Polo-like kinase-1 is activated by Aurora A to promote checkpoint recovery

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

ABSTRACT 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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Available from: Stephen S Taylor, Sep 28, 2015
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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.
    Zygote 07/2015; DOI:10.1017/S0967199415000222 · 1.42 Impact Factor
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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.
    Cold Spring Harbor Perspectives in Medicine 02/2015; 7(1-2). DOI:10.1101/cshperspect.a015800 · 9.47 Impact Factor
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    • "In fact, several regulators of Cyclin B1-Cdk1 have been proposed to be phosphorylated and regulated by Plk1 in vertebrates including Wee1, Myt1, Cdc25B, and Cdc25C [26] [27] [28] [29] [30] [31] [32]. The activation kinetics of Plk1 during cell cycle progression has been investigated using both a phosphospecific antibody directed against the Aurora-A phosphorylation site Thr210 located in the activation loop of Plk1 kinase domain and a Plk1 biosensor using a previously identified Plk1 dependent Myt1 phosphorylation site [30] [33]. "
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    ABSTRACT: Mitosis has been studied since the early 1880s as a key event of the cell division cycle where remarkable changes in cellular architecture take place and ultimately lead to an equal segregation of duplicated chromosomes into two daughter cells. A detailed description of the complex and highly ordered cellular events taking place is now available. Many regulators involved in key steps including entry into mitosis, nuclear envelope breakdown, microtubule (MT) spindle formation, and chromosome attachment, as well as mitotic exit and cytokinesis, have also been identified. However, understanding the precise spatio-temporal contribution of each regulator in the cell reorganization process has been technically challenging. This review will focus on a number of recent advances in our understanding of the spatial distribution of protein activities and the temporal regulation of their activation and inactivation during entry and progression through mitosis by the use of intramolecular Förster resonance energy transfer (FRET)-based biosensors.
    Biotechnology Journal 02/2014; 9(2). DOI:10.1002/biot.201300194 · 3.49 Impact Factor
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