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https://www.readbyqxmd.com/read/27794612/phosphoproteome-profiling-reveals-molecular-mechanisms-of-growth-factor-mediated-kinase-inhibitor-resistance-in-egfr-overexpressing-cancer-cells
#1
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 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...
October 30, 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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
https://www.readbyqxmd.com/read/26192590/selectivity-profiling-and-biological-activity-of-novel-%C3%AE-carbolines-as-potent-and-selective-dyrk1-kinase-inhibitors
#14
Katharina Rüben, Anne Wurzlbauer, Agnes Walte, Wolfgang Sippl, Franz Bracher, Walter Becker
DYRK1A is a pleiotropic protein kinase with diverse functions in cellular regulation, including cell cycle control, neuronal differentiation, and synaptic transmission. Enhanced activity and overexpression of DYRK1A have been linked to altered brain development and function in Down syndrome and neurodegenerative diseases such as Alzheimer's disease. The β-carboline alkaloid harmine is a high affinity inhibitor of DYRK1A but suffers from the drawback of inhibiting monoamine oxidase A (MAO-A) with even higher potency...
2015: PloS One
https://www.readbyqxmd.com/read/25854549/borealin-dimerization-mediates-optimal-cpc-checkpoint-function-by-enhancing-localization-to-centromeres-and-kinetochores
#15
Michael E Bekier, Travis Mazur, Maisha S Rashid, William R Taylor
The chromosomal passenger complex (CPC) localizes to centromeres where it activates the mitotic checkpoint in response to inappropriate inter-kinetochore tension. This error correction function is essential for proper chromosome segregation. Here we define several critical features of CPC localization and function. First, the Borealin dimerization domain suppresses dynamic exchange at the centromere to allow optimal CPC function. Second, Borealin dimerization is essential to target a subpopulation of CPC proximal to the kinetochore when the mitotic spindle is disrupted...
2015: Nature Communications
https://www.readbyqxmd.com/read/25595038/bisubstrate-inhibitor-approach-for-targeting-mitotic-kinase-haspin
#16
Katrin Kestav, Darja Lavogina, Gerda Raidaru, Apirat Chaikuad, Stefan Knapp, Asko Uri
During the past decade, the basophilic atypical kinase Haspin has emerged as a key player in mitosis responsible for phosphorylation of Thr3 residue of histone H3. Here, we report the construction of conjugates comprising an aromatic fragment targeted to the ATP-site of Haspin and a peptide mimicking the N-terminus of histone H3. The combination of effective solid phase synthesis procedures and a high throughput binding/displacement assay with fluorescence anisotropy readout afforded the development of inhibitors with remarkable subnanomolar affinity toward Haspin...
February 18, 2015: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/25315835/phosphorylation-of-threonine-3-on-histone-h3-by-haspin-kinase-is-required-for-meiosis-i-in-mouse-oocytes
#17
Alexandra L Nguyen, Amanda S Gentilello, Ahmed Z Balboula, Vibha Shrivastava, Jacob Ohring, Karen Schindler
Meiosis I (MI), the division that generates haploids, is prone to errors that lead to aneuploidy in females. Haspin is a kinase that phosphorylates histone H3 on threonine 3, thereby recruiting Aurora kinase B (AURKB) and the chromosomal passenger complex (CPC) to kinetochores to regulate mitosis. Haspin and AURKC, an AURKB homolog, are enriched in germ cells, yet their significance in regulating MI is not fully understood. Using inhibitors and overexpression approaches, we show a role for haspin during MI in mouse oocytes...
December 1, 2014: Journal of Cell Science
https://www.readbyqxmd.com/read/25195011/a-unique-inhibitor-binding-site-in-erk1-2-is-associated-with-slow-binding-kinetics
#18
Apirat Chaikuad, Eliana M C Tacconi, Jutta Zimmer, Yanke Liang, Nathanael S Gray, Madalena Tarsounas, Stefan Knapp
Activation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induces a so-far-unknown binding pocket that accommodates the piperazine-phenyl-pyrimidine decoration. This new binding pocket was created by an inactive conformation of the phosphate-binding loop and an outward tilt of helix αC...
October 2014: Nature Chemical Biology
https://www.readbyqxmd.com/read/24732914/modulation-of-the-chromatin-phosphoproteome-by-the-haspin-protein-kinase
#19
Alessio Maiolica, Maria de Medina-Redondo, Erwin M Schoof, Apirat Chaikuad, Fabrizio Villa, Marco Gatti, Siva Jeganathan, Hua Jane Lou, Karel Novy, Simon Hauri, Umut H Toprak, Franz Herzog, Patrick Meraldi, Lorenza Penengo, Benjamin E Turk, Stefan Knapp, Rune Linding, Ruedi Aebersold
Recent discoveries have highlighted the importance of Haspin kinase activity for the correct positioning of the kinase Aurora B at the centromere. Haspin phosphorylates Thr(3) of the histone H3 (H3), which provides a signal for Aurora B to localize to the centromere of mitotic chromosomes. To date, histone H3 is the only confirmed Haspin substrate. We used a combination of biochemical, pharmacological, and mass spectrometric approaches to study the consequences of Haspin inhibition in mitotic cells. We quantified 3964 phosphorylation sites on chromatin-associated proteins and identified a Haspin protein-protein interaction network...
July 2014: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/24531719/plk1-puts-a-has-pin-on-the-mitotic-histone-code
#20
COMMENT
Tatiana Moutinho-Santos, Helder Maiato
Haspin is an atypical mitotic kinase that phosphorylates histone H3 on threonine 3 (H3T3), which is required to target Aurora B to centromeres. However, how Haspin is activated upon mitotic entry remained unknown. Two independent studies, published in Molecular Cell and in this issue of EMBO reports by Ghenoiu et al and Zhou et al, respectively, now show that Plk1 is responsible for Haspin activation as a H3T3 kinase. These results shed light on the spatiotemporal regulation of Aurora B to ensure mitotic fidelity...
March 2014: EMBO Reports
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