Key Points
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Mitotic exit comprises all the mitotic stages after 'satisfaction' of the spindle assembly checkpoint, including chromosome segregation, cytokinesis and reassembly of interphase cell structures.
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Mitotic exit is largely driven by inactivation of mitotic kinases, as well as by activation of counteracting mitotic exit phosphatases, which leads to a net dephosphorylation of a large range of substrates.
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The key mitotic exit phosphatase in budding yeast is Cdc14, which is regulated by two regulatory networks: Cdc14 early anaphase release (FEAR) and mitotic exit network (MEN).
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Animal cell mitotic exit depends on protein phosphatases PP1 and PP2A, and the key function of Cdc14 does not seem to be conserved in species other than budding yeast.
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A regulatory network involving Greatwall kinase and its substrates, the PP2A-inhibitors α-endosulphine (ENSA) and cyclic AMP-regulated phosphoprotein 19 (ARPP19), establishes a mutual inhibition between cyclin-dependent kinase 1 (CDK1) and PP2A.
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Mitotic exit phosphatases are attractive candidate targets for the development of future cancer therapeutics.
Abstract
The mitosis-to-interphase transition involves dramatic cellular reorganization from a state that supports chromosome segregation to a state that complies with all functions of an interphase cell. This process, termed mitotic exit, depends on the removal of mitotic phosphorylations from a broad range of substrates. Mitotic exit regulation involves inactivation of mitotic kinases and activation of counteracting protein phosphatases. The key mitotic exit phosphatase in budding yeast, Cdc14, is now well understood. By contrast, in animal cells, it is now emerging that mitotic exit relies on distinct regulatory networks, including the protein phosphatases PP1 and PP2A.
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Acknowledgements
We thank A. Dick for comments on the manuscript. Research in the laboratory of D.W.G. has received funding from the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreements number 241548 (MitoSys) and number 258068 (Systems Microscopy), and from a European Young Investigator (EURYI) award of the European Science Foundation and a European Molecular Biology Organization (EMBO) Young Investigators Programme (YIP) fellowship to D.W.G. Work by C.W. was funded by a Boehringer Ingelheim Fonds fellowship.
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Glossary
- Nuclear envelope
-
Two membranes surrounding the cell nucleus, of which the outer membrane is continuous with the endoplasmic reticulum. The nuclear envelope in higher eukaryotes also contains a lamina adjacent to the inner nuclear membrane.
- Mitotic spindle
-
An assembly of centrosomes, microtubules and chromosomes that supports chromosome segregation.
- Kinetochores
-
Multiprotein structures that assemble at the centromere and mediate attachment of chromosomes to microtubules of the mitotic spindle.
- APC/C
-
(Anaphase-promoting complex, also known as the cyclosome). A large E3 ubiquitin ligase protein complex that targets mitotic cyclins and securin for 26S proteasome-mediated proteolysis. CDC20 or CDC20 homologue 1 (CDH1) are alternative APC/C co-activators that determine substrate specificity.
- E3 ubiquitin ligase
-
An enzyme that, in conjunction with an E2 ubiquitin-conjugating enzyme, covalently attaches ubiquitin to a Lys residue on target proteins.
- 26S proteasome
-
A large protein complex that degrades Lys48-linked polyubiquitylated proteins by proteolysis.
- Ubiquitin
-
A 76-amino-acid regulatory protein that can be covalently linked to target proteins by E3 ubiquitin ligases. Chains of ubiquitin linked by a Lys48 residue target proteins for 26S proteasome-mediated destruction.
- Spindle assembly checkpoint
-
A signalling network that inhibits the activity of the APC/C (anaphase-promoting complex, also known as the cyclosome) and its co-activator CDC20 in the presence of unattached or tension-less kinetochores.
- Separase
-
A protease that cleaves cohesin complexes at the metaphase-to-anaphase transition to enable chromosome segregation. In budding yeast, separase further inhibits protein phosphatase PP2A–CDC55 independently of its catalytic activity.
- Cohesin
-
A protein complex that mediates cohesion between replicated sister chromatids.
- Dual-specificity phosphatase
-
A phosphatase that removes phosphates from Ser/Thr and Tyr.
- Chromosomal passenger complex
-
A complex of Aurora B kinase and its regulatory cofactors, inner centromere protein (INCENP), borealin and survivin. It is activated on centromeres during early mitosis and is then transferred to the central spindle at anaphase onset.
- Nucleolus
-
A non-membrane-bounded nuclear structure at which ribosomal gene transcription and pre-ribosome assembly occurs.
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Wurzenberger, C., Gerlich, D. Phosphatases: providing safe passage through mitotic exit. Nat Rev Mol Cell Biol 12, 469–482 (2011). https://doi.org/10.1038/nrm3149
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DOI: https://doi.org/10.1038/nrm3149
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