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Cell Signaling by Rho and Miro Gtpases

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Cell Signaling by Rho and Miro Gtpases Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 320 Cell signaling by Rho and Miro GTPases Studies of Rho GTPases in Cytoskeletal Reorganizations and of Miro GTPases in Mitochondrial Dynamics ÅSA FRANSSON ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 UPPSALA ISBN 978-91-554-7122-4 2008 urn:nbn:se:uu:diva-8514 ! " #$ $$% $&'#( ) ! ) ) *! ! ! + , ! - . $$% /! 0 * 1 ) /! 0 * 2 / 3 ) 0 * ! " $ 4 516 &4%7&#7((74#7 ! / ) ) 0 * 8 ! ) ' ! / / / ") /! ) ! 8 ) 0 * ) +! ! + 0 *7 0*7 ! ! + ) ! ) ) ! /! ! /! 0 * ! 3 ) ! 2 ! +! ! 0 * ) ! ! " ) ! ))2 2 /! 0 * "! ! ! /! 0 * $ /! 0 * ! ) ! ! /! " /# +!! ! ) 7 5 )) ! )) ) /! 0 * ! + ) /! 0 * ! 9*",: ! )) ! 3 ) ! 2 ; ) ) ) ! )) ) ! /! 0 * + ! ! + )) ) /! 0 * ! ) ! ! ! 5 ) /72 0 * + ) ! 0 * 9 ! /! : 5 !3 ) + ! ! ! ) ! ! ) ! ) ! ! " + ! ) !+ ! !! ! ! ! ) ! +! 5 ) ! ) ! ) /! 0 * / ) /! 0 * 2 0 * ! ! " # $ %&% '()%*+, < . - $$% 5116 #=(#7=$= 516 &4%7&#7((74#7 ' ''' 7%(# 9! '>> 2> ? @ ' ''' 7%(#: Till mina nära och kära The big wheel keeps on turning On a simple line day by day The earth spins on its axis One man struggles while another relaxes (Massive Attack, Hymn of the Big Wheel) LIST OF PUBLICATIONS This thesis is based on the following publications, which will be referred to in the text by their Roman numerals: I. Pontus Aspenström, Åsa Fransson and Jan Saras “Rho GTPases have diverse effects on the organization of the actin filament system” Biochem J. 377:327-37, 2004. II. Åsa Fransson, Aino Ruusala and Pontus Aspenström “Atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis” J Biol Chem. 278: 6495-502, 2003. III. Åsa Fransson, Aino Ruusala and Pontus Aspenström “The Atypical Rho GTPases Miro1 and Miro2 have essential roles in mitochondrial trafficking” Biochem Biophys Res Commun. 344:500-10, 2006. Reprints were made with permission from the publishers. RELATED PUBLICATIONS i. Pontus Aspenström, Åsa Fransson and Ninna Richnau “Pombe Cdc15 homology proteins: regulators of membrane dynamics and the actin cytoskeleton” Trends Biochem Sci.31:670-9, 2006. ii. Ninna Richnau, Åsa Fransson, Khashayar Farsad and Pontus Aspenström “RICH-1 has a BIN/Amphiphysin/Rvsp domain responsible for binding to membrane lipids and tubulation of liposomes” Biochem Biophys Res Commun. 320:1034-42, 2004. CONTENTS ABBREVIATIONS .....................................................................................13 INTRODUCTION .......................................................................................15 1 The Ras Superfamily of GTPases .....................................................15 1.1 Regulation and Localization of GTPases....................................16 1.2 Applied Mutations in GTPases...................................................19 2 The Cytoskeleton ..............................................................................19 2.1 Actin Polymerization..................................................................21 3 The Rho GTPases..............................................................................21 3.1 Rho GTPases in Actin Dynamics ...............................................24 3.1.1 Cell Migration....................................................................24 3.1.1.1 Protrusive Force...........................................................24 3.1.1.2 Formation and Turnover of Cell-Substrate Adhesions ..................................................................................25 3.1.1.3 Cell Contraction...........................................................25 3.1.1.4 Directional Sensing .....................................................26 3.1.2 Membrane Trafficking .......................................................27 3.2 Additional roles for Rho GTPases..............................................27 3.3 Rho GTPases in Diseases ...........................................................28 4 The Miro GTPases ............................................................................29 5 Mitochondria 30 5.1 Mitochondrial Dynamics ............................................................31 5.1.1 Mitochondrial Transport ....................................................32 5.1.1.1 Microtubule-Based Transport......................................32 5.1.1.2 Actin in Transport and Docking ..................................35 5.1.1.3 Links between Intermediate Filaments and Mitochondria .............................................................................36 5.1.2 Mitochondrial Fusion.........................................................36 5.1.3 Mitochondrial Fission ........................................................39 5.2 Mitochondria-Shaping Proteins in Cell Death............................41 5.3 Mitochondrial Dynamics in Disease...........................................41 PRESENT INVESTIGATION.....................................................................44 Aims ........................................................................................................44 Paper I: Rho GTPases have Diverse Effects on the Organization of the Actin Filament System ..................................................................44 Paper II: Atypical Rho GTPases have Roles in Mitochondrial Homeostasis and Apoptosis.....................................................................45 Paper III: The Atypical Rho GTPases Miro-1 and Miro-2 have Essential Roles in Mitochondrial Trafficking .........................................46 REFLECTIONS ...........................................................................................49 ACKNOWLEDGEMENTS .........................................................................52 REFERENCES.............................................................................................54 ABBREVIATIONS Arp Actin-related protein ALS Amyotrophic lateral sclerosis ATP Adenosine triphosphate Bcl-2 B-cell lymphoma 2 BTB Broad Compex/Tramtrack/Brick à brac DRF Diaphanous-related formin Drp1 Dynamin-related protein-1 EGF Epidermal growth factor GAP GTPase-activating protein GDF GDI-displacement factor GDI Guanine nucleotide dissociation inhibitor GDP Guanosine-5’-diphosphate GEF Guanine nucleotide exchange factor GRIF1 GABAA receptor interacting factor 1 GTP Guanosine-5’-triphosphate IF Intermediate filament JIP JNK-interacting protein JNK c-Jun N-terminal kinase MAP Microtubule-associated protein Mfn Mitofusin Miro Mitochondrial Rho MLC Myosin light chain OIP106 O-linked N-acetylglucosamine transferase interacting protein 106 Opa1 Dominant optic atrophy associated protein PDGF Platelet-derived growth factor PLD Phospholipase D Ras Rat Sarcoma viral oncogene homolog Rho Ras homologous ROCK Rho-associated kinase ROS Reactive oxygen species VDAC Voltage-dependent anion-selective channel WASP Wiskott-Aldrich syndrome protein WAVE WASP-like verprolin-homologous protein INTRODUCTION Cells in multicellular organisms like humans exhibit a wide variety of distinct shapes and internal organizations. With delicate timing and precision, cells alter their structure and behavior in response to internal and extracellular signals. Cells adapt to their ever-changing environment by changing polarity, crawling, dividing, transporting organelles, extending and retracting processes and establishing and breaking contacts with neighboring cells. All these processes require extensive remodeling of the cytoskeleton, a dynamic network of different types of protein filaments extending throughout the cytosol. Cytoskeletal remodeling consumes energy. Mitochondria are the power plants of the cell converting the energy of food into the high-energy compound, ATP, used to fuel cell reactions. Mitochondria acquire specialized conformations and undergo changes in intracellular distribution, often in response to the metabolic needs of the cell. Defects in either cytoskeletal regulation or mitochondrial dynamics inevitably lead to diseases. This thesis will focus primarily on the biological functions of two groups of Ras superfamily GTPases: Rho and Miro. The Rho GTPases respond to extracellular signals and transduce these signals to cytoskeletal rearrangements, whereas the Miro GTPases are regulators of mitochondrial movement and morphology. 1 The Ras Superfamily of GTPases The founding members of the Ras superfamily are K-Ras, H-Ras and N- Ras, identified in the early 1980 as oncogenes mutated in human cancers of different origins (Krontiris et al. 1981; Perucho et al. 1981; Shih et al. 1981). The oncogenic properties of these proteins triggered interest in exploring the biological roles of related proteins. Members of the Ras superfamily function as molecular switches and alternate between an active, GTP-bound, and an inactive, GDP-bound state (Takai et al. 2001). In humans, the Ras superfamily of proteins comprises more than 150 members that can be divided into six subfamilies: Ras, Rab, Arf, Ran, Rho and Miro. Members of the Ras subfamily regulate gene 15 expression, Arf proteins control microtubule dynamics and, together with Rab, regulate intracellular vesicle trafficking, whereas Ran masters nucleocytoplasmic transport, mitotic spindle and nuclear
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