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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: 42.35). 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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    • "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 · 7.56 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 · 3.71 Impact Factor
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    • "CDK1–CYCB, AURKA, and PLK1 form a positive feedback circuit that leads ultimately to maximal activation of each kinase (Lens et al. 2010). This circuit activates PLK1 through AURKA phosphorylation of T210 on PLK1 and the localization of PLK1 through its Polo box domain to CDK-phosphorylated S/TP sites (Elia et al. 2003; Macurek et al. 2008). Therefore, inhibition of CDK1, AURKA, or PLK1 should each limit the activation of PLK1. "
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    ABSTRACT: The ATR-CHK1 axis stabilizes stalled replication forks and prevents their collapse into DNA double-strand breaks (DSBs). Here, we show that fork collapse in Atr-deleted cells is mediated through the combined effects the sumo targeted E3-ubiquitin ligase RNF4 and activation of the AURKA-PLK1 pathway. As indicated previously, Atr-deleted cells exhibited a decreased ability to restart DNA replication following fork stalling in comparison with control cells. However, suppression of RNF4, AURKA, or PLK1 returned the reinitiation of replication in Atr-deleted cells to near wild-type levels. In RNF4-depleted cells, this rescue directly correlated with the persistence of sumoylation of chromatin-bound factors. Notably, RNF4 repression substantially suppressed the accumulation of DSBs in ATR-deficient cells, and this decrease in breaks was enhanced by concomitant inhibition of PLK1. DSBs resulting from ATR inhibition were also observed to be dependent on the endonuclease scaffold protein SLX4, suggesting that RNF4 and PLK1 either help activate the SLX4 complex or make DNA replication fork structures accessible for subsequent SLX4-dependent cleavage. Thus, replication fork collapse following ATR inhibition is a multistep process that disrupts replisome function and permits cleavage of the replication fork.
    Genes & development 10/2013; 27(20):2259-73. DOI:10.1101/gad.223180.113 · 12.64 Impact Factor
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