Research ArticleMitosis

Global assessment of its network dynamics reveals that the kinase Plk1 inhibits the phosphatase PP6 to promote Aurora A activity

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Science Signaling  15 May 2018:
Vol. 11, Issue 530, eaaq1441
DOI: 10.1126/scisignal.aaq1441

Plk1 network dynamics

Mitosis, a process of cell division, is regulated by a network of kinases, including Plk1 and Aurora A. Kettenbach et al. examined the Plk1 protein interaction network upon disruption of phosphorylation-dependent substrate targeting. From the interactions that persisted, the authors discovered that Plk1 promotes amplification of Aurora A activity during mitosis by binding to, phosphorylating, and inhibiting the phosphatase PP6. This explains the previously puzzling finding that Plk1 not only is activated by Aurora A but is also critical for Aurora A activity. The wealth of network data in this study more generally furthers our understanding of mitosis control, which may inform drug development against cancer and other diseases.


Polo-like kinase 1 (Plk1) is an essential protein kinase that promotes faithful mitotic progression in eukaryotes. The subcellular localization and substrate interactions of Plk1 are tightly controlled and require its binding to phosphorylated residues. To identify phosphorylation-dependent interactions within the Plk1 network in human mitotic cells, we performed quantitative proteomics on HeLa cells cultured with kinase inhibitors or expressing a Plk1 mutant that was deficient in phosphorylation-dependent substrate binding. We found that many interactions were abolished upon kinase inhibition; however, a subset was protected from phosphatase opposition or was unopposed, resulting in persistent interaction of the substrate with Plk1. This subset includes phosphoprotein phosphatase 6 (PP6), whose activity toward Aurora kinase A (Aurora A) was inhibited by Plk1. Our data suggest that this Plk1-PP6 interaction generates a feedback loop that coordinates and reinforces the activities of Plk1 and Aurora A during mitotic entry and is terminated by the degradation of Plk1 during mitotic exit. Thus, we have identified a mechanism for the previously puzzling observation of the Plk1-dependent regulation of Aurora A.

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