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https://www.readbyqxmd.com/read/28436952/playing-polo-during-mitosis-plk1-takes-the-lead
#1
REVIEW
G Combes, I Alharbi, L G Braga, S Elowe
Polo-like kinase 1 (PLK1), the prototypical member of the polo-like family of serine/threonine kinases, is a pivotal regulator of mitosis and cytokinesis in eukaryotes. Many layers of regulation have evolved to target PLK1 to different subcellular structures and to its various mitotic substrates in line with its numerous functions during mitosis. Collective work is starting to illuminate an important set of substrates for PLK1: the mitotic kinases that together ensure the fidelity of the cell division process...
April 24, 2017: Oncogene
https://www.readbyqxmd.com/read/28413956/structure-roles-and-inhibitors-of-a-mitotic-protein-kinase-haspin
#2
Katrin Kestav, Asko Uri, Darja Lavogina
Background Haspin (haploid germ cell-specific nuclear protein kinase) is an atypical serine/threonine-protein kinase that was for a long time considered an inactive pseudokinase due to low degree of structural homology of Haspin with the 'classical' protein kinases. However, the discovery of Haspin-catalyzed phosphorylation of histone H3 at Thr3 residue unveiled importance of Haspin in mitosis and provided yet another link between mitotic phosphorylation pathways and chromatin modifications. Results In this review of 111 publications, we have (1) briefly summarized catalytic properties and physiological roles of Haspin, (2) focussed on the architecture of Haspin and mechanisms behind its substrate recognition, (3) provided detailed insight into the advances in the development and characterization of Haspin-selective inhibitors, and (4) given overview of inhibitor scaffolds that despite targeting other protein kinases feature Haspin as a common off-target...
April 14, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28343969/pds5-regulates-sister-chromatid-cohesion-and-chromosome-bi-orientation-through-a-conserved-protein-interaction-module
#3
Yuhei Goto, Yuya Yamagishi, Miyuki Shintomi-Kawamura, Mayumi Abe, Yuji Tanno, Yoshinori Watanabe
Sister-chromatid cohesion is established by the cohesin complex in S phase and persists until metaphase, when sister chromatids are captured by microtubules emanating from opposite poles [1]. The Aurora-B-containing chromosome passenger complex (CPC) plays a crucial role in achieving chromosome bi-orientation by correcting erroneous microtubule attachment [2]. The centromeric localization of the CPC relies largely on histone H3-T3 phosphorylation (H3-pT3), which is mediated by the mitotic histone kinase Haspin/Hrk1 [3-5]...
April 3, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28343965/the-n-terminal-non-kinase-domain-mediated-binding-of-haspin-to-pds5b-protects-centromeric-cohesion-in-mitosis
#4
Linli Zhou, Cai Liang, Qinfu Chen, Zhenlei Zhang, Bo Zhang, Haiyan Yan, Feifei Qi, Miao Zhang, Qi Yi, Youchen Guan, Xingfeng Xiang, Xiaoqing Zhang, Sheng Ye, Fangwei Wang
Sister-chromatid cohesion, mediated by the multi-subunit cohesin complex, must be precisely regulated to prevent chromosome mis-segregation. In prophase and prometaphase, whereas the bulk of cohesin on chromosome arms is removed by its antagonist Wapl, cohesin at centromeres is retained to ensure chromosome biorientation until anaphase onset. It remains incompletely understood how centromeric cohesin is protected against Wapl in mitosis. Here we show that the mitotic histone kinase Haspin binds to the cohesin regulatory subunit Pds5B through a conserved YGA/R motif in its non-catalytic N terminus, which is similar to the recently reported YSR-motif-dependent binding of Wapl to Pds5B...
April 3, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28302507/design-and-synthesis-of-selective-cdk8-19-dual-inhibitors-discovery-of-4-5-dihydrothieno-3-4-3-4-benzo-1-2-d-isothiazole-derivatives
#5
Koji Ono, Hiroshi Banno, Masanori Okaniwa, Takaharu Hirayama, Naoki Iwamura, Yukiko Hikichi, Saomi Murai, Maki Hasegawa, Yuka Hasegawa, Kazuko Yonemori, Akito Hata, Kazunobu Aoyama, Douglas R Cary
To develop a novel series of CDK8/19 dual inhibitors, we employed structure-based drug design using docking models based on a library compound, 4,5-dihydroimidazolo[3',4':3,4]benzo[1,2-d]isothiazole 16 bound to CDK8. We designed various [5,6,5]-fused tricyclic scaffolds bearing a carboxamide group to maintain predicted interactions with the backbone CO and NH of Ala100 in the CDK8 kinase hinge region. We found that 4,5-dihydrothieno[3',4':3,4]benzo[1,2-d]isothiazole derivative 29a showed particularly potent enzymatic inhibitory activity in both CDK8/19 (CDK8 IC50: 0...
February 22, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28181383/slowly-on-slowly-off-bisubstrate-analogue-conjugates-of-5-iodotubercidin-and-histone-h3-peptide-targeting-protein-kinase-haspin
#6
Katrin Kestav, Kaido Viht, Anton Konovalov, Erki Enkvist, Asko Uri, Darja Lavogina
The atypical protein kinase haspin is a key player in mitosis by catalysing the phosphorylation of Thr3 in histone H3, and thus ensuring the normal function of the chromosomal passenger complex. Here, we report the development of bisubstrate-analogue inhibitors targeting haspin. The compounds were constructed by linking 5-iodotubercidin to the N terminus of histone H3 peptide. The new conjugates show high affinity (sub-nanomolar KD ) towards haspin as well as slow kinetics of association and dissociation (residence time of several hours)...
February 9, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28101375/aurora-a-promotes-the-establishment-of-spindle-assembly-checkpoint-by-priming-the-haspin-aurora-b-feedback-loop-in-late-g2-phase
#7
Fazhi Yu, Ya Jiang, Lucy Lu, Mimi Cao, Yulong Qiao, Xing Liu, Dan Liu, Terry Van Dyke, Fangwei Wang, Xuebiao Yao, Jing Guo, Zhenye Yang
Aurora-A kinase functions mainly in centrosome maturation, separation and spindle formation. It has also been found to be amplified or overexpressed in a range of solid tumors, which is linked with tumor progression and poor prognosis. Importantly, Aurora-A inhibitors are being studied in a number of ongoing clinical trials. However, whether and how Aurora-A has a role in the regulation of the mitotic checkpoint is controversial. Additionally, the function of nuclear-accumulated Aurora-A in late G2 phase is not clear...
2017: Cell Discovery
https://www.readbyqxmd.com/read/27794612/phosphoproteome-profiling-reveals-molecular-mechanisms-of-growth-factor-mediated-kinase-inhibitor-resistance-in-egfr-overexpressing-cancer-cells
#8
Heiner Koch, Mathias Wilhelm, Benjamin Ruprecht, Scarlet Beck, Martin Frejno, Susan Klaeger, Bernhard Kuster
Although substantial progress has been made regarding the use of molecularly targeted cancer therapies, resistance almost invariably develops and presents a major clinical challenge. The tumor microenvironment can rescue cancer cells from kinase inhibitors by growth-factor-mediated induction of pro-survival pathways. Here we show that epidermal growth factor receptor (EGFR) inhibition by Gefitinib is counteracted by growth factors, notably FGF2, and we assessed the global molecular consequences of this resistance at the proteome and phosphoproteome level in A431 cells...
December 2, 2016: Journal of Proteome Research
https://www.readbyqxmd.com/read/27562071/haspin-kinase-regulates-microtubule-organizing-center-clustering-and-stability-through-aurora-kinase-c-in-mouse-oocytes
#9
Ahmed Z Balboula, Alexandra L Nguyen, Amanda S Gentilello, Suzanne M Quartuccio, David Drutovic, Petr Solc, Karen Schindler
Meiotic oocytes lack classic centrosomes and, therefore, bipolar spindle assembly depends on clustering of acentriolar microtubule-organizing centers (MTOCs) into two poles. However, the molecular mechanism regulating MTOC assembly into two poles is not fully understood. The kinase haspin (also known as GSG2) is required to regulate Aurora kinase C (AURKC) localization at chromosomes during meiosis I. Here, we show that inhibition of haspin perturbed MTOC clustering into two poles and the stability of the clustered MTOCs...
October 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27325792/sumoylation-of-dna-topoisomerase-ii%C3%AE-regulates-histone-h3-kinase-haspin-and-h3-phosphorylation-in-mitosis
#10
Makoto M Yoshida, Lily Ting, Steven P Gygi, Yoshiaki Azuma
DNA topoisomerase II (TOP2) plays a pivotal role in faithful chromosome separation through its strand-passaging activity that resolves tangled genomic DNA during mitosis. Additionally, TOP2 controls progression of mitosis by activating cell cycle checkpoints. Recent work showed that the enzymatically inert C-terminal domain (CTD) of TOP2 and its posttranslational modification are critical to this checkpoint regulation. However, the molecular mechanism has not yet been determined. By using Xenopus laevis egg extract, we found that SUMOylation of DNA topoisomerase IIα (TOP2A) CTD regulates the localization of the histone H3 kinase Haspin and phosphorylation of histone H3 at threonine 3 at the centromere, two steps known to be involved in the recruitment of the chromosomal passenger complex (CPC) to kinetochores in mitosis...
June 20, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27325791/a-noncatalytic-function-of-the-topoisomerase-ii-ctd-in-aurora-b-recruitment-to-inner-centromeres-during-mitosis
#11
Heather Edgerton, Marnie Johansson, Daniel Keifenheim, Soumya Mukherjee, Jeremy M Chacón, Jeff Bachant, Melissa K Gardner, Duncan J Clarke
Faithful chromosome segregation depends on the precise timing of chromatid separation, which is enforced by checkpoint signals generated at kinetochores. Here, we provide evidence that the C-terminal domain (CTD) of DNA topoisomerase IIα (Topo II) provides a novel function at inner centromeres of kinetochores in mitosis. We find that the yeast CTD is required for recruitment of the tension checkpoint kinase Ipl1/Aurora B to inner centromeres in metaphase but is not required in interphase. Conserved CTD SUMOylation sites are required for Ipl1 recruitment...
June 20, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27219518/differentially-isotope-labeled-nucleosomes-to-study-asymmetric-histone-modification-crosstalk-by-time-resolved-nmr-spectroscopy
#12
Stamatios Liokatis, Rebecca Klingberg, Song Tan, Dirk Schwarzer
Post-translational modifications (PTMs) of histones regulate chromatin structure and function. Because nucleosomes contain two copies each of the four core histones, the establishment of different PTMs on individual "sister" histones in the same nucleosomal context, that is, asymmetric histone PTMs, are difficult to analyze. Here, we generated differentially isotope-labeled nucleosomes to study asymmetric histone modification crosstalk by time-resolved NMR spectroscopy. Specifically, we present mechanistic insights into nucleosomal histone H3 modification reactions in cis and in trans, that is, within individual H3 copies or between them...
July 11, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27139824/co-crystal-structures-of-the-protein-kinase-haspin-with-bisubstrate-inhibitors
#13
Darja Lavogina, Katrin Kestav, Apirat Chaikuad, Christina Heroven, Stefan Knapp, Asko Uri
Haspin is a mitotic protein kinase that is responsible for the phosphorylation of Thr3 of histone H3, thereby creating a recognition motif for docking of the chromosomal passenger complex that is crucial for the progression of cell division. Here, two high-resolution models of haspin with previously reported inhibitors consisting of an ATP analogue and a histone H3(1-7) peptide analogue are presented. The structures of the complexes confirm the bisubstrate character of the inhibitors by revealing the signature binding modes of the moieties targeting the ATP-binding site and the protein substrate-binding site of the kinase...
May 2016: Acta Crystallographica. Section F, Structural Biology Communications
https://www.readbyqxmd.com/read/27089349/search-for-potent-and-selective-aurora-a-inhibitors-based-on-general-ser-thr-kinase-pharmacophore-model
#14
Natalya I Vasilevich, Victor V Tatarskiy, Elena A Aksenova, Denis N Kazyulkin, Ilya I Afanasyev
Based on the data for compounds known from the literature to be active against various types of Ser/Thr kinases, a general pharmachophore model for these types of kinases was developed. The search for the molecules fitting to this pharmacophore among the ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against Ser/Thr kinases such as Aurora A, Aurora B and Haspin. Our work on the optimization of these molecules against Aurora A kinase allowed us to achieve several hits in a 3-5 nM range of activity with rather good selectivity and Absorption, Distribution, Metabolism, and Excretion (ADME) properties, and cytotoxicity against 16 cancer cell lines...
2016: Pharmaceuticals
https://www.readbyqxmd.com/read/27082996/otssp167-abrogates-mitotic-checkpoint-through-inhibiting-multiple-mitotic-kinases
#15
Wenbin Ji, Christopher Arnst, Aaron R Tipton, Michael E Bekier, William R Taylor, Tim J Yen, Song-Tao Liu
OTSSP167 was recently characterized as a potent inhibitor for maternal embryonic leucine zipper kinase (MELK) and is currently tested in Phase I clinical trials for solid tumors that have not responded to other treatment. Here we report that OTSSP167 abrogates the mitotic checkpoint at concentrations used to inhibit MELK. The abrogation is not recapitulated by RNAi mediated silencing of MELK in cells. Although OTSSP167 indeed inhibits MELK, it exhibits off-target activity against Aurora B kinase in vitro and in cells...
2016: PloS One
https://www.readbyqxmd.com/read/26872832/haspin-has-multiple-functions-in-the-plant-cell-division-regulatory-network
#16
Elena Kozgunova, Takamasa Suzuki, Masaki Ito, Tetsuya Higashiyama, Daisuke Kurihara
Progression of cell division is controlled by various mitotic kinases. In animal cells, phosphorylation of histone H3 at Thr3 by the kinase Haspin (haploid germ cell-specific nuclear protein kinase) promotes centromeric Aurora B localization to regulate chromosome segregation. However, less is known about the function of Haspin in regulatory networks in plant cells. Here, we show that inhibition of Haspin with 5-iodotubercidin (5-ITu) in Bright Yellow-2 (BY-2) cells delayed chromosome alignment. Haspin inhibition also prevented the centromeric localization of Aurora3 kinase (AUR3) and disrupted its function...
April 2016: Plant & Cell Physiology
https://www.readbyqxmd.com/read/26685311/requirement-for-plk1-kinase-activity-in-the-maintenance-of-a-robust-spindle-assembly-checkpoint
#17
Aisling O'Connor, Stefano Maffini, Michael D Rainey, Agnieszka Kaczmarczyk, David Gaboriau, Andrea Musacchio, Corrado Santocanale
During mitotic arrest induced by microtubule targeting drugs, the weakening of the spindle assembly checkpoint (SAC) allows cells to progress through the cell cycle without chromosome segregation occurring. PLK1 kinase plays a major role in mitosis and emerging evidence indicates that PLK1 is also involved in establishing the checkpoint and maintaining SAC signalling. However, mechanistically, the role of PLK1 in the SAC is not fully understood, with several recent reports indicating that it can cooperate with either one of the major checkpoint kinases, Aurora B or MPS1...
2015: Biology Open
https://www.readbyqxmd.com/read/26636626/h3-thr3-phosphorylation-is-crucial-for-meiotic-resumption-and-anaphase-onset-in-oocyte-meiosis
#18
Qian Wang, Haojie Wei, Juan Du, Yan Cao, Nana Zhang, Xiaoyun Liu, Xiaoyu Liu, Dandan Chen, Wei Ma
Haspin-catalyzed histone H3 threonine 3 (Thr3) phosphorylation facilitates chromosomal passenger complex (CPC) docking at centromeres, regulating indirectly chromosome behavior during somatic mitosis. It is not fully known about the expression and function of H3 with phosphorylated Thr3 (H3T3-P) during meiosis in oocytes. In this study, we investigated the expression and sub-cellular distribution of H3T3-P, as well as its function in mouse oocytes during meiotic division. Western blot analysis revealed that H3T3-P expression was only detected after germinal vesicle breakdown (GVBD), and gradually increased to peak level at metaphase I (MI), but sharply decreased at metaphase II (MII)...
2016: Cell Cycle
https://www.readbyqxmd.com/read/26522592/histone-h3-threonine-phosphorylation-regulates-asymmetric-histone-inheritance-in-the-drosophila-male-germline
#19
Jing Xie, Matthew Wooten, Vuong Tran, Bi-Chang Chen, Caitlin Pozmanter, Christine Simbolon, Eric Betzig, Xin Chen
A long-standing question concerns how stem cells maintain their identity through multiple divisions. Previously, we reported that pre-existing and newly synthesized histone H3 are asymmetrically distributed during Drosophila male germline stem cell (GSC) asymmetric division. Here, we show that phosphorylation at threonine 3 of H3 (H3T3P) distinguishes pre-existing versus newly synthesized H3. Converting T3 to the unphosphorylatable residue alanine (H3T3A) or to the phosphomimetic aspartate (H3T3D) disrupts asymmetric H3 inheritance...
November 5, 2015: Cell
https://www.readbyqxmd.com/read/26223676/chromosome-segregation-regulation-in-human-zygotes-altered-mitotic-histone-phosphorylation-dynamics-underlying-centromeric-targeting-of-the-chromosomal-passenger-complex
#20
C van de Werken, M Avo Santos, J S E Laven, C Eleveld, B C J M Fauser, S M A Lens, E B Baart
STUDY QUESTION: Are the kinase feedback loops that regulate activation and centromeric targeting of the chromosomal passenger complex (CPC), functional during mitosis in human embryos? SUMMARY ANSWER: Investigation of the regulatory kinase pathways involved in centromeric CPC targeting revealed normal phosphorylation dynamics of histone H2A at T120 (H2ApT120) by Bub1 kinase and subsequent recruitment of Shugoshin, but phosphorylation of histone H3 at threonine 3 (H3pT3) by Haspin failed to show the expected centromeric enrichment on metaphase chromosomes in the zygote...
October 2015: Human Reproduction
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