. cerevisiae homologue of Cdc11, might be the direct or indirect target of Cdc5's activity in promoting Cdc15 SPB association (Rock and Amon, 2011), as was reported previously for Cdc11 (Schmidt et al., 1997; Krapp et al., 2003, 2004a). Thus, it is likely that the mechanism we propose here for Cdc11 phosphoregulation is conserved. "
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    ABSTRACT: The Schizosaccharomyces pombe septation initiation network (SIN) is an Spg1-GTPase-mediated protein kinase cascade that triggers actomyosin ring constriction, septation, and cell division. The SIN is assembled at the spindle pole body (SPB) on the scaffold proteins Cdc11 and Sid4, with Cdc11 binding directly to SIN signaling components. Proficient SIN activity requires the asymmetric distribution of its signaling components to one of the two SPBs during anaphase, and Cdc11 hyperphosphorylation correlates with proficient SIN activity. In this paper, we show that the last protein kinase in the signaling cascade, Sid2, feeds back to phosphorylate Cdc11 during mitosis. The characterization of Cdc11 phosphomutants provides evidence that Sid2-mediated Cdc11 phosphorylation promotes the association of the SIN kinase, Cdc7, with the SPB and maximum SIN signaling during anaphase. We also show that Sid2 is crucial for the establishment of SIN asymmetry, indicating a positive-feedback loop is an important element of the SIN.
    Molecular biology of the cell 03/2012; 23(9):1636-45. DOI:10.1091/mbc.E11-09-0792 · 4.47 Impact Factor
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