SIGNAL TRANSDUCTION: STRUCTURE, MECHANISMS, REGULATION of EVOLUTION Organizers: Merl F
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Genetic and Epigenetic Mechanisms of the Regulation of Mouse Embryonic Stem Cells Self-Renewal by the Pluripotency Transcription Factor Nanog
Genetic and epigenetic mechanisms of the regulation of mouse embryonic stem cells self-renewal by the pluripotency transcription factor Nanog Victor HEURTIER Thèse de doctorat de Biologie Dirigée par Pablo NAVARRO GIL Laboratoire Epigénétique des cellules souches – Institut Pasteur Sorbonne Université Ecole doctorale Complexité du Vivant (ED 515) Présentée et soutenue publiquement le 18/09/2018 Devant un jury composé de : Président : Pr MOUCHEL-VIELH Emmanuèle, Professeur Rapporteur : Dr SAVATIER Pierre, Directeur de Recherche Rapporteur : Dr RADA-IGLESIAS Alvaro, Chef d’équipe Examinateur : Dr AZUARA Veronique, Maître de conférences Examinateur : Dr PINSKAYA Marina, Maître de conférences Directeur de thèse : Dr NAVARRO GIL Pablo, Chef d’équipe Abstract Mouse embryonic stem (ES) cells are derived from the pre-implantation blastocyst and are able to maintain their pluripotent state through virtually limitless cell divisions in vitro. The study of the mechanisms regulating the specific features of ES cells led to the discovery of the transcription factors (TFs) governing their unique transcriptome. Among those TFs, Nanog plays a central role in the gene regulatory network that supports ES cells self-renewal. However, the molecular mechanisms by which Nanog exerts its functions are not fully elucidated. We adapted an inducible CRISPR activation (CRISPRa) system in mouse ES cells and demonstrated its functionality to stimulate transcription at endogenous loci. We then accurately determined the list of Nanog responsive genes using gain (CRISPRa cell line) and loss of function experiments and total RNA sequencing. Moreover, the DNA binding profiles of distinct pluripotency TFs were assessed genome-wide by chromatin immunoprecipitation (ChIP) and sequencing upon Nanog depletion and revealed the importance of the latter in the regulation of the pluripotency network activity at thousands of loci. -
Crystal Structure of a Small G Protein in Complex with the Gtpase
letters to nature of apolipoproteins2,12–14. However, our results show that the residues lipoprotein metabolism involving cell surface heparan sulfate proteoglycans. J. Biol. Chem. 269, 2764– 2+ 2772 (1994). in the conserved acidic motif of LR5 are buried to participate in Ca 16. Innerarity, T. L., Pitas, R. E. & Mahley, R. W. Binding of arginine-rich (E) apoprotein after coordination, instead of being exposed on the surface of the domain recombination with phospholipid vesicles to the low density lipoprotein receptors of fibroblasts. J. Biol. Chem. 254, 4186–4190 (1979). (Fig. 4a). Although lipoprotein uptake by members of the LDLR 17. Otwinowski, Z. & Minor, W. Data Collection and Processing (eds Sawyer, L., Isaacs, N. & Bailey, S.) family may involve an electrostatic component, perhaps through 556–562 (SERC Daresbury Laboratory, Warrington, UK, 1993). association of the lipoproteins with cell-surface proteoglycans15, the 18. CCP4. The SERC (UK) Collaborative Computing Project No. 4 A Suite of Programs for Protein Crystallography (SERC Daresbury Laboratory, Warrington, UK, 1979). LR5 structure demonstrates that the primary role for the conserved 19. Cowtan, K. D. Joint CCP4 and ESF-EACBM Newsletter on Protein Crystallography 31, 34–38 (1994). acidic residues in LDL-A modules is structural. It has been noted 20. Jones, T. A., Zou, J. Y., Cowan, S. W. & Kjeldgaard, M. Improved methods for binding protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 previously that only lipid-associated apolipoproteins bind with (1991). 16 high affinity to the LDLR ; the LR5 structure suggests an alternative 21. -
Table 2. Significant
Table 2. Significant (Q < 0.05 and |d | > 0.5) transcripts from the meta-analysis Gene Chr Mb Gene Name Affy ProbeSet cDNA_IDs d HAP/LAP d HAP/LAP d d IS Average d Ztest P values Q-value Symbol ID (study #5) 1 2 STS B2m 2 122 beta-2 microglobulin 1452428_a_at AI848245 1.75334941 4 3.2 4 3.2316485 1.07398E-09 5.69E-08 Man2b1 8 84.4 mannosidase 2, alpha B1 1416340_a_at H4049B01 3.75722111 3.87309653 2.1 1.6 2.84852656 5.32443E-07 1.58E-05 1110032A03Rik 9 50.9 RIKEN cDNA 1110032A03 gene 1417211_a_at H4035E05 4 1.66015788 4 1.7 2.82772795 2.94266E-05 0.000527 NA 9 48.5 --- 1456111_at 3.43701477 1.85785922 4 2 2.8237185 9.97969E-08 3.48E-06 Scn4b 9 45.3 Sodium channel, type IV, beta 1434008_at AI844796 3.79536664 1.63774235 3.3 2.3 2.75319499 1.48057E-08 6.21E-07 polypeptide Gadd45gip1 8 84.1 RIKEN cDNA 2310040G17 gene 1417619_at 4 3.38875643 1.4 2 2.69163229 8.84279E-06 0.0001904 BC056474 15 12.1 Mus musculus cDNA clone 1424117_at H3030A06 3.95752801 2.42838452 1.9 2.2 2.62132809 1.3344E-08 5.66E-07 MGC:67360 IMAGE:6823629, complete cds NA 4 153 guanine nucleotide binding protein, 1454696_at -3.46081884 -4 -1.3 -1.6 -2.6026947 8.58458E-05 0.0012617 beta 1 Gnb1 4 153 guanine nucleotide binding protein, 1417432_a_at H3094D02 -3.13334396 -4 -1.6 -1.7 -2.5946297 1.04542E-05 0.0002202 beta 1 Gadd45gip1 8 84.1 RAD23a homolog (S. -
Ras Gtpase Chemi ELISA Kit Catalog No
Ras GTPase Chemi ELISA Kit Catalog No. 52097 (Version B3) Active Motif North America 1914 Palomar Oaks Way, Suite 150 Carlsbad, California 92008, USA Toll free: 877 222 9543 Telephone: 760 431 1263 Fax: 760 431 1351 Active Motif Europe Waterloo Atrium Drève Richelle 167 – boîte 4 BE-1410 Waterloo, Belgium UK Free Phone: 0800 169 31 47 France Free Phone: 0800 90 99 79 Germany Free Phone: 0800 181 99 10 Telephone: +32 (0)2 653 0001 Fax: +32 (0)2 653 0050 Active Motif Japan Azuma Bldg, 7th Floor 2-21 Ageba-Cho, Shinjuku-Ku Tokyo, 162-0824, Japan Telephone: +81 3 5225 3638 Fax: +81 3 5261 8733 Active Motif China 787 Kangqiao Road Building 10, Suite 202, Pudong District Shanghai, 201315, China Telephone: (86)-21-20926090 Hotline: 400-018-8123 Copyright 2021 Active Motif, Inc. www.activemotif.com Information in this manual is subject to change without notice and does not constitute a commit- ment on the part of Active Motif, Inc. It is supplied on an “as is” basis without any warranty of any kind, either explicit or implied. Information may be changed or updated in this manual at any time. This documentation may not be copied, transferred, reproduced, disclosed, or duplicated, in whole or in part, without the prior written consent of Active Motif, Inc. This documentation is proprietary information and protected by the copyright laws of the United States and interna- tional treaties. The manufacturer of this documentation is Active Motif, Inc. © 2021 Active Motif, Inc., 1914 Palomar Oaks Way, Suite 150; Carlsbad, CA 92008. -
Protein Identities in Evs Isolated from U87-MG GBM Cells As Determined by NG LC-MS/MS
Protein identities in EVs isolated from U87-MG GBM cells as determined by NG LC-MS/MS. No. Accession Description Σ Coverage Σ# Proteins Σ# Unique Peptides Σ# Peptides Σ# PSMs # AAs MW [kDa] calc. pI 1 A8MS94 Putative golgin subfamily A member 2-like protein 5 OS=Homo sapiens PE=5 SV=2 - [GG2L5_HUMAN] 100 1 1 7 88 110 12,03704523 5,681152344 2 P60660 Myosin light polypeptide 6 OS=Homo sapiens GN=MYL6 PE=1 SV=2 - [MYL6_HUMAN] 100 3 5 17 173 151 16,91913397 4,652832031 3 Q6ZYL4 General transcription factor IIH subunit 5 OS=Homo sapiens GN=GTF2H5 PE=1 SV=1 - [TF2H5_HUMAN] 98,59 1 1 4 13 71 8,048185945 4,652832031 4 P60709 Actin, cytoplasmic 1 OS=Homo sapiens GN=ACTB PE=1 SV=1 - [ACTB_HUMAN] 97,6 5 5 35 917 375 41,70973209 5,478027344 5 P13489 Ribonuclease inhibitor OS=Homo sapiens GN=RNH1 PE=1 SV=2 - [RINI_HUMAN] 96,75 1 12 37 173 461 49,94108966 4,817871094 6 P09382 Galectin-1 OS=Homo sapiens GN=LGALS1 PE=1 SV=2 - [LEG1_HUMAN] 96,3 1 7 14 283 135 14,70620005 5,503417969 7 P60174 Triosephosphate isomerase OS=Homo sapiens GN=TPI1 PE=1 SV=3 - [TPIS_HUMAN] 95,1 3 16 25 375 286 30,77169764 5,922363281 8 P04406 Glyceraldehyde-3-phosphate dehydrogenase OS=Homo sapiens GN=GAPDH PE=1 SV=3 - [G3P_HUMAN] 94,63 2 13 31 509 335 36,03039959 8,455566406 9 Q15185 Prostaglandin E synthase 3 OS=Homo sapiens GN=PTGES3 PE=1 SV=1 - [TEBP_HUMAN] 93,13 1 5 12 74 160 18,68541938 4,538574219 10 P09417 Dihydropteridine reductase OS=Homo sapiens GN=QDPR PE=1 SV=2 - [DHPR_HUMAN] 93,03 1 1 17 69 244 25,77302971 7,371582031 11 P01911 HLA class II histocompatibility antigen, -
H-Ras Gtpase
H-Ras GTPase Key to Understanding Cancer? Marquette University High School SMART Team: Mohammed Ayesh, Wesley Borden, Andrew Bray, Brian Digiacinto, Patrick Jordan, David Moldenhauer, Thomas Niswonger, Joseph Radke, Amit Singh, Alex Vincent, and Caleb Vogt Teachers: Keith Klestinski and David Vogt Mentor: Evgenii Kovrigin, Ph.D., Medical College of Wisconsin Abstract Cell Cycle Control The protein known as H-Ras GTPase is essential to H-ras is activated late in the G1 phase. proper biological functioning in the entire web of life. The Once H-ras is activated, the cell advances main function of this protein is giving the "stop" signal to past the G1 checkpoint and is compelled to the process of cell reproduction. Unfortunately, this protein complete mitosis. is not perfect and severe consequences, such as cancer, can arise when H-Ras GTPase malfunctions. H-Ras GTPase is a protein from the large family of enzymes that bind and split GTP. H-Ras GTPase is vital in processes like cell-to-cell communication, protein translation in ribosomes, and programmed cell death Ras GTPase Ras GDPase (apoptosis). Its main fields of operation are determining Active Inactive stem cell into specific functioning cells, as well as replicating preexisting "specialized" cells. All G domain based proteins have a universal structure and two Controlling the “Switch” between universal switch mechanisms, which consist of a mixed, six-stranded beta sheet and five alpha helices. H-Ras Active and Inactive States GTPase works by first dissociating from GDP and binding In the graphics (above and below), H-ras is shown in both © 2008, Physiomics, Corp. -
Rhodopsin Kinase Activity Modulates the Amplitude of the Visual Response in Drosophila
Rhodopsin kinase activity modulates the amplitude of the visual response in Drosophila Seung-Jae Lee*, Hong Xu, and Craig Montell† Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved June 30, 2004 (received for review March 29, 2004) A feature shared between Drosophila rhodopsin and nearly all tractability of fly genetics (14). As in mammals, light-activated other G protein-coupled receptors is agonist-dependent protein rhodopsin is phosphorylated and interacts with a protein, arres- phosphorylation. Despite extensive analyses of Drosophila photo- tin, which facilitates deactivation of the receptor. However, transduction, the identity and function of the rhodopsin kinase unlike mammalian phototransduction, light activation in Dro- (RK) have been elusive. Here, we provide evidence that G protein- sophila is coupled to stimulation of phospholipase C rather than coupled receptor kinase 1 (GPRK1), which is most similar to the a cGMP-phosphodiesterase. -adrenergic receptor kinases, G protein-coupled receptor kinase 2 Two Drosophila genes encoding putative GRKs (GPRK1 and (GRK2) and GRK3, is the fly RK. We show that GPRK1 is enriched in GPRK2) were isolated more than a decade ago (15), but were photoreceptor cells, associates with the major Drosophila rhodop- dismissed as candidate RKs due in part to their much greater sin, Rh1, and phosphorylates the receptor. As is the case with similarity to mammalian nonvisual GRKs than to mammalian mammalian GRK2 and GRK3, Drosophila GPRK1 includes a C- RKs. Subsequent analysis of GPRK2 demonstrated that it is terminal pleckstrin homology domain, which binds to phosphoi- expressed in the ovaries and required for egg morphogenesis nositides and the G␥ subunit. -
Bulletin the Canadian Society for Molecular Biosciences La Société Canadienne Pour Les Biosciences Moléculaires
Bulletin The Canadian Society for Molecular Biosciences La Société Canadienne pour les Biosciences Moléculaires 2013 www.csmb-scbm.ca Bulletin The Canadian Society for Molecular Biosciences La Société Canadienne pour les Biosciences Moléculaires 2013 www.csmb-scbm.ca Cover images were provided by Dr. Benoit Chabot (see article standing on p32). 2 CSMB | SCBM Bulletin 2013 CSMB Board for 2013 ...............................................................................................................................................................5 President’s Report 2013 .........................................................................................................................................................7 Incoming Member of the Executive Board Martin Bisaillon, Councillor ...............................................................................................................................................9 Minutes of the 56th Annual General Meeting 2013 ...................................................................................................10 Financial Statement 2013 ....................................................................................................................................................12 56th Annual Meeting, Niagara-on-the Lake Meeting Schedule ..............................................................................................................................................................17 Scenes from the Meeting .................................................................................................................................................25 -
Review Ras-Catalyzed Hydrolysis of GTP: a New Perspective from Model
Proc. Natl. Acad. Sci. USA Vol. 93, pp. 8160-8166, August 1996 Review Ras-catalyzed hydrolysis of GTP: A new perspective from model studies Karen A. Maegley, Suzanne J. Admiraal, and Daniel Herschlag* Department of Biochemistry, B400 Beckman Center, Stanford University, Stanford, CA 94305-5307 Communicated by James A Spudich, Stanford University Medical Center, Stanford, CA, March 6, 1996 (received for review December 21, 1995) ABSTRACT Despite the biological and medical impor- A new catalytic mechanism is then proposed, involving a tance of signal transduction via Ras proteins and despite hydrogen bond to the ,3-y bridge oxygen of GTP. This proposal considerable kinetic and structural studies of wild-type and is consistent with pre-existing structural, spectral, and ener- mutant Ras proteins, the mechanism of Ras-catalyzed GTP getic data. hydrolysis remains controversial. We take a different ap- proach to this problem: the uncatalyzed hydrolysis of GTP is Background: The Nature of the Transition State analyzed, and the understanding derived is applied to the for GTP Hydrolysis Ras-catalyzed reaction. Evaluation of previous mechanistic proposals from this chemical perspective suggests that proton There is a continuum of potential transition state structures for abstraction from the attacking water by a general base and phosphoryl transfer reactions, ranging from dissociative to stabilization of charge development on the y-phosphoryl associative depending on the nature of the bonding (i.e., the oxygen atoms would not be catalytic. Rather, this analysis electronic distribution; Scheme I). focuses attention on the GDP leaving group, including the 1-y bridge oxygen of GTP, the atom that undergoes the largest change in charge in going from the ground state to the transition state. -
Balancing the Photoreceptor Proteome: Proteostasis Network Therapeutics for Inherited Retinal Disease
G C A T T A C G G C A T genes Review Balancing the Photoreceptor Proteome: Proteostasis Network Therapeutics for Inherited Retinal Disease Siebren Faber and Ronald Roepman * Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands * Correspondence: [email protected] Received: 10 June 2019; Accepted: 16 July 2019; Published: 24 July 2019 Abstract: The light sensing outer segments of photoreceptors (PRs) are renewed every ten days due to their high photoactivity, especially of the cones during daytime vision. This demands a tremendous amount of energy, as well as a high turnover of their main biosynthetic compounds, membranes, and proteins. Therefore, a refined proteostasis network (PN), regulating the protein balance, is crucial for PR viability. In many inherited retinal diseases (IRDs) this balance is disrupted leading to protein accumulation in the inner segment and eventually the death of PRs. Various studies have been focusing on therapeutically targeting the different branches of the PR PN to restore the protein balance and ultimately to treat inherited blindness. This review first describes the different branches of the PN in detail. Subsequently, insights are provided on how therapeutic compounds directed against the different PN branches might slow down or even arrest the appalling, progressive blinding conditions. These insights are supported by findings of PN modulators in other research disciplines. Keywords: protein trafficking; protein folding; protein degradation; chaperones; chaperonins; heat shock response; unfolded protein response; autophagy; therapy 1. Introduction The rod and cone photoreceptor (PR) cells are the most abundant cell types in the human retina, with ~6.4 million cones and up to 125 million rods per adult retina [1]. -
Editorial Board
MOLECULAR AND CELLULAR BIOLOGY VOLUME 29 ● JULY 2009 ● NUMBER 13 Roger J. Davis, Editor in Chief (2012) B. Franklin Pugh, Editor (2012) University of Massachusetts Medical School Pennsylvania State University Antony M. Carr, Editor (2012) J. Wade Harper, Editor (2013) Anjana Rao, Editor (2012) University of Sussex Harvard Medical School Immune Disease Institute, Inc. John L. Cleveland, Editor (2014) David E. Levy, Editor (2012) Joel D. Richter, Editor (2013) Scripps Florida New York University School of Medicine University of Massachusetts Medical School James Douglas Engel, Editor (2012) James L. Manley, Editor (2013) Andrey S. Shaw, Editor (2013) University of Michigan Medical School Columbia University Washington University School of Medicine Mark E. Ewen, Editor (2014) Christopher J. Marshall, Editor (2012) Ali Shilatifard, Editor (2012) Dana-Farber Cancer Institute Institute of Cancer Research Stowers Institute for Medical Research Leonard P. Freedman, Editor (2011) Jeremy W. Thorner, Editor (2013) Thomas Jefferson University University of California, Berkeley EDITORIAL BOARD Cory Abate-Shen (’09) Sharon Y. R. Dent (’10) Peter M. Howley (’09) Aaron P. Mitchell (’09) Edward Seto (’09) Peter D. Adams (’11) Melvin L. DePamphilis (’10) Kazuhiko Igarashi (’09) Cornelis Murre (’09) Andrew D. Sharrocks (’11) Dario Alessi (’10) Channing J. Der (’09) Anton Jetten (’09) Carol Newlon (’09) Ramin Shiekhattar (’11) Marisa Bartolomei (’11) Robert N. Eisenman (’09) Roland Kanaar (’10) Timothy Nilsen (’09) M. Celeste Simon (’11) Michelle C. Barton (’11) Sarah C. R. Elgin (’09) Gerard Karsenty (’09) Tomoo Ogi (’11) David Stern (’09) Claudio Basilico (’09) Scott Emr (’09) Michael B. Kastan (’09) Eric N. Olson (’10) Philip Stork (’10) Anton Bennett (’11) Gen-Sheng Feng (’11) Andrius Kazlauskas (’10) Moshe Oren (’11) Brian D. -
(12) Patent Application Publication (10) Pub. No.: US 2010/0158968 A1 Panitch Et Al
US 20100158968A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0158968 A1 Panitch et al. (43) Pub. Date: Jun. 24, 2010 (54) CELL-PERMEANT PEPTIDE-BASED Publication Classification INHIBITOR OF KINASES (51) Int. Cl. (76) Inventors: Alyssa Panitch, West Lafayette, IN st e8 CR (US); Brandon Seal, West ( .01) Lafayette, IN (US) A638/10 (2006.01) s A638/16 (2006.01) Correspondence Address: A6IP 43/00 (2006.01) GREENBERG TRAURIG, LLP (52) U.S. Cl. ................ 424/422:514/15: 514/13: 514/14 200 PARKAVE., P.O. BOX 677 FLORHAMPARK, NJ 07932 (US) (57) ABSTRACT The described invention provides kinase inhibiting composi (21) Appl. No.: 12/634,476 tions containing a therapeutic amount of a therapeutic inhibi (22) Filed: Dec. 9, 2009 torpeptide that inhibits at least one kinase enzyme, methods e 19 for treating an inflammatory disorder whose pathophysiology comprises inflammatory cytokine expression, and methods Related U.S. Application Data for treating an inflammatory disorder whose pathophysiology (60) Provisional application No. 61/121,396, filed on Dec. comprises inflammatory cytokine expression using the kinase 10, 2008. inhibiting compositions. 20 { ki> | 0: & c s - --- 33- x: SE PEPELE, ics 1.-- E- X K. AAA 22.9 --- KKK. Y.A., 3.2; C. -r { AAEASA. A. E. i : A X AAAAAAA; ; ; ; :-n. 4:-: is SEEKESAN.ARESA, 3523 -- -- Yili.A.R.AKA: 5,342 3. {{RCE: Rix i: Patent Application Publication US 2010/0158968A1 & ******** NO s ***** · Patent Application Publication Jun. 24, 2010 Sheet 2 of 11 US 2010/0158968A1 it, O Peptide: Cso: g E 100 WRRKAWRRKANRO, GWAA.