DOCSLIB.ORG

Covalent Aurora a Regulation by the Metabolic Integrator Coenzyme a T Yugo Tsuchiyaa,#, Dominic P

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Covalent Aurora a Regulation by the Metabolic Integrator Coenzyme a T Yugo Tsuchiyaa,#, Dominic P Redox Biology 28 (2020) 101318 Contents lists available at ScienceDirect Redox Biology journal homepage: www.elsevier.com/locate/redox Research Paper Covalent Aurora A regulation by the metabolic integrator coenzyme A T Yugo Tsuchiyaa,#, Dominic P. Byrneb,#, Selena G. Burgessc,#, Jenny Bormannd, Jovana Bakovića, Yueyang Huanga, Alexander Zhyvoloupa, Bess Yi Kun Yua, Sew Peak-Chewe, Trang Tranf, Fiona Bellanyf, Alethea B. Taborf, AW Edith Chang, Lalitha Guruprasadh, Oleg Garifulini, Valeriy Filonenkoi, Matthias Vonderachj, Samantha Ferriesj, Claire E. Eyersb,j, John Carrolld,1, ∗∗ ∗∗∗ ∗ Mark Skehele, Richard Baylissc, , Patrick A. Eyersb, , Ivan Gouta,i, a Department of Structural and Molecular Biology, University College London, London, WC1E 6BT, UK b Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK c School of Molecular and Cellular Biology, Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK d Department of Cell and Developmental Biology, University College London, London, WC1E 6BT, UK e MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK f Department of Chemistry, University College London, London, WC1E 6BT, UK g Wolfson Institute for Biomedical Research, University College London, London, WC1E 6BT, UK h School of Chemistry, University of Hyderabad, Hyderabad, 500 046, India i Department of Cell Signaling, Institute of Molecular Biology and Genetics, Kyiv 143, Ukraine j Centre for Proteome Research, Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK ABSTRACT Aurora A kinase is a master mitotic regulator whose functions are controlled by several regulatory interactions and post-translational modifications. It is frequently dysregulated in cancer, making Aurora A inhibition a very attractive antitumor target. However, recently uncovered links between Aurora A, cellular metabolism and redox regulation are not well understood. In this study, we report a novel mechanism of Aurora A regulation in the cellular response to oxidative stress through CoAlation. A combination of biochemical, biophysical, crystallographic and cell biology approaches revealed a new and, to our knowledge, unique mode of Aurora A inhibition by CoA, involving selective binding of the ADP moiety of CoA to the ATP binding pocket and covalent modification of Cys290 in the activation loop bythe thiol group of the pantetheine tail. We provide evidence that covalent CoA modification (CoAlation) of Aurora A is specific, and that it can be induced byoxidative stress in human cells. Oxidising agents, such as diamide, hydrogen peroxide and menadione were found to induce Thr 288 phosphorylation and DTT-dependent dimerization of Aurora A. Moreover, microinjection of CoA into fertilized mouse embryos disrupts bipolar spindle formation and the alignment of chromosomes, consistent with Aurora A inhibition. Altogether, our data reveal CoA as a new, rather selective, inhibitor of Aurora A, which locks this kinase in an inactive state via a “dual anchor” mechanism of inhibition that might also operate in cellular response to oxidative stress. Finally and most importantly, we believe that these novel findings provide a new rationale for developing effective and irreversible inhibitors of Aurora A, and perhaps other protein kinases containing appropriately conserved Cysresidues. 1. Introduction distinct sub-families composed of Aurora A and Aurora B and C [5]. Aurora kinases contain a conserved C-terminal kinase domain, which Aurora kinases are Ser/Thr kinases that play well-documented roles phosphorylates substrates with a minimal R-X-S/T consensus motif in eukaryotes, where they control meiosis, mitosis and cell division [1]. [6,7]. The Aurora kinase domain is itself regulated by a critical au- Aurora kinases differ in relative expression levels, stability and sub- tophosphorylation event in the activation loop [8–11], which is asso- cellular localization, the latter linked to single amino acid differences ciated with catalytic activation and timely execution of different phases that dramatically affect biological distribution and function [2–4]. In of mitosis [12–15] and meiosis [16]. During the cell cycle, Aurora A has vertebrates, the Aurora family of protein kinases are grouped into two canonical roles in centrosome duplication, spindle bipolarity, ∗ Corresponding author. Department of Structural and Molecular Biology, University College London, London, WC1E 6BT, UK. ∗∗ Corresponding author. ∗∗∗ Corresponding author. E-mail addresses: [email protected] (R. Bayliss), [email protected] (P.A. Eyers), [email protected] (I. Gout). # These authors contributed equally to this study. 1 Current address: Development and Stem Cell Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia. https://doi.org/10.1016/j.redox.2019.101318 Received 10 April 2019; Received in revised form 14 August 2019; Accepted 1 September 2019 Available online 05 September 2019 2213-2317/ © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/). Y. Tsuchiya, et al. Redox Biology 28 (2020) 101318 chromosome segregation and spindle checkpoint maintenance [17], CoA. Intracellular levels of CoA and its thioester-derivatives are tightly which together contribute to fundamental processes such as cen- regulated by a variety of stimuli, including hormones, nutrients, me- trosomal and genomic stability and likely reflect the long-recognised tabolites and stresses [43,44]. The main rate-limiting enzyme in CoA oncogenic properties associated with overexpressed Aurora A [18]. biosynthesis is pantothenate kinase which initiates the biosynthetic Interestingly, Aurora A has also recently been implicated in the control pathway [45]. Furthermore, the activity of the last enzyme in the of energy production in cancer cells through mitochondrial targeting pathway, CoA synthase, is regulated by extracellular stimuli and stress [19]. In contrast, Aurora B is a chromosomal passenger protein required response [46–49]. for the spindle assembly checkpoint and rate-limiting for cytokinesis in CoA and its thioester derivatives are strategically positioned at the cells [20]. Aurora C is most highly expressed in germ cells, where it can crossroads of cellular anabolic and catabolic pathways, controlling the functionally replace Auora B as a chromosome passenger protein [1]. Krebs cycle, ketogenesis, the biosynthesis of proteins, lipids and cho- Aurora A biology is controlled via targeted subcellular localization lesterol, oxidation of fatty acids and degradation of amino acids. In mediated through the formation of dynamic protein complexes with addition, they are also involved in the regulation of gene expression and non-catalytic binding partners such as TPX2 [9,10,21–23], TACC3 [24] cellular metabolism via post-translational modifications, such as pro- and NMYC [25], which control distinct Aurora A signaling outputs. tein acetylation, butyrylation, malonylation and succinylation. Indeed, Aurora A/TPX2 holoenzyme complexes co-localise at the polar Abnormal biosynthesis and homeostasis of CoA and its derivatives is end of spindle microtubules, where Aurora A is maintained in dynamic associated with various human pathologies, including neurodegenera- pools alongside the mitoitc kinesin Eg5, which is localised by a C- tion, cancer, metabolic disorders and cardiac hypertrophy [44]. terminal motif in TPX2 [22,26,27]. Allosteric Aurora A activation on Protein CoAlation is a recently described post-translational mod- the spindle is thought to occur by binding to microtubule-associated ification (PTM) that involves covalent modification of cysteine residues proteins (which are also Aurora A substrates) such as TPX2 and TACC3 by CoA [50]. New research tools and methodologies have revealed [28]. Mechanistically, Aurora A activation requires autopho- protein CoAlation as a widespread and reversible PTM involved in sphorylation of Thr 288 (and possibly Thr 287), which drives the kinase cellular redox regulation [51]. To date, more than one thousand pro- into the most catalytically-competent conformation [3,9,29]. Interest- teins have been found to be CoAlated in a variety of prokaryotic and ingly, the TPX2 complex also protects Aurora A from Thr 288 depho- eukaryotic cells [50,52]. Protein CoAlation occurs at a low level in sphorylation by PP1 and PP2A phosphatases in vitro [3,9], although exponentialy growing cells, but is strongly induced in reponse to var- accumulating evidence suggests that the PP6 Ser/Thr phosphatase is ious oxidising agents, including H2O2, diamide, menadione and t-butyl rate-limiting for mitotic dephosphorylation at this site in cells [27]. In hydroperoxide. Protein CoAlation alters the molecular mass, charge, addition to TPX2, Aurora A is targeted to core protein co-factors, in- and activity of modified proteins, and is thought to protect them from cluding the centrosomal protein Cep192, the mitotic entry factor BORA irreversible over-oxidation. and the transcription factor NMYC [30], whose interaction with a The presence of exposed cysteine residues on the surface of proteins specific inactive Aurora A conformation is important for controlling provides a simple, sometimes reversible, mechanism for post-transla- NMYC stability in cells, and the basis for new approaches
Load more

Recommended publications
  • Aurora Kinase a in Gastrointestinal Cancers: Time to Target Ahmed Katsha1, Abbes Belkhiri1, Laura Goff3 and Wael El-Rifai1,2,4*
    Katsha et al. Molecular Cancer (2015) 14:106 DOI 10.1186/s12943-015-0375-4 REVIEW Open Access Aurora kinase A in gastrointestinal cancers: time to target Ahmed Katsha1, Abbes Belkhiri1, Laura Goff3 and Wael El-Rifai1,2,4* Abstract Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. During the last two decades, several studies have shown amplification and overexpression of Aurora kinase A (AURKA) in several GI malignancies. These studies demonstrated that AURKA not only plays a role in regulating cell cycle and mitosis, but also regulates a number of key oncogenic signaling pathways. Although AURKA inhibitors have moved to phase III clinical trials in lymphomas, there has been slower progress in GI cancers and solid tumors. Ongoing clinical trials testing AURKA inhibitors as a single agent or in combination with conventional chemotherapies are expected to provide important clinical information for targeting AURKA in GI cancers. It is, therefore, imperative to consider investigations of molecular determinants of response and resistance to this class of inhibitors. This will improve evaluation of the efficacy of these drugs and establish biomarker based strategies for enrollment into clinical trials, which hold the future direction for personalized cancer therapy. In this review, we will discuss the available data on AURKA in GI cancers. We will also summarize the major AURKA inhibitors that have been developed and tested in pre-clinical and clinical settings. Keywords: Aurora kinases, Therapy, AURKA inhibitors, MNL8237, Alisertib, Gastrointestinal, Cancer, Signaling pathways Introduction stage [9-11]. Furthermore, AURKA is critical for Mitotic kinases are the main proteins that coordinate ac- bipolar-spindle assembly where it interacts with Ran- curate mitotic processing [1].
    [Show full text]
  • The Role of P21-Activated Protein Kinase 1 in Metabolic Homeostasis
    THE ROLE OF P21-ACTIVATED PROTEIN KINASE 1 IN METABOLIC HOMEOSTASIS by YU-TING CHIANG A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Physiology University of Toronto © Copyright by Yu-ting Chiang 2014 The Role of P21-Activated Protein Kinase 1 in Metabolic Homeostasis Yu-ting Chiang Doctor of Philosophy Department of Physiology University of Toronto 2014 Abstract Our laboratory has demonstrated previously that the proglucagon gene (gcg), which encodes the incretin hormone GLP-1, is among the downstream targets of the Wnt signaling pathway; and that Pak1 mediates the stimulatory effect of insulin on Wnt target gene expression in mouse gut non- endocrine cells. Here, I asked whether Pak1 controls gut gcg expression and GLP-1 production, and whether Pak1 deletion leads to impaired metabolic homeostasis in mice. I detected the expression of Pak1 and two other group I Paks in the gut endocrine L cell line GLUTag, and co- localized Pak1 and GLP-1 in the mouse gut. Insulin was shown to stimulate Pak1 Thr423 and β-cat Ser675 phosphorylation. The stimulation of insulin on β-cat Ser675 phosphorylation, gcg promoter activity and gcg mRNA expression could be attenuated by the Pak inhibitor IPA3. Male Pak1-/- mice showed significant reduction in both gut and brain gcg expression levels, and attenuated elevation of plasma GLP-1 levels in response to oral glucose challenge. Notably, the Pak1-/- mice were intolerant to both intraperitoneal and oral glucose administration. Aged Pak1-/- mice showed a severe defect in response to intraperitoneal pyruvate challenge (IPPTT).
    [Show full text]
  • RASSF1A Interacts with and Activates the Mitotic Kinase Aurora-A
    Oncogene (2008) 27, 6175–6186 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc ORIGINAL ARTICLE RASSF1A interacts with and activates the mitotic kinase Aurora-A L Liu1, C Guo1, R Dammann2, S Tommasi1 and GP Pfeifer1 1Division of Biology, Beckman Research Institute, City of Hope Cancer Center, Duarte, CA, USA and 2Institute of Genetics, University of Giessen, Giessen, Germany The RAS association domain family 1A (RASSF1A) gene tumorigenesis and carcinogen-induced tumorigenesis is located at chromosome 3p21.3 within a specific area of (Tommasi et al., 2005; van der Weyden et al., 2005), common heterozygous and homozygous deletions. RASS- supporting the notion that RASSF1A is a bona fide F1A frequently undergoes promoter methylation-asso- tumor suppressor. However, it is not fully understood ciated inactivation in human cancers. Rassf1aÀ/À mice how RASSF1A is involved in tumor suppression. are prone to both spontaneous and carcinogen-induced The biochemical function of the RASSF1A protein is tumorigenesis, supporting the notion that RASSF1A is a largely unknown. The homology of RASSF1A with the tumor suppressor. However, it is not fully understood how mammalian Ras effector novel Ras effector (NORE)1 RASSF1A is involved in tumor suppression pathways. suggests that the RASSF1A gene product may function Here we show that overexpression of RASSF1A inhibits in signal transduction pathways involving Ras-like centrosome separation. RASSF1A interacts with Aurora-A, proteins. However, recent data indicate that RASSF1A a mitotic kinase. Surprisingly, knockdown of RASS- itself binds to RAS only weakly and that binding to F1A by siRNA led to reduced activation of Aurora-A, RAS may require heterodimerization of RASSF1A and whereas overexpression of RASSF1A resulted in in- NORE1 (Ortiz-Vega et al., 2002).
    [Show full text]
  • Therapeutic Implications for Ovarian Cancer Emerging from the Tumor Cancer Genome Atlas
    Review Article Therapeutic implications for ovarian cancer emerging from the Tumor Cancer Genome Atlas Claire Verschraegen, Karen Lounsbury, Alan Howe, Marc Greenblatt University of Vermont Cancer Center, Burlington, VT 05405, USA Correspondence to: Claire Verschraegen, MD. University of Vermont Cancer Center, 89 Beaumont Avenue, Given E 214, Burlington, VT 05405, USA. Email: [email protected] Abstract: With increasing insights into the molecular landscape of ovarian cancer, subtypes are emerging that might require differential targeted therapies. While the combination of a platinum and a taxane remains the standard of care, newer therapies, specifically targeted to molecular anomalies, are rapidly being tested in various cancers. A major effort to better understand ovarian cancer occurred through the Cancer Atlas Project. The Catalogue of Somatic Mutations in Cancer (COSMIC) is a database that collates mutation data and associated information extracted from the primary literature. The information from the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), which systematically analyzed hundreds of ovarian cancer, are included in COSMIC, sometimes with discordant results. In this manuscript, the published data (mainly from TCGA) on somatic high grade papillary serous ovarian cancer (HGSOC) mutations has been used as the basis to propose a more granular approach to ovarian cancer treatment, already a reality for tumors such as lung and breast cancers. TP53 mutations are the most common molecular anomaly in HGSOC, and lead to genomic instability, perhaps through the FOXM1 node. Normalizing P53 has been a therapeutic challenge, and is being extensively studied. BRCAness is found an about 50% of HGSOC and can be targeted with poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, recently approved for ovarian cancer treatment.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Viewer 4.0 Software [73]
    BMC Genomics BioMed Central Research Open Access Bioinformatic search of plant microtubule-and cell cycle related serine-threonine protein kinases Pavel A Karpov1, Elena S Nadezhdina2,3,AllaIYemets1, Vadym G Matusov1, Alexey Yu Nyporko1,NadezhdaYuShashina3 and Yaroslav B Blume*1 Addresses: 1Institute of Food Biotechnology and Genomics, National Academy of Sciences of Ukraine, 04123 Kyiv, Ukraine, 2Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russian Federation and 3AN Belozersky Institute of Physical- Chemical Biology, Moscow State University, Leninsky Gory, 119992 Moscow, Russian Federation E-mail: Pavel A Karpov - [email protected]; Elena S Nadezhdina - [email protected]; Alla I Yemets - [email protected]; Vadym G Matusov - [email protected]; Alexey Yu Nyporko - [email protected]; Nadezhda Yu Shashina - [email protected]; Yaroslav B Blume* - [email protected] *Corresponding author from International Workshop on Computational Systems Biology Approaches to Analysis of Genome Complexity and Regulatory Gene Networks Singapore 20-25 November 2008 Published: 10 February 2010 BMC Genomics 2010, 11(Suppl 1):S14 doi: 10.1186/1471-2164-11-S1-S14 This article is available from: http://www.biomedcentral.com/1471-2164/11/S1/S14 Publication of this supplement was made possible with help from the Bioinformatics Agency for Science, Technology and Research of Singapore and the Institute for Mathematical Sciences at the National University of Singapore. © 2010 Karpov et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
    [Show full text]
  • The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer
    cancers Article The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor Andreia Brandão 1 , Paula Paulo 1, Sofia Maia 1, Manuela Pinheiro 1, Ana Peixoto 2, Marta Cardoso 1, Maria P. Silva 1, Catarina Santos 2, Rosalind A. Eeles 3,4 , Zsofia Kote-Jarai 3, 5,6 7, 8,9 10 Kenneth Muir , UKGPCS Collaborators y, Johanna Schleutker , Ying Wang , Nora Pashayan 11,12 , Jyotsna Batra 13,14, APCB BioResource 13,14, Henrik Grönberg 15, David E. Neal 16,17,18, Børge G. Nordestgaard 19,20 , Catherine M. Tangen 21, Melissa C. Southey 22,23,24, Alicja Wolk 25,26, Demetrius Albanes 27, Christopher A. Haiman 28, Ruth C. Travis 29, Janet L. Stanford 30,31, Lorelei A. Mucci 32, Catharine M. L. West 33, Sune F. Nielsen 19,20, Adam S. Kibel 34, Olivier Cussenot 35,36, Sonja I. Berndt 27, Stella Koutros 27, Karina Dalsgaard Sørensen 37,38 , Cezary Cybulski 39 , Eli Marie Grindedal 40, Jong Y. Park 41 , Sue A. Ingles 42, Christiane Maier 43, Robert J. Hamilton 44,45, Barry S. Rosenstein 46,47, 48,49,50 7, Ana Vega , The IMPACT Study Steering Committee and Collaborators z, Manolis Kogevinas 51,52,53,54, Fredrik Wiklund 15 , Kathryn L. Penney 55, Hermann Brenner 56,57,58 , Esther M. John 59, Radka Kaneva 60, Christopher J. Logothetis 61, Susan L. Neuhausen 62, Kim De Ruyck 63, Azad Razack 64, Lisa F. Newcomb 30,65, Canary PASS Investigators 30,65, Davor Lessel 66 , Nawaid Usmani 67,68, Frank Claessens 69, Manuela Gago-Dominguez 70,71 , Paul A.
    [Show full text]
  • Identification of Potential Key Genes and Pathway Linked with Sporadic Creutzfeldt-Jakob Disease Based on Integrated Bioinformatics Analyses
    medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Identification of potential key genes and pathway linked with sporadic Creutzfeldt-Jakob disease based on integrated bioinformatics analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 , Iranna Kotturshetti 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. 3. Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, Karnataka 562209, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Abstract Sporadic Creutzfeldt-Jakob disease (sCJD) is neurodegenerative disease also called prion disease linked with poor prognosis. The aim of the current study was to illuminate the underlying molecular mechanisms of sCJD. The mRNA microarray dataset GSE124571 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened.
    [Show full text]
  • Supplementary Materials
    Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine
    [Show full text]
  • The Role of the Rho Gtpases in Neuronal Development
    Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW The role of the Rho GTPases in neuronal development Eve-Ellen Govek,1,2, Sarah E. Newey,1 and Linda Van Aelst1,2,3 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 11724, USA; 2Molecular and Cellular Biology Program, State University of New York at Stony Brook, Stony Brook, New York, 11794, USA Our brain serves as a center for cognitive function and and an inactive GDP-bound state. Their activity is de- neurons within the brain relay and store information termined by the ratio of GTP to GDP in the cell and can about our surroundings and experiences. Modulation of be influenced by a number of different regulatory mol- this complex neuronal circuitry allows us to process that ecules. Guanine nucleotide exchange factors (GEFs) ac- information and respond appropriately. Proper develop- tivate GTPases by enhancing the exchange of bound ment of neurons is therefore vital to the mental health of GDP for GTP (Schmidt and Hall 2002); GTPase activat- an individual, and perturbations in their signaling or ing proteins (GAPs) act as negative regulators of GTPases morphology are likely to result in cognitive impairment. by enhancing the intrinsic rate of GTP hydrolysis of a The development of a neuron requires a series of steps GTPase (Bernards 2003; Bernards and Settleman 2004); that begins with migration from its birth place and ini- and guanine nucleotide dissociation inhibitors (GDIs) tiation of process outgrowth, and ultimately leads to dif- prevent exchange of GDP for GTP and also inhibit the ferentiation and the formation of connections that allow intrinsic GTPase activity of GTP-bound GTPases (Zalc- it to communicate with appropriate targets.
    [Show full text]
  • Ncomms4885.Pdf
    ARTICLE Received 4 Feb 2014 | Accepted 14 Apr 2014 | Published 30 May 2014 DOI: 10.1038/ncomms4885 Microcephaly disease gene Wdr62 regulates mitotic progression of embryonic neural stem cells and brain size Jian-Fu Chen1,2, Ying Zhang1, Jonathan Wilde1, Kirk C. Hansen3, Fan Lai4 & Lee Niswander1 Human genetic studies have established a link between a class of centrosome proteins and microcephaly. Current studies of microcephaly focus on defective centrosome/spindle orientation. Mutations in WDR62 are associated with microcephaly and other cortical abnormalities in humans. Here we create a mouse model of Wdr62 deficiency and find that the mice exhibit reduced brain size due to decreased neural progenitor cells (NPCs). Wdr62 depleted cells show spindle instability, spindle assembly checkpoint (SAC) activation, mitotic arrest and cell death. Mechanistically, Wdr62 associates and genetically interacts with Aurora A to regulate spindle formation, mitotic progression and brain size. Our results suggest that Wdr62 interacts with Aurora A to control mitotic progression, and loss of these interactions leads to mitotic delay and cell death of NPCs, which could be a potential cause of human microcephaly. 1 Howard Hughes Medical Institute, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children’s Hospital Colorado, Aurora, Colorado 80045, USA. 2 Department of Genetics, Department of Biochemistry & Molecular Biology, University of Georgia, Athens, Georgia 30602, USA. 3 Biochemistry & Molecular Genetics, University of Colorado Denver, Aurora, Colorado 80045, USA. 4 The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA. Correspondence and requests for materials should be addressed to J-F.C. (email: [email protected]) or to L.N.
    [Show full text]
  • Phosphorylation Sites in Protein Kinases and Phosphatases Regulated by Formyl Peptide Receptor 2 Signaling
    International Journal of Molecular Sciences Review Phosphorylation Sites in Protein Kinases and Phosphatases Regulated by Formyl Peptide Receptor 2 Signaling Maria Carmela Annunziata 1, Melania Parisi 1, Gabriella Esposito 2 , Gabriella Fabbrocini 1, Rosario Ammendola 2 and Fabio Cattaneo 2,* 1 Department of Clinical Medicine and Surgery, School of Medicine, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; [email protected] (M.C.A.); [email protected] (M.P.); [email protected] (G.F.) 2 Department of Molecular Medicine and Medical Biotechnology, School of Medicine,, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; [email protected] (G.E.); [email protected] (R.A.) * Correspondence: [email protected]; Fax: +39-081-7464-359 Received: 5 May 2020; Accepted: 25 May 2020; Published: 27 May 2020 Abstract: FPR1, FPR2, and FPR3 are members of Formyl Peptides Receptors (FPRs) family belonging to the GPCR superfamily. FPR2 is a low affinity receptor for formyl peptides and it is considered the most promiscuous member of this family. Intracellular signaling cascades triggered by FPRs include the activation of different protein kinases and phosphatase, as well as tyrosine kinase receptors transactivation. Protein kinases and phosphatases act coordinately and any impairment of their activation or regulation represents one of the most common causes of several human diseases. Several phospho-sites has been identified in protein kinases and phosphatases, whose role may be to expand the repertoire of molecular mechanisms of regulation or may be necessary for fine-tuning of switch properties. We previously performed a phospho-proteomic analysis in FPR2-stimulated cells that revealed, among other things, not yet identified phospho-sites on six protein kinases and one protein phosphatase.
    [Show full text]