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CHARACTERISATION of A-CHIMAERIN ISOFORMS and A2 SH2 DOMAIN MUTANTS EXPRESSED in NEUROBLASTOMA CELLS

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CHARACTERISATION of A-CHIMAERIN ISOFORMS and A2 SH2 DOMAIN MUTANTS EXPRESSED in NEUROBLASTOMA CELLS CHARACTERISATION OF a-CHIMAERIN ISOFORMS AND a2 SH2 DOMAIN MUTANTS EXPRESSED IN NEUROBLASTOMA CELLS A Thesis by NANSI EMMA CANN Submitted to University College London for the Degree of Doctor of Philosophy, PhD 2000 Miriam Marks Department of Neurochemistry Institute of Neurology University College London Queen Square London WC1N 3BG ProQuest Number: 10609000 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 10609000 Published by ProQuest LLC(2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 Dedicated to my parents, Mary and Brian Cann Dedication Acknowledgements I wish to thank Professor Louis Lim for the opportunity to study for a PhD in his laboratory as a member of the Glaxo-IMCB group. I would also like to thank both him and my co-supervisor Dr Christine Hall for their help and encouragement during my period of study, especially Dr Hall for all her advice during the writing of this thesis. I would also like to thank the other laboratory members; Clinton Monfries, Rob Kozma, Sally Williams, Kate Marler, Giovanna Ferrari, Elena Prigmore, Ric Passey, and especially Shanta Cariese, Shula Sarner and Sheila Govind for their help in various techniques and in providing an enjoyable working environment. Thanks also to my friends and family for their support and tolerance during my study period. Finally, to Stuart who has helped me through all the hard times, supported me and tolerated a lot, thank you for everything. Acknowledgements 3 ABSTRACT Rac is a member of the Rho family of low molecular weight GTPases (p21s) which is involved in diverse processes including regulation of the actin cytoskeleton and transcriptional activation. Chimaerin, a multidomain GTPase activating protein (GAP) downregulates Rac by increasing its intrinsic rate of GTP hydrolysis. Two splice variants of the chimaerin gene differ in tissue and developmental expression patterns and a2-chimaerin contains an N terminal SH2 domain which is absent from a l- chimaerin. The distribution and morphological effects of the chimaerins, a2-chimaerin SH2 domain mutants and potential a2-chimaerin targets in N1E 115 neuroblastoma cells were investigated. The distribution of al-chimaerin was predominantly cytoskeletal and a2-chimaerin cytosolic. In transiently transfected N1E 115 cells, al-chimaerin was concentrated in the perinuclear region and its expression induced cell rounding, whilst a2-chimaerin was expressed throughout flattened, neurite bearing cells. A point mutation in the SH2 domain of a2-chimaerin induced an al-chimaerin-like protein distribution and morphology. The effects of long term chimaerin overexpression on cell morphology and potential protein interactions were also investigated. Overexpression of ot2-chimaerin induced an enlarged, flattened morphology and neurite outgrowth in the presence of serum, whilst overexpression of al-chimaerin induced a rounded morphology with multiple peripheral actin microspikes and inhibited neurite outgrowth. p35, the neuronal cdk5 regulator and also an 130 kDa tyrosine phosphorylated protein were immunoprecipitated with chimaerin from these cell lines. Similarly an 180 kDa tyrosine phosphorylated protein was identified as a potential target of the a2-chimaerin SH2 domain. Investigation into the effects of chimaerin on activation of the transcription factor NFk B demonstrated cell type specific differences in NFk B signalling pathways between HeLa and N1E 115 cells. These results suggest that functional differences in the chimaerin isoforms are specified by the divergent N terminal sequences. Abstract 4 TABLE OF CONTENTS Title page ............................................................................................................................1 Dedication ......................................................................................................................... 2 Acknowledgements ..........................................................................................................3 Abstract............................................................................................................................. 4 Table of Contents ............................................................................................................. 5 List of Figures ..................................................................................................................14 Abbreviations ...................................................................................................................17 CHAPTER ONE: Introduction ................................................................................... 23 1.1 Receptor tyrosine kinases.......................................................................................25 1.1.1 Substrates of receptor tyrosine kinases ..................................................... 25 1.1.2 Multiple substrates of receptor tyrosine kinases ...................................... 26 1.2 Activation of downstream signalling pathways .................................................. 26 1.2.1 MAPK pathways........................................................................................26 1.2.1 A ERK pathway........................................................................... 27 1.2.IB JNK and p38 pathways ...............................................................27 1.2.2 Phospholipid signalling pathways .............................................................28 1.2.2A Phospholipase C and phospholipase D ...................................... 28 1.2.2B Phosphatidylinositol-4-phosphate-5-kinase ...............................28 1.2.2C Phosphatidylinositol-3-kinase .................................................... 29 1.3 The Cytoskeleton......................................................................................................29 1.3.1 The actin cytoskeleton ............................................................................... 29 1.3.1A Polymerisation of the actin cytoskeleton ................................... 29 1.3. IB Actin polymerisation at the leading edge ..................................30 1.3.1C Regulation of actin depolymerisation ........................................ 31 1.3. ID Actin crosslinking .......................................................................31 1.3. IE Cross linkage of the actin cytoskeleton and membranes by ERM proteins .................................................................................... 32 1.3.2 The microtubule network ...........................................................................33 1.3.2AMicrotubule structure ................................................................. 34 1.3.2B Microtubule associated proteins .................................................34 1.3.3 The intermediate filament network ...........................................................35 1.3.3A Intermediate filament associated proteins ................................. 36 Table of Contents 5 1.4 Protein domains ....................................................................................................... 36 1.4.1 SH2 domains .............................................................................................. 37 1.4.1A Unusual SH2 domains ................................................................ 38 1.4.IB Non phosphotyrosine dependent SH2 interactions ................... 38 1.4.2 Phosphotyrosine binding domains .............................................................39 1.4.3 SH3 domains .............................................................................................. 39 1.4.4 Pleckstrin homology domains ................................................................... 40 1.4.5 Other protein domains ............................................................................... 42 1.5 GTPase superfamily.................................................................................................42 1.5.1 Heterotrimeric G proteins ..........................................................................42 1.5.2 Ras subfamilies of low molecular weight GTPases .................................44 1.5.2A Ras............................................................................................... 45 1.5.3 The regulation of GTPase proteins ............................................................45 1.5.3A GAPs for heterotrimeric G proteins ...........................................45 1.5.3B GAPs for R as .............................................................................. 46 1.5.3C GAPs for Rho family proteins ................................................... 46 1.5.3D Multidomain nature of GAPs......................................................48 1.5.3E RasGEFs .....................................................................................49 1.5.3F GEFs for Rho family proteins .....................................................50 1.5.3F1 Cdc42 specific GEFs .....................................................50 1.5. 3F2 Rho specific GEFs.........................................................51
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