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VOLUME ONE HUNDRED AND FOURTY ONE PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE Ubiquitination and Transmembrane Signaling VOLUME ONE HUNDRED AND FOURTY ONE PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE Ubiquitination and Transmembrane Signaling Edited by Sudha K Shenoy Department of Medicine, Duke University Medical Center, Durham, NC, United States AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1800, San Diego, CA 92101-4495, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK First edition 2016 Copyright © 2016 Elsevier Inc All Rights Reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-12-809386-3 ISSN: 1877-1173 For information on all Academic Press publications visit our website at Publisher: Zoe Kruze Acquisition Editor: Mary Ann Zimmerman Editorial Project Manager: Helene Kabes Production Project Manager: Magesh Kumar Mahalingam Designer: Maria Ines Cruz Typeset by Thomson Digital CONTRIBUTORS A Conte IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy C Crudden Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden N.J Freedman Department of Medicine (Cardiology), Duke University Medical Center, Durham, NC, United States; Department of Cell Biology, Duke University Medical Center, Durham, NC, United States T Fukushima Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan; Department of Biological Sciences, Faculty of Bioscience and Biotechnology, Tokyo Institute of Technology, Kanagawa, Japan H Furuta Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan A Girnita Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Dermatology Department, Karolinska University Hospital, Stockholm, Sweden L Girnita Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden F Hakuno Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan M.A Harrison School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom P.-Y Jean-Charles Department of Medicine (Cardiology), Duke University Medical Center, Durham, NC, United States ix x Contributors S.M Lamothe Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Canada P Penela Department of Molecular Biology and Centre of Molecular Biology “Severo Ochoa” (CSIC-UAM), Madrid, Autonomous University of Madrid, Madrid, Spain; Spain Health Research Institute The Princesa, Madrid, Spain S Ponnambalam School of Molecular & Cellular Biology, University of Leeds, Leeds, United Kingdom S.K Shenoy Department of Medicine (Cardiology), Duke University Medical Center, Durham, NC, United States; Department of Cell Biology, Duke University Medical Center, Durham, NC, United States S Sigismund IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy G.A Smith School of Molecular & Cellular Biology, University of Leeds, Leeds, United Kingdom J.C Snyder Department of Cell Biology, Duke University Medical Center, Durham, NC, United States S.-I Takahashi Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan D.C Tomlinson School of Molecular & Cellular Biology, University of Leeds, Leeds, United Kingdom M Torres Georgia Institute of Technology, School of Biology, Atlanta, GA, United States R.J.H Wojcikiewicz Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, United States C Worrall Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden F.A Wright Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, United States Contributors H Yoshihara Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan S Zhang Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Canada xi PREFACE Transmission of diverse extracellular signals to the intracellular biochemical machinery is mediated by cell-surface receptors, and the intracellular chemical reactions triggered by these receptors elicit specific physical or physiological cellular responses Three classes of cell-surface receptors constitute the primary conduits of transmembrane signaling: (1) chemically gated, multitransmembrane ion channels, (2) seven-transmembrane receptors, or G protein–coupled receptors, and (3) single-transmembrane, kinasecontaining enzymic receptors Accumulating evidence indicates that the posttranslational modification called ubiquitination has a significant impact on the strength and duration of transmembrane signaling For most cellsurface receptors, ubiquitination of the receptor protein dictates its expression level and longevity Additionally, for almost all cell-surface receptors ubiquitination regulates intracellular trafficking, signaling activity, and protein–protein association that can create intracellular signaling complexes of receptors and other intracellular proteins This volume summarizes the current state of knowledge on ubiquitination of cell-surface receptors, associated kinases, effectors, and adaptors Chapter (P.-Y Jean-Charles et al.) describes the roles of ubiquitination in the regulation of the largest family of cell-surface receptors—namely, seven-transmembrane receptors (7TMRs, also known as G protein–coupled receptors or GPCRs) Chapter (M Torres) discusses the relationship between ubiquitination of heterotrimeric G proteins and their signaling Chapter (P Penela) presents an overview of ubiquitin-dependent regulation of GPCR kinases and the impact of their ubiquitination on signal transduction Chapter (F.A Wright and R.J.H Wojcikiewicz) summarizes how ubiquitination regulates inositol 1,4, 5-trisphosphate receptor–mediated Ca2+ responses in the cell Chapter (S.M Lamothe and S Zhang) is a comprehensive review of ubiquitindependent downregulation of ion channels and ion transporters Chapter 6, (A Conte and S Sigismund), Chapter (L Girnita et al.), and Chapter (G.A Smith et al.) shed light on the ubiquitin-dependent regulation of growth factor receptors and their signal transduction pathways Chapter (P.-Y JeanCharles et al.) highlights the functional roles of ubiquitination and deubiquitination of the versatile adaptor proteins called beta-arrestins, which also act xiii xiv Preface as critical scaffolds that connect a number of cell-surface receptors with the ubiquitination machinery I hope the information included in this volume will provide the readers with a broad perspective on the importance of ubiquitination in the regulation of cell-surface receptors and the control of transmembrane signaling This volume was made possible, of course, only by the outstanding efforts of its contributors, to whom I am very grateful I thank P Michael Conn, the Chief Editor of this series (Progress in Molecular Biology and Translational Science), for providing me the opportunity to synthesize a volume on the roles of ubiquitination in cell signaling I also thank Mary Ann Zimmerman, the Senior Acquisitions Editor and Helene Kabes, Senior Editorial Project Manager of Elsevier, for their help Finally, I thank my postdoctoral mentor Robert J Lefkowitz for introducing me to the fascinating field of 7TMRs and signal transduction SUDHA K SHENOY Durham, NC CHAPTER ONE Ubiquitination and Deubiquitination of G ProteinCoupled Receptors P.-Y Jean-Charles*, J.C Snyder**, S.K Shenoy*,**,1 * Department of Medicine (Cardiology), Duke University Medical Center, Durham, NC, United States Department of Cell Biology, Duke University Medical Center, Durham, NC, United States ** Corresponding author E-mail address: Contents Introduction 1.1 G Protein-Coupled Receptors 1.2 Ubiquitination and Deubiquitination Ubiquitination of GPCRs 2.1 β2 Adrenergic Receptor 2.2 Chemokine Receptors 2.3 Proteinase Activated Receptors 2.4 Opioid Receptors 2.5 Noncanonical GPCRs and Ubiquitin Ligases 2.6 Yeast GPCRs Deubiquitination of GPCRs 3.1 Overview 3.2 Recycling and Resensitization 3.3 Accelerated Degradation 3.4 Alternate Effects Concluding Remarks Acknowledgments References 2 6 18 22 26 28 35 35 35 36 38 39 40 42 42 Abstract The seven-transmembrane containing G protein-coupled receptors (GPCRs) constitute the largest family of cell-surface receptors Transmembrane signaling by GPCRs is fundamental to many aspects of physiology including vision, olfaction, cardiovascular, and reproductive functions as well as pain, behavior and psychomotor responses The duration and magnitude of signal transduction is tightly controlled by a series of coordinated trafficking events that regulate the cell-surface expression of GPCRs at the plasma membrane Progress in Molecular BiologyandTranslational Science, Volume 141 ISSN 1877-1173 © 2016 Elsevier Inc All rights reserved P.-Y Jean-Charles et al Moreover, the intracellular trafficking profiles of GPCRs can correlate with the signaling efficacy and efficiency triggered by the extracellular stimuli that activate GPCRs Of the various molecular mechanisms that impart selectivity, sensitivity and strength of transmembrane signaling, ubiquitination of the receptor protein plays an important role because it defines both trafficking and signaling properties of the activated GPCR Ubiquitination of proteins was originally discovered in the context of lysosome-independent degradation of cytosolic proteins by the 26S proteasome; however a large body of work suggests that ubiquitination also orchestrates the downregulation of membrane proteins in the lysosomes In the case of GPCRs, such ubiquitin-mediated lysosomal degradation engenders long-term desensitization of transmembrane signaling To date about 40 GPCRs are known to be ubiquitinated For many GPCRs, ubiquitination plays a major role in postendocytic trafficking and sorting to the lysosomes This chapter will focus on the patterns and functional roles of GPCR ubiquitination, and will describe various molecular mechanisms involved in GPCR ubiquitination INTRODUCTION 1.1 G Protein-Coupled Receptors G protein-coupled receptors (GPCRs), also known as seven-transmembrane receptors (7TMRs), constitute the largest family of cell-surface receptors, and are encoded by roughly 800 genes in the human genome.1 GPCRs transduce specific intracellular signals in response to a wide variety of extracellular stimuli that range from photons, ions, organic odorants, amino acids, lipids, nucleotides, peptides, and proteins (Fig 1) Signal transduction by GPCRs is fundamental for most physiological processes and include vision, smell, and taste as well as neurological, cardiovascular, endocrine, and reproductive functions.2–4 Consequently, the GPCR superfamily is a major target for therapeutic intervention and about 40% of prescription drugs target GPCR activity.5–7 GPCRs have a conserved structural architecture of seven transmembrane helices that traverse the membrane bilayer such that the amino terminus is exposed to extracellular milieu and the carboxyl terminus is intracellular in contact with the cytoplasm (Fig 1) Upon ligand binding and activation, specific conformational changes are triggered in the GPCR molecule This conformational switch facilitates GTP/GDP exchange on the Gα subunit of bound heterotrimeric G proteins and results in the dissociation of active Gα and Gβγ This stimulates catalytic activation of various downstream effectors (eg, adenylyl cyclase) and activation of kinase cascades and subsequent physiological responses.3 Agonist-activated GPCRs are rapidly phosphorylated by cognate GPCR kinases or GRKs on specific intracellular seryl/threonyl Index Central catalytic cysteine domain (CCD), 313 Cetuximab, 254 CFTR See Cystic fibrosis transmembrane conductance regulator (CFTR) Chaperone-mediated control of VEGFR turnover, 324 Charged multivesicular body protein (CHMP3), 180 CHIP See Carboxyl terminus of Hsc70interacting protein (CHIP) Chloride channel, expression cloning from torpedomarmorat, 189 Chromatin regulation, 107 C-Jun N-terminal kinase (JNK), 230, 278 Clamshell, 140 Clathrin-coated pits (CCP), 238 Clathrin-coated vesicle (CCV), 162 238, 318 Clathrin-dependent pathway, 171 Clathrin-mediated endocytosis (CME), 67, 236, 238, 322 CLC family, 189–191 channel CLC-1, 189 CLC-2, 189 CLC-Ka, 189 CLC-Kb, 189 location, 189 CLC-2 human disease progression, role in, 190 inward rectifying chloride channel, 190 CLC-5 dysfunction, 190 Dent’s disease, 190 endocytosis, 190 function Cl-/H+ exchanger, 190 reabsorption of proteins, 190 transporter, 189 Cl- channels/transporter ubiquitination, 186–191 CLC-Ka dysfunction, 191 Bartter syndrome, 191 373 deafness, 191 regulation Nedd4-2, role of, 191 CLC-Kb regulation Nedd4-2, role of, 191 Clients, 116 Hsp70, effect of, 116 Hsp90, interaction with, 116 Closed conformation, 224 CME See Clathrin-mediated endocytosis (CME) c-Met, 315 Congenital autosomal dominant genetic disorder, 169 Connexin (Cx), 196 Connexin 43 (Cx43), 180 Constitutive RTK recycling, 321 Contractile arrest, 124 COP9 signalosome, 103 Copurifying protein, 145 c-Src engagement βÀarrestin mediated, 92 C-terminal ubiquitination site, 75 Cul4A-ROC1 ligase, 101 Cx See Connexins (Cx) C-X-C chemokine receptor type (CXCR4), 352 ligand-induced degradation, 20 receptor, 96 ubiquitination, 20, 38 C-X-C chemokine receptor type (CXCR4) activation endogenous chemokine, effect of, 20 CXCL12-induced cell migration, 38 CXCR4 See C-X-C chemokine receptor type (CXCR4) CXCR2 internalization, interleukin (IL8) effect, 18 CXCR7 receptor cancer metastases, role in, 21 tumor progression, role in, 21 ubiquitination, 21 Cx32 protein, ERAD regulation, 197 Cx43 protein, ERAD regulation, 197 Cyclin-docking motifs (RLX), 110 Cycloheximide, 87, 102 374 Cystathionine-βÀsynthase (CBS) domain, 189 Cysteine protease, 316 Cystic fibrosis, 186 fatty stool, 186 infertility, 186 poor weight gain, 186 stubby phalanges, 186 stunted growth, 186 Cystic fibrosis transmembrane conductance regulator (CFTR), 180, 186 ATP-gated anion channel, 186 channel cytoplasmic regulatory (R) domain, 186 internalization, 188 clathrin-dependent pathway, 188 lysosomal degradation, 188 membrane-spanning domain, 186 nucleotide-binding domain (NBD), 186 phosphorylation site, 186 ΔF508, 186, 188, 189 mutation, 189 E3 ubiquitin ligase c-Cbl-mediated endocytosis, 186 lysosomal degradation, 186 potentiator, 189 ubiquitination, 186–189 Cytoplasmic protein clearance, 117 Cytoplasmic tyrosine kinase domain activation, 310 D DAG See Diacylglycerol (DAG) DDB1-interacting receptor, 104 DEGs See Delayed early genes (DEGs) Delayed early genes (DEGs), 231 Dent’s disease, 190 characterization albumin, elevated level of, 190 kidney stone, 190 nephrocalcinosis, 190 Dephosphorylation, 310 Deubiquitinase (DUB), 289, 311, 339 Deubiquitinating enzymes (DUBs), 163, 232, 314–315 Index Deubiquitination, 5–6, 315 Diacylglycerol (DAG), 335 Divalent metal ion transporter (DMT1) iron transport, role in, 195 DNA- RNA-Protein dogma, 274 Dopamine transporter distribution in brain mesolimbic system, 193 substantia nigra, 193 encoding SLC6A3 gene, 193 functional alteration, 193 ubiquitination PKC-dependent, 194 Down syndrome critical region (DSCR3), 350 Drosophila, signal transduction, 34 DSCR3 See Down syndrome critical region (DSCR3) DUB See Deubiquitinase (DUB) DUBs See Deubiquitinases (DUBs) Deubiquitinating enzymes (DUBs) DWD (DDB1-binding WD40) proteins, 101 Dynamin-2, 318 E EAG gene See Ether-a-go-go (EAG) gene Early endosomal antigen (EEA1), 286, 318 Early endosomes (EEs), 227 EEA1 See Early endosome antigen (EEA1) E1–E2–E3 ubiquitin conjugation system, 312 E3 enzymes homology to RING/U-box subfamilies, 313 E1 enzymes mediate UBL activation, 312 EEs See Early endosomes (EEs) E2 gene products, 313 EGFR See Epidermal growth factor receptor (EGFR) EGFR–Cbl complex, 323 E2-like enzymes, facilitate UBL conjugation, 313 Endocytic itineraries, 68 375 Index Endocytic pathways, 236 internalization, 237 Endocytosis, 236, 310, 313 Endoplasmic reticulum (ER), 140, 309 quality control UPP, role of, 144 tetrameric ion channel, 140 Endosomal sorting complexes required for transport (ESCRT), 16, 67, 350 endosomal sorting and trafficking, 315–316 ESCRT-0 complex, 315 Endosome–lysosome system, 313, 315, 323 Endosome–lysosome trafficking, 313 Endosomes, 316 EPI See Epigen (EPI) Epidermal growth factor (EGF), 110 Epidermal growth factor receptor (EGFR), 222 activation, 222 dependent signal transduction, 229 gene, 222 ligand-induced dimerization and activation, 223 ligands and their role in physiology, 226 mechanism of activation, 224 modeling network, 255 models, 256 protein, 222 signaling cascade, 223 signaling, endocytic control, 248 control at endosomes, 250 regulation by different entry routes, 249 structure, 222 timing of transcriptional response, 231 ubiquitination, 231, 318 and cancer, 252 ligand-induced, 235 Epigen (EPI), 226 Epithelial Na+ channels (ENaC), 165, 169–173 ubiquitination, 168–175 ER See Endoplasmic reticulum (ER) ERAD pathway See ER-associated degradation (ERAD) pathway ER-associated degradation (ERAD) pathway, 140 substrate recognition, 147 ER-associated protein degradation system, 162 ErbB1 maturation Hsp90, effect of, 120 E1-related genes, 312 E3 RING finger adaptor RNF121, 315 ERK activation, βÀarrestin-dependent, 20 ERLIN1/2 complex, 146–147 Erlin2 gene exon sequence, 151 genetic alteration, 151 mutations of, 151 perturbation, 151 two-nucleotide insertion, 151 Erlin1protien, 145 Erlin2 protien, 145 ERp44 protein, 147 ESCRT See Endosomal sorting complexes required for transport (ESCRT) Ether-a-go-go (EAG) gene, 179 E1-ubiquitin complex, 313 E3 ubiquitin ligase, 65, 337 Euphoria, 26 Excitable cell cardiac tissue, 174 neurons, 174 skeletal muscle, 174 Excitatory amino acid transporter (EAAT2) regulation Nedd4-2, role of, 195 SGK, role of, 195 Extended conformation, 224 Extended P2-P1 rule, 126 Extracellular ligand-binding domain, 309 F FAK See Focal adhesion kinase (FAK) Fast endophilin–mediated endocytosis (FEME), 240 F-box protein, 67 FEME See Fast endophilin-mediated endocytosis (FEME) 376 Flotillin-dependent pathway, 146, 240 Fluorescence recovery after photobleaching (FRAP), 69 Focal adhesion kinase (FAK), 278 FOXO ubiquitination, 295 Frizzled (Fzd) receptor deubiquitination, role of, 37 G Gαi2, ubiquitination, 73–73 Gαi3, ubiquitination, 72 Gap junction, ubiquitination, 196–197 Gα subunits adenylyl cyclase activation, 73 polyubiquitination, 74 subfamilies Gα12/13, 71 Gαi, 71 Gαq, 71 Gαs, 71 ubiquitination, 73–74 Gαt, ubiquitination, 71 Gβγ, ubiquitination, 71 GCN2 See General control nonderepressible kinase (GCN2) Geldanamycin, 117 Gene amplification, 275 Gene mutation, 275 Gene overexpression, 275 General control nonderepressible kinase (GCN2), 351 Gli response, 33 Glycine, 313 Glycoprotein, 309 Golgi apparatus, 183 Gonadotropin-releasing hormone (GnRH), 141 Gpa1 endosomal signaling, role in, 70 monoubiquitination, 64 mutants, 64 phosphatidylinositol 3-kinase, interaction with, 70 phosphatidylinositol 3-phosphate production, role in, 70 polyubiquitination, 63 Index GPCR See G protein-coupled receptors (GPCRs) GPCR kinases (GRK), regulation Hsp90 chaperone, role of, 116–123 stability Hsp90, role of, 119 turnover ischemic condition, 124–128 GPCRs See G protein-coupled receptors (GPCRs) G protein-coupled receptor kinase (GRK2), 346 allosteric activation, 109 biogenesis Hsp90, role of, 122 degradation altered patterns, 112 basal, 88 GPCR-induced, 88 GPCR-mediated modulator, role of, 96–97 other E3-ligases, role of, 96–97 GRK2 phosphorylation, role of, 92 proteasome-mediated regulation mechanism, 90 proteasome System, 87–89 ubiquitin-proteasome mediated, 87–102 downmodulation oxidative stress-induced, 125 localization to mitochondria, 122 mitogenic effect, 99 protein level cellular ratios of Pin1and Hsp90β protein expression, effect of, 115 recruitment Gβγ-mediated, 123 regulation Mdm2, role of, 97–99 S670 phosphorylation, importance of, 108 stability cullin E3-RING ligase complexes, role of, 101–102 Index kinase activity, effect of, 89–92 modulation cell cycle progression, 100 scaffold role of βÀarrestins, effect of, 89–92 turnover β2AR-stimulated, 92 Mdm2, role of, 93–94 basal Mdm2, role of, 93–94 tyrosine-phosphorylated β-arrestin, role of, 94 ubiquitination cullin E3-RING ligase complexes, role of, 101 N-terminal lysine residues, 105 potential modulation, 101–102 G protein-coupled receptor kinases (GRKs), 84, 284, 335 αC Àβ4 loop, 121 degradation proteasome-dependent, 103–105 GPCR, homologous desensitization of, 85 maturation Hsp90, role of, 120 stabilization Hsp90, role of, 120 subfamily GRK4, 5, and 6, 84 GRK1 and GRK7, 84 GRK2 and GRK3, 84 G protein-coupled receptors (GPCRs), 2–5, 57, 140, 335 agonist-stimulated phosphorylation, 62 amino terminus, carboxyl terminus, catalytic activation, 90 desensitization, 87 deubiquitination, 35–40 accelerated degradation, 38 alternate effect, 39–40 recycling and resensitization, 36–37 docking site, 105 downstream common signaling events, 90 frizzled (Fzd), 37 377 internalization βÀarrestin mediated, 85 intracellular trafficking agonist stimulated, 2, phosphorylation GRK-mediated, 85 postendocytic sorting βÀarrestins, role of, 16 posttranslational modification, responsiveness calpains, effect of, 124–128 proteasome, effect of, 124–128 signal transduction, 2, smoothened (Smo), 37 structural architecture, 2, ubiquitination, 6–7, 35 β2 adrenergicreceptor (β2AR), 6–18 CCR7, 22 chemokine receptor, 18, 19 CXCR2, 18 CXCR4, 20 CXCR7, 21 noncanonical GPCR hedgehog (Hh) signaling, 33–34 Wnt/βÀcatenin signaling, 29–33 opioid receptors (ORs), 26, 27 proteinase activated receptor, 22–25 yeast GPCR, 35 G protein gated potassium (GIRK) channel, 70 G proteins, 57 deubiquitination, 57, 68–69 independent signal transduction, 336 mammals, ubiquitin-mediated regulation, 71–74 monoubiquitination trafficking pathways, 67–68 polyubiquitination, 61 posttranslational modification (PTM), 57 ubiquitination, 57 recycling, 68–69 regulation ubiquitin mediated, 57, 59 signal transduction, 57 subunit Gα, 57 Gβ, 57 378 G proteins (cont.) Gγ, 57 GTPase activity, 57 ubiquitination deubiquitinating enzyme, 58 hotspot degree of sequence conservation, 74 observation count, 74 protein interface residence, 74 solvent accessible surface area, 74 structural analysis, 74, 76 unknown function, 74–75 site, identification, 58 site, proteomics analysis, 74 ubiquitin ligases, 58 yeast model system, 58–70 Gα/Gpa1, 61–62 ligases, 65–67 signal initiation, 62–65 signal regulation, role in, 69–70 Grb10 adaptor, 324 Grb2 proteins, 319 GRK See GPCR kinases (GRK) GRK2 See G protein-coupled receptor kinase (GRK2) GRK2 E3-ligase, 97 GRK4γ, ubiquitination, 105 GRK5 phosphorylation ERK1/2, role of, 105 GRKs See G protein-coupled receptor kinases (GRKs) GRK4, ubiquitination site, 105 Growth factor receptor EGFR, 99 ERBB2, 99 IGF1R, 99 Growth factors, 309 GTPase-activating proteins (GAPs), 318 GTP loading, 296 Guanine nucleotide exchange factors (GEFs), 318 H HB-EGF See Heparin-binding EGF-like growth factor (HB-EGF) Heat shock proteins 70 kDa (HSP70), 186, 324 Index HECT See Homologous to the E6-AP carboxyl terminus (HECT) Hedgehog (Hh) signaling βÀarrestin2, role of, 33 HEK293 cell, 174, 180 Hela cell, 69 Hematopoietic stem-cell precursors, 309 Heparin-binding EGF-like growth factor (HB-EGF), 226 Herbymicin A, 281 Hereditary spastic paraplegia (HSP), 151 hERG See Human ether-a-go-go related gene (hERG) Heroin, 26 HflC/K, 146 HIV See Human immunodeficiency viral protein (HIV) Homeostasis, 232 Homogeneous polyubiquitin chain, 107 Homologous to the E6-AP carboxyl terminus (HECT), 348 Homosapiens, 311 HRS (hepatocyte growth factor- regulated tyrosine kinase substrate), 16 Hsp90 Hsp90-GRK2 complex, 87 inhibition by, 103 ATP-mimetic drug, geldanamycin, 117 interaction with, 116 vs other chaperone, 116 Hsp70, effect of, 116 Human ether-a-go-go related gene (hERG), 179–184 cardiac repolarization, role in, 179 cell-surface channel, 180 channel hypokalemia-induced reduction, 180 proteasomal degradation polyubiquitination-mediated, 184 cyclic nucleotide-binding domain (cNBD), 179 mutation, 179 Per-Arnt-Sim (PAS) domain, 179 potassium channel Index Nedd4-2-mediated degradation, 182 Nedd4-2-mediated ubiquitination, 182 Human immunodeficiency viral protein (HIV), 73 Human Nedd4 substrate PY motif, with, 164 HUVEC cell, 100 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGR), 144 Hypoxia, 192 I IEGs See Immediate early genes (IEGs) IGF1R.See Insulin-like growth factor receptor (IGF1R) iJM region See Intracellular juxtamembrane (iJM) region ILVs See Intraluminal vesicles (ILVs) Immediate early genes (IEGs), 231 Immunoglobulin (Ig)-like repeats, 309 Inositol 1,4,5-trisphosphate receptors (IP3Rs), 140 activation model, 145 C-terminal domain (CTD), 140 ERAD, 144–145 role of, 150–151 homolog IP3R1, 140 tetrameric channel, 140, 143 IP3R2, 140 IP3R3, 140 induced Ca2+ mobilization UPP-mediated IP3R1 degradation, effect of, 150 IP3R-ERLIN1/2 complex-RNF170 axis diseases of, 151–152 molecular biology, 140–141 second messenger, role as, 140 targetting ERAD pathway, role of, 144 ubiquitination model, 145, 148–149 Insertion domain, 36 Insulin-like growth factor (IGF), 167 Insulin-like growth factor type receptor (IGF-1R), 276, 339 379 activation, 97 control by Mdm2 and GRKs/ β-Arrestins System, 284 control c-Cbl, 284 control of by SUMOylation, 288 ubiquitination process, 97, 285 Insulin receptor (IR), 276 control by Nedd4 and Grb10, 281 IGF-1R family, 280 p53-dependent mechanism, 282 signaling downstream, 288 ubiquitin-mediated regulation, 280 Insulin-receptor-related receptor (IRR), 276 Insulin receptor substrate (IRS-1), 347 Insulin receptor substrates (IRSs), 278 quality control by ubiquitination, 291 quantity control by ubiquitination, 289 ubiquitin-mediated regulation, 289 Internalized GPCR recycling deubiquitination, role of, 36 resensitization deubiquitination, role of, 36 Intracellular juxtamembrane (iJM) region, 225 Intracellular loop 1(ICL1), 26 Intraluminal vesicles (ILVs), 241 Intramyocardial ATP, 124 Intrinsic VEGFR2 tyrosine kinase, 322 Inward-rectifying potassium channels (Kir), 184 Inward rectifying potassium current, 184 Ion channels endocytosis, 162 caveolin-dependent pathway, 162 clathrin-dependent pathway, 162 flow of fluids, role in, 159 flow of ions, role in, 159 maintenance, 159 overall function, 159 physiological function, role in hormonal secretion, 159 muscle contraction, 159 nerve impulse, 159 salt homeostasis, 159 water homeostasis, 159 380 Ion channels (cont.) regulation ubiquitin, 159 trafficking process, 162 ubiquitination, 161, 162 ubiquitin-mediated degradation, 159, 161 Ion transporter regulation ubiquitin, 159 IP3Rs See Inositol 1,4,5-trisphosphate receptors (IP3Rs) IR See Insulin receptor (IR) IRR See Insulin-receptor-related receptor (IRR) IRS-1 See Insulin receptor substrate (IRS-1) IRSs See Insulin receptor substrates (IRSs) Ischemia, 165 Ischemia-reperfusion injury rat hearts, 124 Ischemic heart failure, 124 Isoproterenol, 102 J Janus kinase (JAK), 230 JNK See C-Jun N-terminal kinase (JNK) Jurkat cells, 125 Juvenile primary lateral sclerosis (PLS), 151 K K+ channel endocrine secretion, role in, 176 muscle contraction, role in, 176 neuronal signaling, role in, 176 tetramerization domain, 39 ubiquitination, 176–185 KCNJ1 gene, 184 KCNQs, 176–178 K48-conjugated ubiquitin chains, 286 K+ homeostasis ROMK, role of, 184 Kinase activation, receptor-stimulated, 105 Kinase domain C-terminal extension active site tether (AST), 105 K+ recycling ROMK, role of, 184 Index L Lactacystin, 103 Liddle’s syndrome, 169 Ligand-induced VEGFR homo- or heterodimerization, 310 Lipid rafts, 239 Lipopolysaccharide (LPS), 340 Lipoprotein recep- tor-related protein (LRP), 29 Long QT syndrome (LQTS), 176 LPS See Lipopolysaccharide (LPS) Lysine 29, 75 Lysine 46, 75 Lysine 51, 75 Lysine 62, 75 Lysine 89, 75 Lysosomal degradation, 160 Lysosomal pathway, 285 M mAbs See Monoclonal antibodies (mAbs) Mammalian cell line, 141 MAPK See Mitogen-activated protein kinase (MAPK) MDCK cell, 178 Mdm2 E3 ligase activity, 93 IGF-1R ubiquitination, 286 nuclear-cytoplasmic shuttling, 97 p53 activity, effect on, 93 Melanocortin 1, 104 Membrane-associated RING-CH (MARCH) family protien, 66 Membrane protein channels, 66 gap junction, 66 signaling receptor, 66 Metabolic pulse-chase assay, 87 Metabotropic αÀaminobutyric acid receptor(GABABR), 39–40 degradation, 39 lysosomal enzyme, role of, 40 proteasomal enzyme, role of, 40 internalization, 39 USP 14, effect of, 40 proteasomal degradation, 39 381 Index ER-associated degradation (ERAD) pathway, role of, 39 signaling AMPK phosphorylation, effect of, 39 PKC phosphorylation, effect of, 39 ubiquitination, 39 Metabotropic glutamate receptors (mGluRs), 124 Metal toxicity, 165 Methionine, 313 Mg2+-ATP binding, 313 Micropinocytosis, 236 Mitogen-activated protein (MAP), 126 Mitogen-activated protein kinase (MAPK), 108, 230, 275 activation, 70 IGF-1 induced, 97 cascade, 296 gene deletion, 63 pathway Epac, 99 GIT-1, 99 PDEγ, 99 Raf, 99 RhoA, 99 RKIP, 99 phosphorylation, 58, 105 scaffold protein, 58 signaling cascade, 254 Monoclonal antibodies (mAbs), 254 Monocytes chemokine-induced migration, 113 Monoubiquitin, 143 Monoubiquitination, 232, 313 of RTKs, 314 Morphine, 26 Mouse oocyte, 141 Mucoviscidosis, 186 Multiple monoubiquitination, 232 Multiple sclerosis (MS), 126 Multivesicular body (MVB) lysosome pathway, 180 machinery, 315 sorting, 247 Muscarine-sensitive K+ current (M-current), 178 Mushroom cap, 149 Mutations in mammalian UBA1 gene, 311 Myocardial infarction, 124 dogs total GRK2 activity, decrease, 124 Myocardial ischemia, 124 Myristoylation, 63 N Na+ channels (ENaC) ubiquitination, 168–175 Na+/K+ ATPase See Sodium-potassium adenosine triphosphatase (Na+/K+ ATPase) endocytic degradation hypoxia-induced, 192 phosphorylation, 192 Nav See Voltage-gated sodium (Nav) Nav gene SCN1A, 174 SCN2A, 174 SCN1B, 174 NCE See Nonclathrin endocytosis (NCE) N-degrons, 128 Nedd4 See Neural precursor cell-expressed developmentally downregulated gene (Nedd4) Nedd4-2 autoinhibition, 166 NEDD8, 312 NEDD4 E3 ubiquitin ligases ubiquitination, 160–169 Nedd4 E3 ubiquitin ligases, 163–163 regulation of, 165–169 Nedd4 family interacting proteins (Ndfips), 163 Nedd4-Grb10 complex, 282 Nedd4 overexpression, 282 Neonatal rat ventricular myocytes, 181 Nerve growth factor (NGF), 318 Neural precursor cell-expressed developmentally downregulated gene (Nedd4), 163 382 Neurokinin/tachykinin receptor (NK1R/TACR1), 321 Neuropathic pain, 175 Noncanonical GPCR smoothened receptor ubiquitination, 31 ubiquitination, 30 Nonclathrin endocytosis, 239 Nonclathrin endocytosis (NCE), 236 Nonoligomerized proteins, 281 N-terminal E1 adenylation domain, 313 O Oligomerization, 353 Oncogenic mutation, 29 Opioid receptor stimulation endogenous peptide agonist, role of, 26 trafficking ubiquitination, role of, 26, 27 types DOR, 26 KOR, 26 MOR, 26 nociceptin receptor (NOR), 26 ubiquitination differential effect, 27 μÀOpioid receptor, 96 GRK2 desensitization, 97 ORs See Opioid receptors (ORs) Osteoporosis transmem- brane protein (Ostm1), 72 P Panitumumab, 254 PAR See Proteinase activated receptor Paraplegia, 151 Parkin, 348 Parkinson’s disease, 191 dopamine transporter (DAT), role of, 191 E3 ubiquitin ligase parkin, role of, 191 PAR1, trypsin-like proteases lysosomal trafficiking, 23 ubiquitination, 23–25 Index PAR2, trypsin-like proteases multi-monoubiquitination, 25 RING domain E3 ligase c-Cbl, role of, 25 ubiquitination, 25 PAR2 ubiquitination, 38 Pathological conditions, 309 PDE4D5 See Phosphodiesterase-4D5 (PDE4D5) Peptidyl-prolyl isomerase (PPIase), 113 Phenylalanine, 186 Pheromone receptor, 62 Pheromone response pathway, 58 Phosducin-like (PDCL3), 324 Phosphatase, 295 Phosphatidylinositol 3-kinase (PI3K) pathway, 18, 275, 289 ubiquitin-mediated regulation, 293 Phosphatydilinositol 3-phosphate (PI(3)P), 241 Phospho-caveolin-1 (pY14), 286 Phosphodegron, 93 Phosphodiesterase-4D5 (PDE4D5), 346 Phosphoinositide-dependent protein kinase-1 (PDK1), 167 Phosphoinositide 3-kinase (PI3K), 230 Phospholipase C (PLC), 73, 230 Phospholipase Cγ1 (PLCγ1), 310 Phosphorylation, 167, 310 of RTKs, 318 Phosphotyrosine binding (PTB) domain, 229, 278 PI3K See Phosphatidylinositol 3-kinase (PI3K) Pin1 protein kinase mediated signaling pathway, regulation of, 113 PI(3)P See Phosphatydilinositol 3phosphate (PI(3)P) Plasma membrane, 309 Platelet-derived growth factors, 110, 309 platelet-derived growth factor receptor (PDGFR), 315 PLC See Phospholipase C (PLC) Pleckstrin homology (PH) domain, 84 PLS See Primary lateral sclerosis (PLS) 383 Index Point mutation functional analysis, 105 Polyubiquitination, 232, 313 Polyubiquitin-binding cofactor Npl4, 145 Ufd1, 145 Polyubiquitin oligomer (K48-polyUb), 313 Polyubiquitin-tagged protein, 107 Posttranslational modifications (PTMs), 337 mechanisms, 274 ubiquitin-based, 143 p85 PI3K regulatory subunit, 293 p53 protein Mdm2 expression, effect on, 93 monoubiquitination, 93 polyubiquitination, 93 Preeclampsia, 309 Primary lateral sclerosis (PLS) upper motor neuron, effect on, 151 Prohibitin, 146 Proline-directed kinases, 108 Prolyl-isomerase Pin1, 100 Promyelocytic leukaemia cell line epithelial Cos-1 cells, 117 HL 60, 117 Proteasomal degradation, 143 Proteasomal pathway, 287 Proteasome, 61, 141 Proteasome inhibition antiarrhythmic effect, 124 Proteasome inhibitors, 103, 282 Proteinase activated receptor (PAR) expression, 22 signaling ubiquitination, role of, 24 trafficking ubiquitination, role of, 24 type PAR1, 22 PAR2, 22 PAR3, 22 PAR4, 22 Protein degradation pathway calpain dependent proteasome system, 86 caspase dependent proteasome system, 86 GRK ubiquitination, role of, 105–107 lysosomal dependent proteasome system, 86 ubiquitin dependent proteasome system, 86 UPP, role of, 143 Protein endocytosis, 107 Protein kinase A (PKA), 167 Protein kinase B, 167 Protein kinase C (PKC), 310 activation, 165 signal transduction, 325 VEGF-A-stimulated activation of, 325 Protein localization, 64, 105 Protein misfolding, 62 3–4 protein–protein interaction domains (WW domains), 163 Protein-protein interactions, 335 Proteins, 309 Protein sorting, 107 Protein trafficking, 162 Protein translation H2O2, 125 Protein tyrosine phosphatases (PTPs), 251, 310 Protein ubiquitination, 311 Pseudohyperaldosteronism, 169 Pseudohypoaldosteronism type I (PHAI), 172 PTB See Phosphotyrosine binding (PTB) PTB domain See Phosphotyrosine binding (PTB) domain PTEN polyubiquitination, 293 PTH1R See Type I parathyroid hormone receptor (PTH1R) PTMs See Posttranslational modifications (PTMs) PTPs See Protein tyrosine phosphatases (PTPs) p53 ubiquitin ligase, 282 pY14 See Phospho-caveolin-1 (pY14) R Rab11a-dependent recycling, 321 Rab GTPase cycling, 318 Rab protein, 162 384 Raf/ERK pathway inhibition, 296 Raf kinase inhibitor protein (RKIP), 90 Raf-MEK- ERK signal transduction pathway, 295 Rapamycin, 99 Ras activation, 296, 319 RAS-MAPK pathway, 295 cascades, 295 control of MAPK cascade, by ubiquitination, 296 control of Ras, by ubiquitination, 296 ubiquitin-mediated regulation, 295 RBR See RING-in-between- RING (RBR) Really interesting new gene (RING) family, 5, 87, 233, 337 RING-in-between- RING (RBR), 348 RING-type E3 ubiquitin ligase, 67 U-box subfamilies, 313 Receptor internalization, 85 βÀarrestin mediated, 92 Receptor tyrosine kinases (RTK), 222, 274 mediated communication, 275 Signaling, 274 subfamily, 309 Rectifier potassium current (IKr), 179 Renal outer medullary K+ channel (ROMK), 184–185 Renal outer medullary potassium channel (ROMK), 176 Rhodopsin kinase, 84 RING See Really interesting new gene (RING) Ring finger-43 (RNF43) gene, 29 RNF170, 146–147 mutations of, 151 point mutation, 152 Rod1 activity calcineurin-mediated dephosphorylation, role of, 35 RTK See Receptor tyrosine kinases (RTK) S Saccharomyces cerevisiae, 35, 57, 243 pheromone signaling, 35 Salt-sensitive hypertension, 169 Index Salt-wasting disorder, 184 SAPH-ire (structural analysis of PTM hotspots), 74 SAPKs See Stress-activated protein kinases (SAPKs) Sclerosis, 151 Secondary response genes (SRGs), 231 Second messenger diacylglycerol (DAG), 73 inositol-1,4,5-triphosphate (IP3), 73 Secretory pathway, 309 Sensory ataxia, 151 Serine/threonine-specific kinases, 116 ERK1/2, 116 JNK, 116 PKA, 116 PKC, 116 Serum and glucocorticoid inducible kinase (SGK), 167 Seven-transmembrane receptors (7TMRs), 335 Seealso G protein-coupled receptors (GPCRs) SH2 See Src homology (SH2) Shc proteins, 319 Signaling adaptor proteins, 319 Signalosome, 86 Signal peptide cleavage, 309 Signal transducer and activator of transcription (STAT), 230 Signal transducing adaptor molecule (STAM), 315 Signal transducing adaptor molecule (STAM-1), 20 Signal transduction pathway UPP, role of, 143 siRNA See Small interfering RNA (siRNA) SMAD ubiquitination regulatory factor-2 (SMURF2), 352 Small interfering RNA (siRNA), 341 Small ubiquitin modifier (SUMO), 312 Smo See Smoothened (Smo) Smo autoinhibitory domain (SAID), 34 Smoothened (Smo) receptor multi-monoubiquitination inhibition hedgehog signaling, role of, 37 Smoothened (Smo) regulation Index deubiquitination, role of, 37 ubiquitination, importance of, 34 Smoothened signalling, 31, 33 Smooth muscle cells, 353 SMURF2 See SMAD ubiquitination regulatory factor-2 (SMURF2) SOCS See Suppressor of cytokine signaling (SOCS) Sodium potassium pump, 192 Solute carriers SLC gene, encoding, 193 Son of Sevenless (SOS) proteins, 319 SPFH1, 146 SPFH2, 146 Src homology (SH2), 229, 278 domain, 310 SRGs See Secondary response genes (SRGs) STAT See Signal transducer and activator of transcription (STAT) STE2 desensitization, 35 Stem cell biology hedgehog (Hh) signaling, importance of, 33 Stomatin, 146 Stress-activated protein kinases (SAPKs), 278 Stress-related kinases cytosolic tyrosine kinase c-Src, 108 MAPK, 108 Substrate recognition Erlin1/2 complex, role of, 147 Sudden cardiac death, 176 Suppressor of cytokine signaling (SOCS), 278 T T-cell-specific adaptor molecule (TSAd), 310 Tethered conformation, 224 TfR See Transferrin receptor (TfR) TGFα See Transforming growth factor-α (TGFα) TGN See trans-Golgi network (TGN) Thiol ester bond, 313 Thiol ester formation, 313 Thiol-linked ubiquitin, 313 385 Thioredoxin-interacting protein (TXNIP), 350 Thioredoxin protein family, 147 Tissue reperfusion, 124 TK See Tyrosine kinase (TK) TKB domain See Tyrosine kinase binding (TKB) domain TLR4 See Toll-like receptor (TLR4) 7TMRs See Seven-transmembrane receptors (7TMRs) Toll-like receptor (TLR4), 339 TRAF6 See Tumor necrosis factor receptor-associated factor (TRAF6) Transcription factor UPP, role of, 143 Transducin Gα regulation polyubiquitination, role of, 71 proteasomal degradation, role of, 71 Gβγ regulation polyubiquitination, role of, 71 proteasomal degradation, role of, 71 ubiquitination, 71 Transduction pathway AKT pathway, 99 mTOR pathway, 99 PI3K pathway, 99 Transferrin receptor (TfR), 239 Transforming growth factor-α (TGFα), 226 trans-Golgi network (TGN), 32, 241 Transient receptor potential cation channel subfamily V member (TRPV4), 351 Transmembrane domain, 309 Transporter function regulation endocytosis, role of, 191 postendocytic trafficking, role of, 191 ubiquitination, 191–196 Na+/K+ ATPase, 192–193 solute carriers, 193–196 divalent metal ion transporter (DMT1), 195 dopamine transporter, 193 excitatory amino acid transporter (EAAT2), 195–196 386 Transporter function (cont.) sodium-coupled neutral amino acid transporter (SNAT2), 195 TRPV4 See Transient receptor potential cation channel subfamily V member (TRPV4) Tumoral proliferation GRK2, role of, 99 Tumor necrosis factor recep- tor-associated factor (TRAF6), 340 TXNIP See Thioredoxin-interacting protein (TXNIP) Type I parathyroid hormone receptor (PTH1R), 37 signaling bone formation, role in, 37 bone resorption, role in, 37 calcium homeostasis, regulation of, 37 ubiquitination, 37 Tyrosine kinase (TK), 276 Tyrosine kinase activation, 310 Tyrosine kinase binding (TKB) domain, 233 Tyrosine kinase domain, 309 U Ub See Ubiquitin (Ub) Ub-binding domains (UBDs), 232 containing proteins Bul1, 67 Ddi1, 67 Ede1, 67 Rup1, 67 UBDs See Ub-binding domains (UBDs) Ubiquitin (Ub), 5, 160, 231, 311, 313 activating (E1) enzyme, 143, 160 activation of E1activating enzyme, 65 role in EGFR CME, 243 role in EGFR endocytosis, 243 transfer E2 conjugating enzymes, 65 Ubiquitin-associated (UBA) protein, 197, 314 Ubiquitination, 5–6, 231 275, 313 β2AR induced, 93 domain, 62 Index enzymes Ub activating enzyme or E1, Ub conjugating enzyme or E2, Ub ligases or E3, ERAD, role of, 143–144 factor, 160 in IGF-1R/IR-mediated signaling, 280 lysine residue, 107 mediated endocytosis, 69 polypeptides, 311, 313 proteases, 68 proteasome pathway, 140 role in EGFR NCE, 246 of RTKs, 318 signals, 314 ubiquitin-activating enzymes (E1s), role of, 87 ubiquitin-binding domain (UBD), 67, 314 ubiquitin carboxyl-terminal hydrolase (UCH-L3), 171 ubiquitin codes, ubiquitin-conjugating enzyme (E2), 143, 160 role of, 87 UBC/ubiquitin E2 variant (UEV), 314 ubiquitin conjugation, 314 ubiquitin-interacting motif (UIM), 314 ubiquitin ligase (E3), 87, 143, 323 class homologous to the E6-AP carboxyl terminus (HECT), 160 plant homeodomain (PHD)finger-type, 160 really interesting new gene (RING), 160 Ubox-type, 160 employed, 285 families, 311 homologous to E6AP carboxyl terminus (HECT) type, 65 really interesting new gene (RING), 65 ubiquitin-like proteins (UBLs), 197, 312 387 Index ubiquitin-proteasome pathway (UPP), 140 role of, 143–144 ubiquitin-protein ligases (E3s) enzyme, 160 role of, 87 ubiquitin specific proteases (USP), 5, 341 ubiquitin system, 160–163 ubiquitin–ubiquitin-binding domain (UBD), 314 Ubiquitin-like proteins (UBLs) conjugation, 313 Ubiquitin-specific protease (USP) β2AR binding, 36 USP14, 39 proteasomal degradation, effect on, 39 USP20, 36 overexpression, 36 USP 33, 36 UPP See Ubiquitin-proteasome pathway (UPP) USP See Ubiquitin-specific protease (USP) V Vacuolar proteases, 61 Vascular endothelial growth factor receptor (VEGFR) cytoplasmic domain, 310 dimer, 310 endocytosis, 317–318 mediated signal transduction, 309 modification, 323 proteolysis, 322 trafficking and signal transduction, 316–317 from endosomes, 319 Rab GTPase control of, 318 ubiquitination, 310 vascular endothelial growth factor receptor 2, 310 expression, 309, 310 internalization, 317 regulated intracellular signaling, 310 trafficking through the endosome–lysosome system, 320 ubiquitination and trafficking, 324 Vascular endothelial growth factors (VEGFs) family, 309 ligands, 309 VEGF-A-activated VEGFR2, 310 VEGF-A binding, to VEGFR1, 310 VEGF-A-induced signal transduction, 309 Vascular endothelial PTP (VE-PTP), 310 Vascular physiology309 Vasopressin, 170 V2 receptor(V2R), 336 Ventricular arrhythmias, 176 Ventricular tachycardia, 124 Voltage-gated Na+ channel, 169, 174–175 abnormal function, 174 action potential initiation, role in, 174 Voltage-gated sodium (Nav), 174 V2R See Vasopressin V2 receptor (V2R) W Wnt/βÀcatenin gene expression program, 29 X Xenopus oocytes, 175 Y Yeast GPCR STE2, 35 STE3, 35 Z Zinc and Ring finger-3 (ZNRF3) gene, 29 ... serines or lysines in this motif affects both ubiquitination and ligand-induced degradation of CXCR4 The HECT-domain E3 ligase called Atrophin-1interacting protein (AIP4) ubiquitinates CXCR4 and. .. called β-arrestins (β-arrestin1 and β-arrestin2; also called arrestin2 and arrestin3).3,8–11 GRK phosphorylation and β-arrestin binding together block G protein coupling and lead to signal desensitization... serine-threonine kinases called GPCR kinases (GRKs) Phosphorylated GPCRs serve as high affinity binding receptacles for recruiting and docking the cytosolic adaptors called β-arrestins β-arrestins
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