Editors' ChoiceMitosis

New connections: Kinases and phosphatases in control of mitosis

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Sci. Signal.  15 May 2018:
Vol. 11, Issue 530, eaau0696
DOI: 10.1126/scisignal.aau0696

Two studies in this week’s issue of Science Signaling reveal coordinated regulation of kinases and phosphatases during cell cycle progression.

Mitosis is an extensively regulated and temporally coordinated process that enables faithful division of cellular components during cell cycle progression. Dysregulated mitosis can lead to cancer and other diseases. In this issue of Science Signaling, two papers expand our knowledge of the intricate interactions between critical kinases and phosphatases that drive mitotic entry and exit. Polo-like kinase 1 (Plk1) is a serine-threonine kinase that is activated by the kinase Aurora A directly and by various other kinases indirectly. Plk1 also appears to be critical for Aurora A activity, but it has been enigmatic as to why. Kettenbach et al. analyzed the Plk1 protein interaction network during mitosis and found that some proteins continued to interact with Plk1 even when the phosphorylation-dependence of Plk1 substrate targeting was inhibited. Among those was the protein phosphatase PP6. Closer biochemical analysis revealed that Plk1 phosphorylated and inhibited PP6, which prevented its inhibitory dephosphorylation of Aurora A, thereby enabling activation of Aurora A during mitotic entry and reinforcing its activity during mitotic progression until Plk1 degradation during mitotic exit interrupted that feedback loop. It also appears that Aurora kinases target protein phosphatases. Nasa et al. found that Aurora B inhibited PP1 by targeting its regulatory subunits. PP1 functions as a holoenzyme, the formation of which is mediated by RVxF motifs in regulatory subunits, where the “x” residue is a serine or threonine. Aurora B phosphorylated these conserved RVxF motifs to prevent assembly of the PP1 holoenzyme during mitosis. The findings altogether reveal fine-tuned regulation in the yin and yang of phosphorylation and dephosphorylation during mitotic progression.

Plk1, the Auroras, and many other mitotic kinases are activated by—and in turn, regulate—their substrates, through serine-threonine phosphorylation. However, in the Archives, Caron et al. defined a mitosis-associated phosphotyrosine network that revealed that Plk1 is inhibited by phosphorylation on a tyrosine residue. Their data suggests that tyrosine phosphorylation is more prevalent during mitosis than previously appreciated, indicating that we have much more to learn about the minutiae of posttranslational regulatory events that control mitosis. These papers collectively provide a wealth of data for further exploration into cell cycle control in physiology and disease.

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