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https://www.readbyqxmd.com/read/28934390/protein-phosphatase-1-regulates-huntingtin-exon-1-aggregation-and-toxicity
#1
Joana Branco-Santos, Federico Herrera, Gonçalo M Poças, Yolanda Pires-Afonso, Flaviano Giorgini, Pedro M Domingos, Tiago F Outeiro
Huntington's disease is neurodegenerative disorder caused by a polyglutamine expansion in the N-terminal region of the huntingtin protein (N17). Here, we analysed the relative contribution of each phosphorylatable residue in the N17 region (T3, S13 and S16) towards huntingtin exon 1 (HTTex1) oligomerization, aggregation and toxicity in human cells and Drosophila neurons. We used bimolecular fluorescence complementation to show that expression of single phosphomimic mutations completely abolished HTTex1 aggregation in human cells...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28934028/toward-neuroproteomics-in-biological-psychiatry-a-systems-approach-unravels-okadaic-acid-induced-alterations-in-the-neuronal-phosphoproteome
#2
Joana Machado Oliveira, Cristóvão B da Cruz E Silva, Thorsten Müller, Tânia Soares Martins, Marta Cova, Odete A B da Cruz E Silva, Ana Gabriela Henriques
Neuroproteomics is an evolving field of postgenomic medicine, highlighting the convergence of psychiatry/neurology and proteomics, yet compared with neurogenetics, it has received little attention. This study in rat primary neuronal cultures provides an example of a neuroproteomic approach relevant to the study of psychiatric disease pathophysiology, focusing on Alzheimer's disease. In this context, okadaic acid (OA) is routinely used in experimental designs to investigate phosphorylation-mediated events. It is a potent protein phosphatase (PP) inhibitor, particularly of PP1 and PP2A...
September 2017: Omics: a Journal of Integrative Biology
https://www.readbyqxmd.com/read/28931335/activation-of-erk-signaling-by-src-family-kinases-sfks-in-drg-neurons-contributes-to-hydrogen-peroxide-h2o2-induced-thermal-hyperalgesia
#3
Ajeet Kumar Singh, Manjula Vinayak
Concomitant generation of reactive oxygen species during tissue inflammation has been recognized as a major factor for development and maintenance of hyperalgesia, out of which H2O2 is the major player. However, molecular mechanism of H2O2 induced hyperalgesia is still obscure. The aim of present study is to analyze the mechanism of H2O2 induced hyperalgesia in rats. Intraplantar injection of H2O2 (5, 10 and 20 µmoles/paw) induced a significant thermal hyperalgesia in the hind paw, confirmed by increased c-Fos activity in dorsal horn of spinal cord...
September 21, 2017: Free Radical Research
https://www.readbyqxmd.com/read/28910568/network-of-phosphatases-and-hdac-complexes-at-repressed-chromatin
#4
I J de Castro, H A Amin, V Vinciotti, P Vagnarelli
Tight regulation of gene expression is achieved by a variety of protein complexes that selectively bind chromatin, modify it and change its transcription competency. Histone acetylases (HATs) and deacetylases (HDACs) play an important role in this process. They can generate transcriptionally active or inactive chromatin through the addition (HATs) or removal (HDACs) of acetyl groups on histones, respectively. Repo-Man is a Protein Phosphatase 1 targeting subunit that accumulates on chromosomes during mitotic exit and mediates the removal of mitotic histone H3 phosphorylations...
September 14, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28893598/microcystins-synthesis-and-structure-activity-relationship-studies-toward-pp1-and-pp2a
#5
REVIEW
Miriam Fontanillo, Maja Köhn
Microcystins are highly toxic cyanotoxins responsible for plant, animal and human poisoning. Exposure to microcystins, mainly through drinkable water and contaminated food, is a current world health concern. Although it is quite challenging, the synthesis of these potent cyanotoxins, analogs and derivatives helps to evaluate their toxicological properties and to elucidate their binding mechanisms to their main targets Protein Phosphatase-1 (PP1) and -2A (PP2A). This review focuses on synthetic approaches to prepare microcystins and analogs and compiles structure-activity relationship (SAR) studies that describe the unique features of microcystins that make them so potent...
August 24, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28890776/discovery-of-a-potent-protein-kinase-d-inhibitor-insights-in-the-binding-mode-of-pyrazolo-3-4-d-pyrimidine-analogues
#6
Klaas Verschueren, Mathias Cobbaut, Joachim Demaerel, Lina Saadah, Arnout R D Voet, Johan Van Lint, Wim M De Borggraeve
In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. The lead compound for this study was 1-NM-PP1, which was previously found by us and others to inhibit PKD. In our screening we identified one compound (3-IN-PP1) displaying a 10-fold increase in potency over 1-NM-PP1, opening new possibilities for specific protein kinase inhibitors for kinases that show sensitivity towards pyrazolo[3,4-d]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-d]pyrimidine compounds are bound in a similar fashion as PKD's natural ligand ATP...
March 1, 2017: MedChemComm
https://www.readbyqxmd.com/read/28878117/tead1-is-required-for-maintaining-adult-cardiomyocyte-function-and-its-loss-results-in-lethal-dilated-cardiomyopathy
#7
Ruya Liu, Jeongkyung Lee, Byung S Kim, Qiongling Wang, Samuel K Buxton, Nikhil Balasubramanyam, Jean J Kim, Jianrong Dong, Aijun Zhang, Shumin Li, Anisha A Gupte, Dale J Hamilton, James F Martin, George G Rodney, Cristian Coarfa, Xander Ht Wehrens, Vijay K Yechoor, Mousumi Moulik
Heart disease remains the leading cause of death worldwide, highlighting a pressing need to identify novel regulators of cardiomyocyte (CM) function that could be therapeutically targeted. The mammalian Hippo/Tead pathway is critical in embryonic cardiac development and perinatal CM proliferation. However, the requirement of Tead1, the transcriptional effector of this pathway, in the adult heart is unknown. Here, we show that tamoxifen-inducible adult CM-specific Tead1 ablation led to lethal acute-onset dilated cardiomyopathy, associated with impairment in excitation-contraction coupling...
September 7, 2017: JCI Insight
https://www.readbyqxmd.com/read/28863192/e2-er-%C3%AE-inhibit-iso-induced-cardiac-cellular-hypertrophy-by-suppressing-ca2-calcineurin-signaling
#8
Cheng-Yen Tsai, Wei-Wen Kuo, Marthandam Asokan Shibu, Yueh-Min Lin, Chien-Nam Liu, Yi-Hui Chen, Cecilia-Hsuan Day, Chia-Yao Shen, Vijaya Padma Viswanadha, Chih-Yang Huang
Cardiovascular incidences are markedly higher in men than in pre-menstrual women. However, this advantage in women declines with aging and therefore can be correlated with the sex hormone 17β-Estradiol (E2) which is reported to protect heart cells by acting though estrogen receptors (ERs). In this study we have determined the effect of E2/ERβ against ISO induced cellular hypertrophy in H9c2 cardiomyoblast cells. The results confirm that ISO induced cardiac-hypertrophy by elevating the levels of hypertrophy associated proteins, ANP and BNP and further by upregulating p-CaMKII, calcineurin, p-GATA4 and NFATc3 which was correlated with a significant enlargement of the H9c2 cardiomyoblast...
2017: PloS One
https://www.readbyqxmd.com/read/28840249/a-kinase-phosphatase-network-that-regulates-kinetochore-microtubule-attachments-and-the-sac
#9
Giulia Vallardi, Marilia Henriques Cordeiro, Adrian Thomas Saurin
The KMN network (for KNL1, MIS12 and NDC80 complexes) is a hub for signalling at the outer kinetochore. It integrates the activities of two kinases (MPS1 and Aurora B) and two phosphatases (PP1 and PP2A-B56) to regulate kinetochore-microtubule attachments and the spindle assembly checkpoint (SAC). We will first discuss each of these enzymes separately, to describe how they are regulated at kinetochores and why this is important for their primary function in controlling either microtubule attachments or the SAC...
2017: Progress in Molecular and Subcellular Biology
https://www.readbyqxmd.com/read/28837860/pomegranate-peel-extract-attenuates-d-galactose-induced-oxidative-stress-and-hearing-loss-by-regulating-pnuts-pp1-activity-in-the-mouse-cochlea
#10
Shuangyue Liu, Tao Xu, Xidi Wu, Yuhan Lin, Dongyan Bao, Yang Di, Tingting Ma, Yan Dang, Peili Jia, Jianqiao Xian, Aimei Wang, Yongxin Liu
Oxidative stress is considered to be a major contributor to age-related hearing loss (ARHL). Here, we investigated whether pomegranate peel extract (PPE) protected against hearing loss by decreased oxidative stress in the cochlea of D-galactose-induced accelerated aging mice. The aging mice exhibited an increase in hearing threshold shifts and hair cells loss, which were improved in the PPE-treated aging mice. The aging mice also exhibited an increase in 4-hydroxynonenal, the expression of protein phosphatase 1 nuclear targeting subunit (PNUTS), p53 and caspase-3, and a decrease in protein phosphatase 1 (PP1) and MDM2 in the cochlea...
July 25, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28827520/platelets-reduce-anoikis-and-promote-metastasis-by-activating-yap1-signaling
#11
Monika Haemmerle, Morgan L Taylor, Tony Gutschner, Sunila Pradeep, Min Soon Cho, Jianting Sheng, Yasmin M Lyons, Archana S Nagaraja, Robert L Dood, Yunfei Wen, Lingegowda S Mangala, Jean M Hansen, Rajesha Rupaimoole, Kshipra M Gharpure, Cristian Rodriguez-Aguayo, Sun Young Yim, Ju-Seog Lee, Cristina Ivan, Wei Hu, Gabriel Lopez-Berestein, Stephen T Wong, Beth Y Karlan, Douglas A Levine, Jinsong Liu, Vahid Afshar-Kharghan, Anil K Sood
Thrombocytosis is present in more than 30% of patients with solid malignancies and correlates with worsened patient survival. Tumor cell interaction with various cellular components of the tumor microenvironment including platelets is crucial for tumor growth and metastasis. Although it is known that platelets can infiltrate into tumor tissue, secrete pro-angiogenic and pro-tumorigenic factors and thereby increase tumor growth, the precise molecular interactions between platelets and metastatic cancer cells are not well understood...
August 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28827282/a-novel-image-based-high-throughput-screening-assay-discovers-therapeutic-candidates-for-adult-polyglucosan-body-disease
#12
Leonardo J Solemsky, Netaly Khazanov, Hanoch Senderowitz, Peixiang Wang, Berge A Minassian, Igor M Ferreira, Wyatt W Yue, Alexander Lossos, Miguel Weil, Or Kakhlon
Glycogen storage disorders (GSDs) are caused by excessive accumulation of glycogen. Some GSDs (Adult Polyglucosan Body Disease (APBD), Tarui and Lafora diseases) are caused by intracellular accumulation of insoluble inclusions, called polyglucosan bodies (PB), which are chiefly composed of malconstructed glycogen. We developed an APBD patient skin fibroblast cell-based assay for PB identification, where the bodies are identified as amylase-resistant periodic acid-Schiff's (PAS) stained structures, and quantified...
August 21, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28818393/the-modulation-of-the-phosphorylation-status-of-nkcc1-in-organ-cultured-bovine-lenses-implications-for-the-regulation-of-fiber-cell-and-overall-lens-volume
#13
Irene Vorontsova, Paul J Donaldson, Zhiying Kong, Chiharu Wickremesinghe, Leo Lam, Julie C Lim
In this study we have used an antibody that specifically detects the phosphorylation status of the Sodium/Potassium/2 Chloride Cotransporter (NKCC1) to study whether the activity of NKCC1 can be regulated in organ cultured bovine lenses. Western blotting was first used to confirm the expression of NKCC1, phosphorylated NKCC1 (NKCC1-P) and the regulatory kinases WNK/SPAK and phosphatases PP1/PP2A in bovine lenses at the protein level. Changes to NKCC1-P status were then assessed by organ culturing bovine lenses in either isotonic, hypertonic or hypotonic solutions in the presence or absence of the NKCC inhibitor, bumetanide, or phosphatase inhibitors okadaic acid and calyculin A...
August 14, 2017: Experimental Eye Research
https://www.readbyqxmd.com/read/28817667/glycoprotein-ib-activation-by-thrombin-stimulates-the-energy-metabolism-in-human-platelets
#14
Norma Corona de la Peña, Manuel Gutiérrez-Aguilar, Ileana Hernández-Reséndiz, Álvaro Marín-Hernández, Sara Rodríguez-Enríquez
Thrombin-induced platelet activation requires substantial amounts of ATP. However, the specific contribution of each ATP-generating pathway i.e., oxidative phosphorylation (OxPhos) versus glycolysis and the biochemical mechanisms involved in the thrombin-induced activation of energy metabolism remain unclear. Here we report an integral analysis on the role of both energy pathways in human platelets activated by several agonists, and the signal transducing mechanisms associated with such activation. We found that thrombin, Trap-6, arachidonic acid, collagen, A23187, epinephrine and ADP significantly increased glycolytic flux (3-38 times vs...
2017: PloS One
https://www.readbyqxmd.com/read/28759048/decoding-the-selectivity-of-eif2%C3%AE-holophosphatases-and-ppp1r15a-inhibitors
#15
Marta Carrara, Anna Sigurdardottir, Anne Bertolotti
The reversible phosphorylation of proteins controls most cellular functions. Protein kinases have been popular drug targets, unlike phosphatases, which remain a drug discovery challenge. Guanabenz and Sephin1 are selective inhibitors of the phosphatase regulatory subunit PPP1R15A (R15A) that prolong the benefit of eIF2α phosphorylation, thereby protecting cells from proteostatic defects. In mice, Sephin1 prevents two neurodegenerative diseases, Charcot-Marie-Tooth 1B (CMT-1B) and SOD1-mediated amyotrophic lateral sclerosis (ALS)...
September 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28751710/aurora-b-kinase-pathway-controls-the-lateral-to-end-on-conversion-of-kinetochore-microtubule-attachments-in-human-cells
#16
Roshan L Shrestha, Duccio Conti, Naoka Tamura, Dominique Braun, Revathy A Ramalingam, Konstanty Cieslinski, Jonas Ries, Viji M Draviam
Human chromosomes are captured along microtubule walls (lateral attachment) and then tethered to microtubule-ends (end-on attachment) through a multi-step end-on conversion process. Upstream regulators that orchestrate this remarkable change in the plane of kinetochore-microtubule attachment in human cells are not known. By tracking kinetochore movements and using kinetochore markers specific to attachment status, we reveal a spatially defined role for Aurora-B kinase in retarding the end-on conversion process...
July 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/28736554/differential-requirements-for-src-family-kinases-in-syk-or-zap70-mediated-slp-76-phosphorylation-in-lymphocytes
#17
Frank Fasbender, Maren Claus, Sabine Wingert, Mina Sandusky, Carsten Watzl
In a synthetic biology approach using Schneider (S2) cells, we show that SLP-76 is directly phosphorylated at tyrosines Y113 and Y128 by SYK in the presence of ITAM-containing adapters such as CD3ζ, DAP12, or FcεRγ. This phosphorylation was dependent on at least one functional ITAM and a functional SH2 domain within SYK. Inhibition of Src-kinases by inhibitors PP1 and PP2 did not reduce SLP-76 phosphorylation in S2 cells, suggesting an ITAM and SYK dependent, but Src-kinase independent signaling pathway...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28701256/toll-like-receptor-expression-patterns-in-the-rat-uterus-during-post-partum-involution
#18
Emel Alan, Narin Liman
Toll-like receptors (TLRs) belong to a family of pathogen recognition receptors and play critical roles in detecting and responding to invading pathogens. TLR expression could be significant because, in the uterus, the reproductive tract is an important site of exposure to and infection by pathogens during the post partum involution period. To clarify the expression and localisation patterns of TLRs in the rat uterus on Days 1, 3, 5 and 10 post partum (PP1, PP3, PP5 and PP10 respectively), immunohistochemistry and western blotting were used to analyse TLR1-7, TLR9 and TLR10...
July 13, 2017: Reproduction, Fertility, and Development
https://www.readbyqxmd.com/read/28688054/erratum-to-differential-regulation-of-protein-phosphatase-1-pp1-isoforms-in-human-heart-failure-and-atrial-fibrillation
#19
Stefanie Meyer-Roxlau, Simon Lämmle, Annett Opitz, Stephan Künzel, Julius P Joos, Stefan Neef, Karolina Sekeres, Samuel Sossalla, Friedrich Schöndube, Konstantin Alexiou, Lars S Maier, Dobromir Dobrev, Kaomei Guan, Silvio Weber, Ali El-Armouche
No abstract text is available yet for this article.
September 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/28681362/protein-phosphatases-1-and-2a-and-their-naturally-occurring-inhibitors-current-topics-in-smooth-muscle-physiology-and-chemical-biology
#20
REVIEW
Akira Takai, Masumi Eto, Katsuya Hirano, Kosuke Takeya, Toshiyuki Wakimoto, Masaru Watanabe
Protein phosphatases 1 and 2A (PP1 and PP2A) are the most ubiquitous and abundant serine/threonine phosphatases in eukaryotic cells. They play fundamental roles in the regulation of various cellular functions. This review focuses on recent advances in the functional studies of these enzymes in the field of smooth muscle physiology. Many naturally occurring protein phosphatase inhibitors with different relative PP1/PP2A affinities have been discovered and are widely used as powerful research tools. Current topics in the chemical biology of PP1/PP2A inhibitors are introduced and discussed, highlighting the identification of the gene cluster responsible for the biosynthesis of calyculin A in a symbiont microorganism of a marine sponge...
July 5, 2017: Journal of Physiological Sciences: JPS
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