Article

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

ABSTRACT

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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    • "Our data do not exclude an important role of Bfa1 as a target for Cdc5 in the adaptation response, but rather indicate that Cdc5 acts in an additional biochemical pathway that has a considerable impact on the process of adaptation. In fact, we envision that Cdc5 could have a dual contribution to the adaptation process: the first one via its housekeeping function in activating mitotic exit (i.e., Bfa1 inhibition and Cdc15 activation;Rock and Amon, 2011), and the second one via its DNA damage-specific function mediated by the RSC pathway identified in this study. It is a formal possibility that the Bfa1-independent contribution of Cdc5 to checkpoint adaptation is mediated through a currently unknown regulatory input on the mitotic exit network, since overexpression of CDC5 can suppress the Cdc14 activation defects of some MEN mutants (Visintin et al., 2003). "
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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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    • "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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