Macurek, L. et al. Polo-like kinase-1 is activated by Aurora A to promote checkpoint recovery. Nature 455, 119-123.References 48-50 establish the role of bora for the activation of PLK1 by Aurora A

Department of Medical Oncology, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands.
Nature (Impact Factor: 41.46). 08/2008; 455(7209):119-23. DOI: 10.1038/nature07185
Source: PubMed


Polo-like kinase-1 (PLK1) is an essential mitotic kinase regulating multiple aspects of the cell division process. Activation of PLK1 requires phosphorylation of a conserved threonine residue (Thr 210) in the T-loop of the PLK1 kinase domain, but the kinase responsible for this has not yet been affirmatively identified. Here we show that in human cells PLK1 activation occurs several hours before entry into mitosis, and requires aurora A (AURKA, also known as STK6)-dependent phosphorylation of Thr 210. We find that aurora A can directly phosphorylate PLK1 on Thr 210, and that activity of aurora A towards PLK1 is greatly enhanced by Bora (also known as C13orf34 and FLJ22624), a known cofactor for aurora A (ref. 7). We show that Bora/aurora-A-dependent phosphorylation is a prerequisite for PLK1 to promote mitotic entry after a checkpoint-dependent arrest. Importantly, expression of a PLK1-T210D phospho-mimicking mutant partially overcomes the requirement for aurora A in checkpoint recovery. Taken together, these data demonstrate that the initial activation of PLK1 is a primary function of aurora A.

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    • "Initially, AUKRA is self-activated and, in complex with its cofactor Bora, is responsible for the initial activation of PLK1 before mitotic entry (Macurek et al., 2008; Seki et al., 2008) and recruitment of ␥ -tubulin (Hannak et al., 2011) and the CDK1–cyclin B complex (Hirota et al., 2003) to centrosomes. Immediately before mitotic entry, activated PLK1 phosphorylates Wee1 and thus activation of CDK1–cyclin B is induced. "
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    ABSTRACT: Aurora-A kinase (AURKA), a member of the serine/threonine protein kinase family, is involved in multiple steps of mitotic progression. It regulates centrosome maturation, mitotic spindle formation, and cytokinesis. While studied extensively in somatic cells, little information is known about AURKA in the early cleavage mouse embryo with respect to acentrosomal spindle assembly. In vitro experiments in which AURKA was inactivated with specific inhibitor MLN8237 during the early stages of embryogenesis documented gradual arrest in the cleavage ability of the mouse embryo. In the AURKA-inhibited 1-cell embryos, spindle formation and anaphase onset were delayed and chromosome segregation was defective. AURKA inhibition increased apoptosis during early embryonic development. In conclusion these data suggest that AURKA is essential for the correct chromosome segregation in the first mitosis as a prerequisite for normal later development after first cleavage.
    Full-text · Article · Jul 2015 · Zygote
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    • "Cite this article as Cold Spring Harb Perspect Biol 2015;7:a015800 ery from DNA damage (Macurek et al. 2008; Seki et al. 2008). A firmer link to centrosomal activities sits at the heart of the promotion of mitotic commitment by Aurora A in C. elegans (Hachet et al. 2007), the acceleration of mitotic commitment in Xenopus egg extracts following the addition of centrosomes (Perez-Mongiovi et al. 2000), and in humans on removal of the centrosomal component MCPH1 (Gruber et al. 2011). "
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    ABSTRACT: The centrosome was discovered in the late 19th century when mitosis was first described. Long recognized as a key organelle of the spindle pole, its core component, the centriole, was realized more than 50 or so years later also to comprise the basal body of the cilium. Here, we chart the more recent acquisition of a molecular understanding of centrosome structure and function. The strategies for gaining such knowledge were quickly developed in the yeasts to decipher the structure and function of their distinctive spindle pole bodies. Only within the past decade have studies with model eukaryotes and cultured cells brought a similar degree of sophistication to our understanding of the centrosome duplication cycle and the multiple roles of this organelle and its component parts in cell division and signaling. Now as we begin to understand these functions in the context of development, the way is being opened up for studies of the roles of centrosomes in human disease. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Full-text · Article · Feb 2015 · Cold Spring Harbor Perspectives in Medicine
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    • "Like several kinases, Plks are activated by phosphorylation in their T-loop (Qian et al., 1999; Archambault and Carmena, 2012). In humans, this phosphorylation of Plk1 occurs at Thr210 and is mediated by Aurora A kinase, with its cofactor Bora in G2 (Jang et al., 2002b; Macůrek et al., 2008; Seki et al., 2008b). Although Bora is degraded in mitosis, persisting low levels of Aurora A–Bora maintain Plk1 activity until anaphase (Chan et al., 2008; Seki et al., 2008a; Bruinsma et al., 2014). "
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    ABSTRACT: Drosophila melanogaster Polo and its human orthologue Polo-like kinase 1 fulfill essential roles during cell division. Members of the Polo-like kinase (Plk) family contain an N-terminal kinase domain (KD) and a C-terminal Polo-Box domain (PBD), which mediates protein interactions. How Plks are regulated in cytokinesis is poorly understood. Here we show that phosphorylation of Polo by Aurora B is required for cytokinesis. This phosphorylation in the activation loop of the KD promotes the dissociation of Polo from the PBD-bound microtubule-associated protein Map205, which acts as an allosteric inhibitor of Polo kinase activity. This mechanism allows the release of active Polo from microtubules of the central spindle and its recruitment to the site of cytokinesis. Failure in Polo phosphorylation results in both early and late cytokinesis defects. Importantly, the antagonistic regulation of Polo by Aurora B and Map205 in cytokinesis reveals that interdomain allosteric mechanisms can play important roles in controlling the cellular functions of Plks.
    Preview · Article · Oct 2014 · The Journal of Cell Biology
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