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The Subcellular Localisation of HAX1 Isoforms and Their Roles in Cancer Cell Migration, Autophagy and Apoptosis

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The Subcellular Localisation of HAX1 Isoforms and Their Roles in Cancer Cell Migration, Autophagy and Apoptosis The Subcellular Localisation of HAX1 Isoforms and Their Roles in Cancer Cell Migration, Autophagy and Apoptosis Chia-Yu Chen Submitted to the University of London for the Degree of Doctor of Philosophy February 2013 Centre for Tumour Biology Barts Cancer Institute- a Cancer Research UK Centre of Excellence Barts and The London School of Medicine and Dentistry Queen Mary, University of London John Vane Science Centre Charterhouse Square London EC1M 6BQ 1 DECLARATION The work described in this thesis was carried out by the author, Chia-Yu Chen, in the Centre for Tumour Biology, Barts Cancer Institute - a Cancer Research UK Centre of Excellence, Queen Mary, University of London. I hereby declare that this thesis entitled “The Subcellular Localisation of HAX1 Isoforms and Their Roles in Cancer Cell Migration, Autophagy and Apoptosis” has not been submitted for the award of any degree, or its equivalent to any other university. (Chia-Yu Chen), February 2013 2 DEDICATION This thesis is dedicated to my beloved grandparents and parents, and to the memory of my grandmother 3 ACKNOWLEDGEMENTS First and foremost I want to thank my supervisor, Dr. John Marshall, who is always patient and encouraging. It has been an honour to work with him and I appreciate all his contributions of time and ideas to make my Ph.D. experience productive and stimulating. I wish to express my gratitude to Dr. Delphine Lees. I have learned a lot, both scientific knowledge and attitude, form her and this work would not have been possible without her support and encouragement. I am also indebted to my guide, Prof. Ian Harts, for providing guidance and resources to allow me to accomplish my research work. I would like to acknowledge the technical support from Dr. Guliemo Rosignoli and Dr. Linda Hammond. I am also thankful to the members of my group: Sab, Kate, Stella, Adrian and Mike for all their scientific advice and support. I would like to thank my lovely colleagues: Ludovic, Kayi, Ling, Cheng, Maria, Silvia, Bernardo, Tony, Margot, Abasi, Rachel, Marianne, Tanguy, Muge, Nuria, Estefania, Isabelle, Debbie, George, James, Eiman, Mo, Katie and Pam; and my friends in Taiwan: Momo, Mary, Hui-Yi and Yumiko for making my PhD full of so much fun and joy. To my family, my grandparents, my parents and my sisters, I cannot do this without them. To my partner Bob,whose love makes everything possible. 4 ABSTRACT It has been reported that HAX1 is a multi-functional protein which protects cells from apoptosis, modulates autophagy, regulates membrane protein trafficking and promotes cell migration. Many studies have shown it has many different intra- cellular binding partners (including integrin β6 subunit) and exists in multiple cellular locations, including the nucleus, mitochondria and cytoplasm. This behaviour seemed unlikely for a single protein. My lab discovered that there are at least eight different HAX1 isoforms in humans and this might explain why multiple roles and sub-cellular locations are described for HAX1. In this study, I sought not only to confirm the role of HAX1 in cell behaviour, but also to examine specifically the role of HAX1 isoforms in different biological functions. I screened a panel of cancer cell lines for αvβ6-dependent migration, including breast (MCF10.CA1a), pancreatic (CFPac1 and Panc04.03), and αvβ1-dependent migration in cervical cancer (HeLa); siRNA designed to knockdown all HAX1 isoforms significantly decreased cell migration indicating HAX1 is required for cell migration in cells from multiple tissues, regulating both αvβ6 and αvβ1-dependent cell migration in various cancer types. In order to establish the functions attributable to individual isoforms, I re-introduced individual HAX1 isoforms into HAX1-null (siRNA knockdown) cells and then studied their subcellular localisation and whether they modulate migration, apoptosis and autophagy. The immunofluorescent staining revealed the predominantly mitochondrial localisation of HAX1.1, HAX1.4, HAX1.5 whereas HAX1.2 showed a very unique pattern of location in the cytoplasm. Overexpression of HAX1.2 decreased cell motility on αv-dependent ligand latency associated peptide (LAP) and knockdown of HAX1.2 increased cell migration. Furthermore, 5 HAX1.2 protected cells from cell death induced by various cytotoxic drugs. Moreover, HAX1.1, HAX1.2 and HAX1.5 increased autophagy by elevating the levels of Beclin-1 and LC3b-II. However, it also is clear that much further study is needed to thoroughly understand the biology of each isoform. These are the first experimental data that demonstrate different HAX1 isoforms have different biological activities in human cancer cells, helping to explain the conflicting literature describing HAX1. 6 TABLE OF CONTENTS DECLARATION ...................................................................................................... 2 DEDICATION ......................................................................................................... 3 ABSTRACT ............................................................................................................. 5 TABLE OF CONTENTS ......................................................................................... 7 LIST OF FIGURES ................................................................................................ 15 LIST OF TABLES ................................................................................................. 19 LIST OF ABBREVIATIONS ................................................................................ 20 CHAPTER 1. INTRODUCTION ...................................................... 23 1.1 Haematopoietic cell-specific protein-associated protein X-1: HAX1 ......... 23 1.1.1 Background of the study ...................................................................... 23 1.1.2 The discovery and the early studies of HAX1 ..................................... 24 1.1.3 Protein domains of HAX1 .................................................................... 28 1.1.3.1 HAX1 distribution in human tissues ............................................. 31 1.1.3.2 Subcellular localisation of HAX1 ................................................. 33 1.1.4 HAX1 functions ................................................................................... 35 1.1.4.1 HAX1 regulates trafficking of membrane proteins ...................... 35 1.1.4.2 HAX1 and mRNA regulation ....................................................... 36 1.1.4.3 HAX1 regulates cell migration ..................................................... 38 1.1.4.3.1 Cytoskeleton dynamics in cell migration ............................................. 38 1.1.4.3.2 HAX1 regulates cell migration via cytoskeleton-associated proteins .. 39 1.1.4.3.3 HAX1 regulates cell migration by mediating endocytosis of integrin αvβ6 ..................................................................................................... 45 1.1.4.3.4 HAX1 regulates cell migration via RhoA ............................................ 47 1.1.4.3.5 HAX1 regulates cell migration via CXCR4 ......................................... 48 1.1.4.4 HAX1 and autophagy ................................................................... 50 1.1.4.4.1 Autophagy ............................................................................................ 50 1.1.4.4.2 The role of HAX1 in autophagy ........................................................... 53 1.1.4.5 HAX1 and apoptosis ..................................................................... 55 1.1.4.5.1 Cell apoptosis ....................................................................................... 55 7 1.1.4.5.2 HAX1 and associated viral proteins in apoptosis................................. 61 1.1.4.5.3 HAX1 regulates apoptosis by regulating caspase activity ................... 64 1.1.4.5.4 HAX1 modulates calcium homeostasis in the sarcoplasmic reticulum (SR) ...................................................................................................... 68 1.1.4.5.5 HAX1 regulates mitochondrial permeability by binding to Omi/HtrA2 and PARL .............................................................................................. 71 1.1.4.5.6 HAX1 modulates cell apoptosis by interaction with a mitochondrial protein, PHB2 (Prohibitin 2) ................................................................. 73 1.1.4.5.7 HAX1 regulates cell apoptosis in neutrophils ...................................... 76 1.1.4.6 Summary of HAX1 functions ....................................................... 76 1.1.5 HAX1: a family of splice variants ....................................................... 80 1.1.6 Association of HAX1 with disease ...................................................... 84 1.1.6.1 HAX1 deficiency in severe congenital neutropaenia (SCN; Kostmann‟s disease)..................................................................... 84 1.1.6.2 HAX1 overexpression in psoriasis ............................................... 88 1.1.6.3 HAX1 overexpression in cancer ................................................... 89 1.2 Integrins ....................................................................................................... 90 1.2.1 Integrin Structure and Function ........................................................... 90 1.2.2 Regulation of integrin activation and signalling .................................. 93 1.2.3 Integrin functions ................................................................................. 98 1.2.3.1 Integrins and cell
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