Inhibition of Polo-like Kinase 1 by Blocking Polo-Box Domain-Dependent Protein-Protein Interactions

Reindl, Wolfgang; Yuan, Juping; Krämer, Andrea; Strebhardt, Klaus; Berg, Thorsten

doi:10.1016/j.chembiol.2008.03.013

Cited by 217 publications

(231 citation statements)

References 35 publications

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“…S2e). Further, this binding was only partially sensitive to the Plk-1 Polo-box-domain-targeting drug thymoquinone 17 ( Supplementary Fig. S2f), suggesting that other parts of the protein outside of the Polo-box domain are involved in the interaction.…”

Section: Resultsmentioning

confidence: 99%

Kindlin-1 regulates mitotic spindle formation by interacting with integrins and Plk-1

et al. 2013

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Kindlin-1 binds to integrins and regulates integrin activation at cell adhesions. Here we report a new function of Kindlin-1 in regulating spindle assembly. We show that Kindlin-1 localizes to centrosomes, its concentration peaking during G2/M, where it associates with various pericentriolar material proteins, including Polo-like kinase 1. Short interfering RNA-mediated depletion of Kindlin-1 increases formation of abnormal mitotic spindles and decreases cellular survival. This effect is dependent not only on the ability of Kindlin-1 to bind integrins but also on Polo-like kinase 1-mediated Kindlin-1 phosphorylation. We demonstrate that a subcellular pool of phosphorylated Kindlin-1 is located exclusively at centrosomes. Our work identifies a novel cellular role for Kindlin-1 in ensuring mitotic spindle assembly and cellular survival that is controlled by phosphorylation via Polo-like kinase 1.

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Section: Resultsmentioning

confidence: 99%

Kindlin-1 regulates mitotic spindle formation by interacting with integrins and Plk-1

et al. 2013

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“…Actually, several novel Plk1 inhibitors have been reported (28 -32), and some of them have proceeded to clinical trials (28,31). While this manuscript was in preparation, another group independently reported that thymoquinone and its derivative have an inhibitory activity to PBD-dependent recognition (52). Their compounds also induced Plk1 mislocalization, chromosomal congression defect, mitotic arrest, and apoptosis at a similar concentration to that for PPG.…”

Section: Discussionmentioning

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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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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“…These inhibitors induced mitotic arrest and apoptosis in HeLa cells 248 . Rosmarinic acid and salvianolic acids blocked some interactions of the SH2 domain of Src-family tyrosine kinases with labelled peptides that were designed to mimic the binding domain of the erythropoietin receptor 255 .…”

Section: Protein Protein Interactions Protein Protein Interactions Amentioning

confidence: 99%

“…Thymoquinone, and its synthetic derivative poloxin inhibited the interaction between polo-like kinase 1 and its intracellular anchoring site 248 .…”

Section: Protein Protein Interactions Protein Protein Interactions Amentioning

confidence: 99%

“…Most of the assays that are used to detect disruption of protein protein interactions involve sophisticated detection methods such as fluorescence polarization 248 , surface plasmon resonance and NMR 249 . A relatively simple and direct assay was described 250 that uses phage display with p53 to monitor binding to MDM2.…”

Section: Protein Protein Interactions Protein Protein Interactions Amentioning

confidence: 99%

See 1 more Smart Citation

The re-emergence of natural products for drug discovery in the genomics era

Harvey

Edrada-Ebel

Quinn

2015

Nat Rev Drug Discov

2,110

1,410

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Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review advances in chemical techniques for the isolation and structural elucidation of natural products that have reduced these technological barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.

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Inhibition of Polo-like Kinase 1 by Blocking Polo-Box Domain-Dependent Protein-Protein Interactions

Cited by 217 publications

References 35 publications

Kindlin-1 regulates mitotic spindle formation by interacting with integrins and Plk-1

Kindlin-1 regulates mitotic spindle formation by interacting with integrins and Plk-1

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

The re-emergence of natural products for drug discovery in the genomics era

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