Plx1 is the 3F3/2 kinase responsible for targeting spindle checkpoint proteins to kinetochores

Wong, Oi Kwan; Fang, Guowei

doi:10.1083/jcb.200502163

Cited by 56 publications

(96 citation statements)

References 46 publications

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“…Proteins such as INCENP (51), PBIP1 (18), and BUB1 (17) are postulated to be PBD-dependent binding partners and to be responsible for the localization of Plk1 to kinetochores, but the functional relationship between these proteins remains to be elucidated. The localization of a checkpoint protein, BubR1, to the kinetochore is dependent on Plk1 (11,17). Their interaction is PBD-dependent, and phosphorylation of BubR1 by Plk1 is essential for the stabilization of kinetochore-microtubule interactions (13,14,40).…”

Section: Discussionmentioning

confidence: 99%

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Deficiency in Chromosome Congression by the Inhibition of Plk1 Polo Box Domain-dependent Recognition

Watanabe

Sekine

Takagi

et al. 2009

Journal of Biological Chemistry

105

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Polo-like kinase 1 (Plk1) is one of the key regulators of mitotic cell division. In addition to an N-terminal protein kinase catalytic domain, Plk1 possesses a phosphopeptide binding domain named polo box domain (PBD) at its C terminus. PBD is postulated to be essential for Plk1 localization and substrate targeting. Here, we developed a high-throughput screening system to identify inhibitors of PBD-dependent binding and screened a chemical library. We isolated a benzotropolone-containing natural compound derived from nutgalls (purpurogallin (PPG)) that inhibited PBD-dependent binding in vitro and in vivo. PPG not only delayed the onset of mitosis but also prolonged the progression of mitosis in HeLa cells. Although apparently normal bipolar spindles were formed even in the presence of PPG, the perturbation of chromosome alignment at metaphase plates activated the spindle assembly checkpoint pathway. These results demonstrate the predominant role of PBD-dependent binding on smooth chromosome congression at metaphase. In eukaryotes, Plk12 (or its orthologs) possesses a wide variety of essential functions during mitosis (1, 2). Although levels of Plk1 increase in late G 2 and rapidly decrease by proteolysis at the end of M phase, Plk1 localization changes dramatically when cells transit through the various mitotic stages. During late G 2 and prophase, Plk1 localizes primarily at the centrosomes, where Plk1 is involved in centrosome maturation, separation, and microtubule nucleation (3-5). At this stage, Plk1 also regulates mitotic entry through the phosphorylation and activation of Cdc25 (6, 7). In parallel, the phosphorylation of Wee1 by Plk1, which is primed by Cdk1, promotes the destruction of Wee1, the inhibitory kinase of mitotic entry (8, 9). By metaphase, a fraction of Plk1 relocalizes to the kinetochores, where it is involved in the regulation of the spindle assembly checkpoint pathway and proper chromosome segregation. Plk1 sensitizes the tension between sister chromatids and regulates the stability of kinetochore-microtubule interactions by phosphorylating kinetochore proteins such as BubR1 and proteins that harbor 3F3/2 epitopes (4, 10 -14). Although Plk1 localization at chromosome arms is required for loss of arm cohesion during M-phase (15, 16), localized Plk1 activity at the kinetochore is important for the proper accumulation of kinetochore proteins such as BubR1, Mad1, Mad2, Cdc20, and centromere/ kinetochore-associated protein-E (CENP-E) (4, 10 -12, 17, 18). During anaphase, Plk1 is concentrated in the spindle midzone, where it may facilitate microtubule sliding. After chromosomal segregation, Plk1 remains in the central spindle and midbody, where it is involved in formation of the cleavage furrow (19 -21).These various localizations of Plk1 are mediated by its noncatalytic C-terminal half, the polo box domain (PBD), which comprises two polo box motifs (22, 23). Recently, Yaffe and co-workers (24, 25) discovered that the PBD constitutes a phosphopeptide binding domain which binds with maximal affin...

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Section: Discussionmentioning

confidence: 99%

“…Cells-Recently, several groups reported that Plk1 interacts with BubR1 at the kinetochores of unaligned chromosomes (11,13,14,17,40). This interaction was shown to be primed by cyclin-dependent kinase 1 phosphorylation of BubR1 in a PBD binding-dependent manner.…”

Section: Microtubule Interactions Are Destabilized In Ppg-treatedmentioning

confidence: 99%

Deficiency in Chromosome Congression by the Inhibition of Plk1 Polo Box Domain-dependent Recognition

Watanabe

Sekine

Takagi

et al. 2009

Journal of Biological Chemistry

105

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“…27 Yet, Plk1 is not required for BubR1's localization at kinetochores in HeLa cells, [27][28][29] although Plx1 is responsible for the loading of xBubR1 onto kinetochores in Xenopus laevis. 28 In DMSO-treated cells, BubR1 localized at kinetochores before chromosome alignment in prometaphase, and it disappeared when chromosomes properly aligned at the equatorial plate in metaphase ( Figure 3A). On the other hand, most of the Poloxin-treated cells were retained during prometaphase, with strong BubR1 staining at kinetochores of not yet aligned chromosomes ( Figure 3A).…”

Section: Poloxin Activates the Spindle Assembly Checkpointmentioning

confidence: 99%

Polo-Box Domain Inhibitor Poloxin Activates the Spindle Assembly Checkpoint and Inhibits Tumor Growth in Vivo

Yuan

Sanhaji

Krämer

et al. 2011

The American Journal of Pathology

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Polo-like kinase 1 (Plk1) is widely established as one of the most promising targets in oncology. Although the protein kinase domain of Plk1 is highly conserved, the polo-box domain (PBD) of Plk1 provides a much more compelling site to specifically inhibit the localization and target binding of Plk1. We recently identified, via fluorescence polarization assay, the natural product derivative, Poloxin, as the first smallmolecule inhibitor specifically targeting the function of the Plk1 PBD. In this study, we characterized its mitotic phenotype and its function in vitro and in vivo. Poloxin induces centrosome fragmentation and abnormal spindle and chromosome misalignment, which activate the spindle assembly checkpoint and prolong mitosis. Notably, centrosomal fragmentation induced by Poloxin is partially attributable to dysfunctional Kizuna, a key substrate of Plk1 at centrosomes. Moreover, Poloxin strongly inhibits proliferation of a panel of cancer cells by inducing mitotic arrest, followed by a surge of apoptosis. More important, we report, for the first time to our knowledge, that the PBD inhibitor, Poloxin, significantly suppresses tumor growth of cancer cell lines in xenograft mouse models by lowering the proliferation rate and triggering apoptosis in treated tumor tissues. The data highlight that targeting the PBD by Poloxin is a powerful approach for selectively inhibiting Plk1 function in vitro and in vivo.

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“…71 Interestingly, INCENP has also been recently shown to interact with, and regulate the kinetochore localization of Polo-like kinase 1 (Plk1). 72 Plk1, in turn, was shown to generate the tension-dependent 3F3/2 phosphoepitope, 73,74 and therefore should be expected to somehow 'measure' the tension at the kinetochore/centromere. To further support this idea, Baumann et al 75 recently identified PICH (Plk1-interacting checkpoint helicase) as a partner and substrate of Plk1.…”

Section: How Does Aurora B Detect Kinetochore-microtubule Mis-attachmmentioning

confidence: 99%

Detection and Correction of Merotelic Kinetochore Orientation by Aurora B and its Partners

Cimini

2007

Cell Cycle

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Merotelic kinetochore orientation is a kinetochore-microtubule mis-attachment in which a single kinetochore binds microtubules to both spindle poles, rather than just one. Merotelic attachments occur frequently in early mitosis and can induce anaphase lagging chromosomes and aneuploidy if not corrected before anaphase onset. Merotelic kinetochore orientation does not interfere with chromosome alignment at the metaphase plate and does not activate the mitotic spindle checkpoint. However, a correction mechanism for merotelic attachment reduces the number of merotelic kinetochores entering anaphase, thus preventing chromosome mis-segregation. Results from many different studies support the idea that Aurora B kinase plays a critical role in this merotelic correction mechanism by phosphorylating key substrates at the kinetochore and promoting turnover of kinetochore microtubules. In addition, recent studies are starting to identify the possible 'sensors' of the system that would be able to detect the mis-attachment and communicate this to Aurora B. Here, I review these studies and discuss a model for how merotelic kinetochore orientation could be detected and corrected before anaphase onset.

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Plx1 is the 3F3/2 kinase responsible for targeting spindle checkpoint proteins to kinetochores

Cited by 56 publications

References 46 publications

Deficiency in Chromosome Congression by the Inhibition of Plk1 Polo Box Domain-dependent Recognition

Deficiency in Chromosome Congression by the Inhibition of Plk1 Polo Box Domain-dependent Recognition

Polo-Box Domain Inhibitor Poloxin Activates the Spindle Assembly Checkpoint and Inhibits Tumor Growth in Vivo

Detection and Correction of Merotelic Kinetochore Orientation by Aurora B and its Partners

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