Trends in Cell Biology

Trends in Cell Biology

Volume 24, Issue 3, March 2014, Pages 145-152
Journal home page for Trends in Cell Biology

Opinion
The Mitotic Exit Network: new turns on old pathways

https://doi.org/10.1016/j.tcb.2013.09.010Get rights and content

Highlights

  • •

    Mitotic exit in budding yeast is controlled by the MEN.

  • •

    We discuss the functions of the MEN in various organisms throughout the cell cycle.

  • •

    We suggest models for how early and late MEN roles are coordinated in time and space.

  • •

    We propose a dynamic model for mitotic exit.

In budding yeast, the Mitotic Exit Network (MEN) is a signaling pathway known to drive cells out of mitosis and promote the faithful division of cells. The MEN triggers inactivation of cyclin-dependent kinase (Cdk1), the master regulator of mitosis, and the onset of cytokinesis after segregation of the daughter nuclei. The current model of the MEN suggests that MEN activity is restricted to late anaphase and coordinated with proper alignment of the spindle pole bodies (SPBs) with the division axis. However, recent evidence suggests that MEN activity may function earlier in mitosis, prompting re-evaluation of the current model. Here we attempt to integrate this recent progress into the current view of mitotic exit.

Section snippets

Mitotic exit in budding yeast

The division of the cell involves its transient but profound reorganization to ensure the coordinated distribution of cellular material between the daughter cells. On completion, mitotic structures disassemble, mitotic regulators are inactivated, and interphase is reinstated. This process, termed mitotic exit, starts with the inactivation of Cdk1, the master regulator of mitosis, and the dephosphorylation of its substrates. As a consequence, the mitotic spindle breaks down, cytokinesis occurs,

Regulation of MEN activity

A large body of work has established that the MEN signals the proper positioning of the SPBs, the yeast equivalent of centrosomes, with respect to the dividing cell. SPBs are embedded in the nuclear envelope and face the cytoplasm with their outer plaque, from which they nucleate astral microtubules (reviewed in [24]). At the SPBs, the MEN proteins interact with the centriolin-related factor Nud1 25, 26. Throughout mitosis, Tem1, Bfa1, and Bub2 localize to SPBs and most strongly to the SPB

Unexpected functions for the MEN in metaphase

Although the current models propose that MEN activation occurs exclusively during exit from mitosis, recent studies suggest that the MEN is active early in mitosis, therefore challenging our current view. Because these insights were obtained from various model organisms, the timing and mechanism of MEN activation may be conserved. We discuss these findings below.

Recent evidence in budding yeast suggests that the MEN plays an important role in spindle asymmetry, the specification of SPB

Defining which SPB carries MEN activity

Nud1 and the MEN distinguish the two SPBs from each other in early yeast mitosis 30, 31, suggesting that these proteins must be differentially active between the old and new SPBs. However, we have no direct information to tell which of the two SPBs harbors MEN activity; therefore, we consider two possible models below.

Based on several studies, the first model suggests that MEN activity rises first on the old, daughter-bound SPB in late anaphase, thereby ensuring progression toward mitotic exit (

Reconciling the roles of the MEN before and after anaphase

If the MEN is already active before anaphase, how do cells prevent premature mitotic exit until anaphase completion? Several converging mechanisms may ensure that the ultimate consequence of MEN activation, namely Cdc14 release and mitotic exit, is restrained until late anaphase.

Evidence shows that Dbf2 kinase activity is just at or below detection level by classical biochemical methods in metaphase-arrested cells, but high in late anaphase cells 7, 28. Thus, a limited amount of MEN activity

Concluding remarks

Although recent progress has yielded important insights into the mechanisms regulating mitotic exit, more questions than answers have been revealed. Little is known about where and when Tem1 and the MEN are active, but recent progress suggests that MEN activity is not restricted to late anaphase. These novel insights allow us to move toward a more integrated and complete view of the regulation of mitotic exit and discuss models and ideas that were previously not evident.

Many questions regarding

Acknowledgments

The authors thank M. Bayer, A. Farcas, J. Lengefeld, and an anonymous reviewer for critical reading and comments on the manuscript. The authors were supported by ETH Zurich, the BarrAge grant from ERC, and the Swiss National Foundation.

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    Current address: Department of Biology, Stanford University, Stanford, CA, USA

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