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https://www.readbyqxmd.com/read/28726638/understanding-inhibitor-resistance-in-mps1-kinase-through-novel-biophysical-assays-and-structures
#1
Yoshitaka Hiruma, Andre Koch, Nazila Hazraty, Foteini Tsakou, Rene H Medema, Robbie P Joosten, Anastassis Perrakis
Monopolar spindle 1 (Mps1/TTK) is a protein kinase essential in mitotic checkpoint signalling, preventing anaphase until all chromosomes are properly attached to spindle microtubules. Mps1 has emerged as a potential target for cancer therapy, and a variety of compounds have been developed to inhibit its kinase activity. Mutations in the catalytic domain of Mps1 that give rise to inhibitor resistance, but retain catalytic activity and do not display cross-resistance to other Mps1 inhibitors, have been described...
July 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28706003/phosphorylation-mediated-regulatory-networks-in-mycelia-of-pyricularia-oryzae-revealed-by-phosphoproteomic-analyses
#2
Ruijin Wang, Junbo Peng, Qing X Li, You-Liang Peng
Protein phosphorylation is known to regulate pathogenesis, mycelial growth, conidiation and stress response in Pyricularia oryzae However, phosphorylation mediated regulatory networks in the fungal pathogen remain largely to be uncovered. In this study, we identified 1621 phosphorylation sites of 799 proteins in mycelia of P. oryzae, including 899 new p-sites of 536 proteins and 47 new p-sites of 31 pathogenesis-relation proteins. From the sequences flanking the phosphorylation sites, 19 conserved phosphorylation motifs were identified...
July 13, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28638452/targeting-tpx2-suppresses-the-tumorigenesis-of-hepatocellular-carcinoma-cells-resulting-in-arrested-mitotic-phase-progression-and-increased-genomic-instability
#3
Chao-Wen Hsu, Yu-Chia Chen, Hsing-Hao Su, Guan-Jin Huang, Chih-Wen Shu, Tony Tong-Lin Wu, Hung-Wei Pan
Hepatocellular carcinoma (HCC) remains one of the most difficult cancers to treat, with chemotherapies being relatively ineffective. Therefore, a better knowledge of molecular hepatocarcinogenesis will provide opportunities for designing targeted therapies. TPX2 (targeting protein for Xklp2) is overexpressed as a consequence of oncogenic alterations and is likely to alter the proper regulation of chromosome segregation in cancer cells. Disrupting the machinery which is responsible for mitosis and chromosome instability in cancer cells can be one of the most successful strategies for cancer therapy...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28585336/liver-directed-human-amniotic-epithelial-cell-transplantation-improves-systemic-disease-phenotype-in-hurler-syndrome-mouse-model
#4
Natalie S Rodriguez, Lisa Yanuaria, Kevin Murphy R Parducho, Irving M Garcia, Bino A Varghese, Brendan H Grubbs, Toshio Miki
Mucopolysaccharidosis type 1 (MPS1) is an inherited lysosomal storage disorder caused by a deficiency in the glycosaminoglycan (GAG)-degrading enzyme α-l-iduronidase (IDUA). In affected patients, the systemic accumulation of GAGs results in skeletal dysplasia, neurological degeneration, multiple organ dysfunction, and early death. Current therapies, including enzyme replacement and bone marrow transplant, improve life expectancy but the benefits to skeletal and neurological phenotypes are limited. In this study, we tested the therapeutic efficacy of liver-directed transplantation of a placental stem cell, which possesses multilineage differentiation potential, low immunogenicity, and high lysosomal enzyme activity...
June 6, 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28558126/cell-wall-peptidolipids-of-mycobacterium-avium-from-genetic-prediction-to-exact-structure-of-a-nonribosomal-peptide
#5
John P Bannantine, Gilles Etienne, Françoise Laval, Judith R Stabel, Anne Lemassu, Mamadou Daffé, Darrell O Bayles, Christelle Ganneau, Frédéric Bonhomme, Maxime Branger, Thierry Cochard, Sylvie Bay, Franck Biet
Mycobacteria have a complex cell wall structure that includes many lipids; however, even within a single subspecies of Mycobacterium avium these lipids can differ. Total lipids from an M. avium subsp. paratuberculosis (Map) ovine strain (S-type) contained no identifiable glycopeptidolipids or lipopentapeptide (L5P), yet both lipids are present in other M. avium subspecies. We determined the genetic and phenotypic basis for this difference using sequence analysis as well as biochemical and physico-chemical approaches...
May 30, 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28539250/target-residence-time-guided-optimization-on-ttk-kinase-results-in-inhibitors-with-potent-anti-proliferative-activity
#6
Joost C M Uitdehaag, Jos de Man, Nicole Willemsen-Seegers, Martine B W Prinsen, Marion A A Libouban, Jan Gerard Sterrenburg, Joeri J P de Wit, Judith R F de Vetter, Jeroen A D M de Roos, Rogier C Buijsman, Guido J R Zaman
The protein kinase threonine tyrosine kinase (TTK; also known as Mps1) is a critical component of the spindle assembly checkpoint and a promising drug target for the treatment of aggressive cancers, such as triple negative breast cancer. While the first TTK inhibitors have entered clinical trials, little is known about how the inhibition of TTK with small-molecule compounds affects cellular activity. We studied the selective TTK inhibitor NTRC 0066-0, which was developed in our own laboratory, together with 11 TTK inhibitors developed by other companies, including Mps-BAY2b, BAY 1161909, BAY 1217389 (Bayer), TC-Mps1-12 (Shionogi), and MPI-0479605 (Myrexis)...
July 7, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28516917/maternal-age-dependent-apc-c-mediated-decrease-in-securin-causes-premature-sister-chromatid-separation-in-meiosis-ii
#7
Ibtissem Nabti, Rosanna Grimes, Hema Sarna, Petros Marangos, John Carroll
Sister chromatid attachment during meiosis II (MII) is maintained by securin-mediated inhibition of separase. In maternal ageing, oocytes show increased inter-sister kinetochore distance and premature sister chromatid separation (PSCS), suggesting aberrant separase activity. Here, we find that MII oocytes from aged mice have less securin than oocytes from young mice and that this reduction is mediated by increased destruction by the anaphase promoting complex/cyclosome (APC/C) during meiosis I (MI) exit. Inhibition of the spindle assembly checkpoint (SAC) kinase, Mps1, during MI exit in young oocytes replicates this phenotype...
May 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28514186/apc-c-cdc20-mediates-deprotection-of-centromeric-cohesin-at-meiosis-ii-in-yeast
#8
Katarzyna Jonak, Ievgeniia Zagoriy, Tugce Oz, Peter Graf, Julie Rojas, Valentina Mengoli, Wolfgang Zachariae
Cells undergoing meiosis produce haploid gametes through one round of DNA replication followed by 2 rounds of chromosome segregation. This requires that cohesin complexes, which establish sister chromatid cohesion during S phase, are removed in a stepwise manner. At meiosis I, the separase protease triggers the segregation of homologous chromosomes by cleaving cohesin's Rec8 subunit on chromosome arms. Cohesin persists at centromeres because the PP2A phosphatase, recruited by the shugoshin protein, dephosphorylates Rec8 and thereby protects it from cleavage...
June 18, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28463114/protein-phosphatase-1-inactivates-mps1-to-ensure-efficient-spindle-assembly-checkpoint-silencing
#9
Margarida Moura, Mariana Osswald, Nelson Leça, João Barbosa, António J Pereira, Helder Maiato, Claudio E Sunkel, Carlos Conde
Faithfull genome partitioning during cell division relies on the Spindle Assembly Checkpoint (SAC), a conserved signaling pathway that delays anaphase onset until all chromosomes are attached to spindle microtubules. Mps1 kinase is an upstream SAC regulator that promotes the assembly of an anaphase inhibitor through a sequential multi-target phosphorylation cascade. Thus, the SAC is highly responsive to Mps1, whose activity peaks in early mitosis as a result of its T-loop autophosphorylation. However, the mechanism controlling Mps1 inactivation once kinetochores attach to microtubules and the SAC is satisfied remains unknown...
May 2, 2017: ELife
https://www.readbyqxmd.com/read/28441529/mps1-regulates-kinetochore-microtubule-attachment-stability-via-the-ska-complex-to-ensure-error-free-chromosome-segregation
#10
John Maciejowski, Hauke Drechsler, Kathrin Grundner-Culemann, Edward R Ballister, Jose-Antonio Rodriguez-Rodriguez, Veronica Rodriguez-Bravo, Mathew J K Jones, Emily Foley, Michael A Lampson, Henrik Daub, Andrew D McAinsh, Prasad V Jallepalli
The spindle assembly checkpoint kinase Mps1 not only inhibits anaphase but also corrects erroneous attachments that could lead to missegregation and aneuploidy. However, Mps1's error correction-relevant substrates are unknown. Using a chemically tuned kinetochore-targeting assay, we show that Mps1 destabilizes microtubule attachments (K fibers) epistatically to Aurora B, the other major error-correcting kinase. Through quantitative proteomics, we identify multiple sites of Mps1-regulated phosphorylation at the outer kinetochore...
April 24, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28436952/playing-polo-during-mitosis-plk1-takes-the-lead
#11
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/28424497/the-glycogen-synthase-kinase-mogsk1-regulated-by-mps1-map-kinase-is-required-for-fungal-development-and-pathogenicity-in-magnaporthe-oryzae
#12
Tengsheng Zhou, Yasin F Dagdas, Xiaohan Zhu, Shiqin Zheng, Liqiong Chen, Zachary Cartwright, Nicholas J Talbot, Zonghua Wang
Magnaporthe oryzae, the causal agent of blast disease, is one of the most destructive plant pathogens, causing significant yield losses on staple crops such as rice and wheat. The fungus infects plants with a specialized cell called an appressorium, whose development is tightly regulated by MAPK signaling pathways following the activation of upstream sensors in response to environmental stimuli. Here, we show the expression of the Glycogen synthase kinase 3 (GSK3) MoGSK1 in M. oryzae is regulated by Mps1 MAP kinase, particularly under the stressed conditions...
April 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28334731/characterisation-of-cct271850-a-selective-oral-and-potent-mps1-inhibitor-used-to-directly-measure-in-vivo-mps1-inhibition-vs-therapeutic-efficacy
#13
Amir Faisal, Grace W Y Mak, Mark D Gurden, Cristina P R Xavier, Simon J Anderhub, Paolo Innocenti, Isaac M Westwood, Sébastien Naud, Angela Hayes, Gary Box, Melanie R Valenti, Alexis K De Haven Brandon, Lisa O'Fee, Jessica Schmitt, Hannah L Woodward, Rosemary Burke, Rob L M vanMontfort, Julian Blagg, Florence I Raynaud, Suzanne A Eccles, Swen Hoelder, Spiros Linardopoulos
BACKGROUND: The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents anaphase onset until the appropriate attachment and tension across kinetochores is achieved. MPS1 kinase activity is essential for the activation of the spindle assembly checkpoint and has been shown to be deregulated in human tumours with chromosomal instability and aneuploidy...
April 25, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28299790/tc-mps1-12-a-novel-mps1-inhibitor-suppresses-the-growth-of-hepatocellular-carcinoma-cells-via-the-accumulation-of-chromosomal-instability
#14
Minji Choi, Yoo Hong Min, Jaehyuk Pyo, Chang-Woo Lee, Chang-Young Jang, Ja-Eun Kim
BACKGROUND AND PURPOSE: Chromosomal instability is not only a hallmark of cancer but also an attractive therapeutic target. A diverse set of mitotic kinases maintains chromosomal stability. One of these is monopolar spindle 1 (Mps1, also known as TTK), which is essential for chromosome alignment and for the spindle assembly checkpoint (SAC). Pharmacological inhibition of Mps1 has been suggested as a cancer therapeutic; however, despite the existence of a novel Mps1 inhibitor, TC Mps1 12, no such studies have been performed...
June 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28287092/loss-of-centromere-cohesion-in-aneuploid-human-oocytes-correlates-with-decreased-kinetochore-localization-of-the-sac-proteins-bub1-and-bubr1
#15
Julie Lagirand-Cantaloube, Cendrine Ciabrini, Sophie Charrasse, Alice Ferrieres, Anna Castro, Tal Anahory, Thierry Lorca
In human eggs, aneuploidy increases with age and can result in infertility and genetic diseases. Studies in mouse oocytes suggest that reduced centromere cohesion and spindle assembly checkpoint (SAC) activity could be at the origin of chromosome missegregation. Little is known about these two features in humans. Here, we show that in human eggs, inter-kinetochore distances of bivalent chromosomes strongly increase with age. This results in the formation of univalent chromosomes during metaphase I (MI) and of single chromatids in metaphase II (MII)...
March 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28278657/the-extraction-and-characterisation-of-a-polysaccharide-from-moniliophthora-perniciosa-ccmb-0257
#16
Gildomar L Valasques Junior, Elisangela F Boffo, Jener David G Santos, Hugo Neves Brandão, Artur J S Mascarenhas, Fernanda T Cruz, Sandra A Assis
The alpha-D-glucans are worldwide acknowledged as powerful immune system stimulants found in several sources; however, the fungal-derived sources appear to respond with higher activity. The present study has investigated polysaccharide production in Moniliophthora perniciosa. The dry biomass was subjected to thermal treatment in alkaline solution after fermentation. The biopolymers dissolved in this solution were precipitated after three volumes of absolute ethanol were added to the supernatant. The pure polysaccharide MPS1 was obtained through molecular exclusion chromatography using the Sephacryl S-200 column...
July 2017: Natural Product Research
https://www.readbyqxmd.com/read/28270606/functional-characterization-of-cfi-402257-a-potent-and-selective-mps1-ttk-kinase-inhibitor-for-the-treatment-of-cancer
#17
Jacqueline M Mason, Xin Wei, Graham C Fletcher, Reza Kiarash, Richard Brokx, Richard Hodgson, Irina Beletskaya, Mark R Bray, Tak W Mak
Loss of cell-cycle control is a hallmark of human cancer. Cell-cycle checkpoints are essential for maintaining genome integrity and balanced growth and division. They are specifically deregulated in cancer cells and contain regulators that represent potential therapeutic targets. Monopolar spindle 1 (Mps1; also known as TTK protein kinase) is a core component of the spindle assembly checkpoint (SAC), a genome-surveillance mechanism that is important for cell survival, and has emerged as a candidate target for anticancer therapy...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28259529/novel-pyrrolopyrimidines-as-mps1-ttk-kinase-inhibitors-for-breast-cancer
#18
Yasuro Sugimoto, Dwitiya B Sawant, Harold A Fisk, Liguang Mao, Chenglong Li, Somsundaram Chettiar, Pui-Kai Li, Michael V Darby, Robert W Brueggemeier
New targeted therapy approaches for certain subtypes of breast cancer, such as triple-negative breast cancers and other aggressive phenotypes, are desired. High levels of the mitotic checkpoint kinase Mps1/TTK have correlated with high histologic grade in breast cancer, suggesting a potential new therapeutic target for aggressive breast cancers (BC). Novel small molecules targeting Mps1 were designed by computer assisted docking analyses, and several candidate compounds were synthesized. These compounds were evaluated in anti-proliferative assays of a panel of 15 breast cancer cell lines and further examined for their ability to inhibit a variety of Mps1-dependent biological functions...
April 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28244240/mst50-is-involved-in-multiple-map-kinase-signaling-pathways-in-magnaporthe-oryzae
#19
Guotian Li, Xue Zhang, Huan Tian, Yoon-E Choi, W Andy Tao, Jin-Rong Xu
Appressorium formation plays a critical role in Magnaporthe oryzae. Mst50 is an adapter protein of the Mst11-Mst7-Pmk1 cascade that is essential for appressorium formation. To further characterize its functions, affinity purification was used to identify Mst50-interacting proteins (MIPs) in this study. Two of the MIPs are Mst11 and Mst7 that are known to interact with Mst50 for Pmk1 activation. Surprisingly, two other MIPs are Mck1 and Mkk2 that are the upstream kinases of the Mps1 pathway. Domain deletion analysis showed that the sterile alpha-motif of Mst50 but not the Ras-association domain was important for its interaction with Mck1 and responses to cell wall and oxidative stresses...
February 28, 2017: Environmental Microbiology
https://www.readbyqxmd.com/read/28206949/micromanaging-checkpoint-proteins
#20
Andrea Ciliberto, Silke Hauf
The kinase Mps1, long known to be the 'boss' in mitotic checkpoint signaling, phosphorylates multiple proteins in the checkpoint signaling cascade.
February 16, 2017: ELife
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