From Plk1 to Plk5

Cárcer, Guillermo de; Manning, Gerard; Malumbres, Marcos

doi:10.4161/cc.10.14.16494

Cited by 234 publications

(147 citation statements)

References 82 publications

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“…In mammals, there are five paralogs of polo-like kinases, PLK1-5, although key kinase residues are absent in PLK5 (de Cárcer et al, 2011). PLK1 is the mammalian ortholog of Cdc5p and is termed a 'master regulator' of cell division (de Cárcer et al, 2011). To probe the role of PLK in desynapsis, we have taken advantage of the nearly synchronous first wave of spermatogenesis in mice (Bellvé et al, 1977;Cohen et al, 2006) and the ability to isolate highly enriched pachytene spermatocytes and induce meiotic prophase exit ex vivo with the phosphatase inhibitor okadaic acid (OA) .…”

Section: Introductionmentioning

confidence: 99%

Polo-like kinase is required for synaptonemal complex disassembly and phosphorylation in mouse spermatocytes

Jordan

Karppinen

Handel

2012

Journal of Cell Science

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During meiosis, accurate coordination of the completion of homologous recombination and synaptonemal complex (SC) disassembly during the prophase to metaphase I (G2/MI) transition is essential to avoid aneuploid gametes and infertility. Previous studies have shown that kinase activity is required to promote meiotic prophase exit. The first step of the G2/MI transition is the disassembly of the central element components of the SC; however, the kinase(s) required to trigger this process remains unknown. Here we assess roles of polo-like kinases (PLKs) in mouse spermatocytes, both in vivo and during prophase exit induced ex vivo by the phosphatase inhibitor okadaic acid. All four PLKs are expressed during the first wave of spermatogenesis. Only PLK1 (not PLK2-4) localizes to the SC during the G2/MI transition. The SC central element proteins SYCP1, TEX12 and SYCE1 are phosphorylated during the G2/MI transition. However, treatment of pachytene spermatocytes with the PLK inhibitor BI 2536 prevented the okadaic-acid-induced meiotic prophase exit and inhibited phosphorylation of the central element proteins as well as their removal from the SC. Phosphorylation assays in vitro demonstrated that PLK1, but not PLK2-4, phosphorylates central element proteins SYCP1 and TEX12. These findings provide mechanistic details of the first stage of SC disassembly in mammalian spermatocytes, and reveal that PLK-mediated phosphorylation of central element proteins is required for meiotic prophase exit.

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Section: Introductionmentioning

confidence: 99%

Polo-like kinase is required for synaptonemal complex disassembly and phosphorylation in mouse spermatocytes

Jordan

Karppinen

Handel

2012

Journal of Cell Science

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“…Mammalian polo-like kinase 1 (PLK1) belongs to a family of 5 serine/threonine kinases (de Carcer et al, 2011). It consists of a kinase domain (KD) at the N-terminus and a highly conserved polo-box domain (PBD) composed of 2 polo boxes near the C-terminus.…”

Section: Introductionmentioning

confidence: 99%

“…Studies have demonstrated that the PBD plays a crucial role in substrate binding and regulation of kinase activity (Lowery et al, 2005). As a master regulator of cell division, PLK1 functions in almost every stage of cell division including mitotic entry, centrosome maturation, bipolar spindle formation, chromatid segregation, mitotic exit, and cytokinesis (de Carcer et al, 2011). Moreover, its role is not limited to mitosis and cytokinesis.…”

Section: Introductionmentioning

confidence: 99%

SUMOylation Promotes Nuclear Import and Stabilization of Polo-like Kinase 1 to Support Its Mitotic Function

Wen

Wang

et al. 2017

Cell Reports

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SUMMARY As a pivotal mitotic regulator, polo-like kinase 1 (PLK1) is under highly coordinated and multilayered regulation. However, the pathways that control PLK1’s activity and function have just begun to be elucidated. PLK1 has recently been shown to be functionally modulated by post-translational modifications (PTMs), including phosphorylation and ubiquitination. Herein, we report that a novel PTM, SUMOylation, plays an essential role in regulating PLK1’s mitotic function. We found that Ubc9 was recruited to PLK1, upon initial phosphorylation and activation by CDK1/cyclin B. By in vivo and in vitro SUMOylation assays, PLK1 was identified as a physiologically relevant SUMO-targeted protein, preferentially modified by SUMO-1. We further showed that K492 on PLK1 is essential for SUMOylation. SUMOylation causes PLK1’s nuclear import and significantly increases its protein stability, both of which are critical for normal mitotic progression and genomic integrity. Our findings suggest that SUMOylation is another important regulatory mechanism governing PLK1’s mitotic function.

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“…The application of this compound was not reported according to SciFinder. Its purity was reconfirmed by 1 H NMR ( Figure S2). [a] BI 2536 was used as a positive control (IC 50 : 11.5 AE 1.3 nm); data are the mean AE SD of three independent experiments.…”

Section: In Vitro Inhibition Of Full-length Plk1 Activitymentioning

confidence: 99%

“…[1,2] It is well characterized and is overexpressed in many cancers. [3] The depletion of Plk1 induces apoptosis of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Non‐ATP‐Competitive Inhibitors of Polo‐like Kinase 1

et al. 2016

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Polo‐like kinase 1 (Plk1) is an evolutionarily conserved serine/threonine kinase, and its N‐terminal kinase domain (KD) controls cell signaling through phosphorylation. Inhibitors of Plk1 are potential anticancer drugs. Most known Plk1 KD inhibitors are ATP‐competitive compounds, which may suffer from low selectivity. In this study we discovered novel non‐ATP‐competitive Plk1 KD inhibitors by virtual screening and experimental studies. Potential binding sites in Plk1 KD were identified by using the protein binding site detection program Cavity. The identified site was subjected to molecular‐docking‐based virtual screening. The activities of top‐ranking compounds were evaluated by in vitro enzyme assay with full‐length Plk1 and direct binding assay with Plk1 KD. Several compounds showed inhibitory activity, and the most potent was found to be 3‐((2‐oxo‐2‐(thiophen‐2‐yl)ethyl)thio)‐6‐(pyridin‐3‐ylmethyl)‐1,2,4‐triazin‐5(4H)‐one (compound 4) with an IC50 value of 13.1±1.7 μm. Our work provides new insight into the design of kinase inhibitors that target non‐ATP binding sites.

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From Plk1 to Plk5

Cited by 234 publications

References 82 publications

Polo-like kinase is required for synaptonemal complex disassembly and phosphorylation in mouse spermatocytes

Polo-like kinase is required for synaptonemal complex disassembly and phosphorylation in mouse spermatocytes

SUMOylation Promotes Nuclear Import and Stabilization of Polo-like Kinase 1 to Support Its Mitotic Function

Discovery of Non‐ATP‐Competitive Inhibitors of Polo‐like Kinase 1

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