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The Role of Transglutaminase 2 in Cell Motility Processes and Its

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The Role of Transglutaminase 2 in Cell Motility Processes and Its The role of transglutaminase 2 in cell motility processes and its effect on cutaneous wound healing by Ting Wai Yiu A Thesis Submitted to the Graduate University of New South Wales in fulfillment of the Requirements for the degree of DOCTOR OF PHILOSOPHY Faculty of Medicine University of New South Wales Sydney December, 2011 ORIGINALITY STATEMENT “I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.” Ting Wai Yiu All Rights Reserved ii CONTENTS CONTENTS ...................................................................................................................... iii LIST OF TABLES ........................................................................................................... vii LIST OF FIGURES ........................................................................................................ viii ACKNOWLEDGMENT .................................................................................................... x ABSTRACT ...................................................................................................................... xi 1. INTRODUCTION ......................................................................................................... 1 1.1 Prelude ................................................................................................................ 1 1.2 TG2 structure and biochemical function ............................................................ 1 1.2.1 TG2 protein, expression and its regulation ............................................. 1 1.2.2 Early work on TG2 three dimensional structure .................................... 3 1.2.3 Crystal structure of TG2 ......................................................................... 4 1.2.4 The two sides of the same coin – TGase and Gh .................................... 6 1.2.5 Other in vitro TG2 biochemical activities ............................................ 10 1.3 Animal models .................................................................................................. 11 1.4 Biological roles of TG2? .................................................................................. 11 1.4.1 Coeliac disease ..................................................................................... 12 1.4.2 Ocular diseases ..................................................................................... 13 1.4.3 Cancer 13 1.4.4 Osteogenesis and osteoarthritis ............................................................ 15 1.4.5 Cardiovascular conditions .................................................................... 16 1.4.6 Neurodegenerative disorders ................................................................ 17 1.4.7 Contribution of TG2 to wound healing? .............................................. 18 1.4.8 Cutaneous wound healing overview ..................................................... 21 2. MATERIALS AND METHODS ............................................................................... 29 2.1 Recombinant rat TG2 protein production ......................................................... 29 2.1.1 Expression vector and host ................................................................... 29 2.1.2 TG2 expression and isolation ............................................................... 29 iii 2.1.3 TG2 purification by glutathione sepharose column affinity chromatography .................................................................................... 30 2.1.4 Fast protein liquid chromatography (FPLC) ........................................ 30 2.1.5 Western blotting for TG2 ..................................................................... 31 2.1.6 Transglutaminase assay by 3H-putrescine incorporation ..................... 32 2.2 Mouse breeding and housekeeping .................................................................. 32 2.2.1 Mouse genotyping ................................................................................ 33 2.3 In vivo wound healing assay ............................................................................ 35 2.4 White blood cell counting from wound histology ............................................ 35 2.4.1 Sample isolation and fixation ............................................................... 35 2.4.2 Sectioning ............................................................................................. 36 2.4.3 Hematoxylin and eosin staining for granulocytes ................................ 36 2.5 Wound analysis ................................................................................................ 37 2.5.1 Microscopic analysis of wound sections .............................................. 37 2.5.2 Wound RNA extraction ........................................................................ 37 2.5.3 Microarray analysis .............................................................................. 38 2.5.4 Reverse transcription of wound total messenger RNA ........................ 38 2.5.5 Quantitative PCR analysis of wound RNA .......................................... 39 2.6 Mouse embryonic fibroblast isolation .............................................................. 39 2.6.1 Freezing, thawing and maintaining MEF cultures ............................... 40 2.6.2 MEF growth curves .............................................................................. 41 2.7 In vitro cell adhesion assay ............................................................................... 41 2.7.1 Preparation of wildtype and point mutant TG2 proteins ...................... 41 2.7.2 Detection of Fn-bound TG2 in tissue culture wells .............................. 41 2.7.3 Cell adhesion determination using crystal violet staining .................... 42 2.8 In vitro cell spreading assay ............................................................................. 43 2.8.1 Cloning of TG2 into a GFP-bicistronic vector ..................................... 43 2.8.2 TG2 transfection into MEF .................................................................. 45 2.8.3 Detection of cytosolic and membrane TG2 .......................................... 46 iv 2.8.4 Cell spreading assay ............................................................................. 47 2.9 Detection of cell surface TG2 by pull-down assay .......................................... 47 2.9.1 Immunostaining of cell surface TG2 .................................................... 48 2.10 RhoA and Rac1 profiling in MEF .................................................................... 49 2.10.1 Expression of GST-Rhotekin Rho-binding or GST-Pak Rac-binding domains from E. coli ............................................................................ 49 2.10.2 Glutathione sepharose beads equilibration ........................................... 49 2.10.3 Pull-down assay of activated RhoA or Rac .......................................... 50 2.11 In vitro scratch wound assay ............................................................................ 51 2.12 Statistical analysis ............................................................................................ 51 3. THE EFFECT OF TG2 ON IN VIVO CUTANEOUS WOUND HEALING ........... 54 3.1 Introduction ...................................................................................................... 54 3.2 Results .............................................................................................................. 54 3.2.1 In vivo wound healing assay in 129T2-TG2 mouse ............................. 54 3.2.2 Exogenous addition of purified TG2 to healing skin wounds .............. 55 3.2.3 Monocytes and neutrophils at the wound site ...................................... 57 3.2.4 Microarray analysis of 129T2-TG2+/+ and 129T2-TG2-/- wounds ....... 58 3.2.5 Quantitative analysis of wound-related genes using real time (RT)-PCR60 3.3 Discussion ......................................................................................................... 79 4. THE ROLE OF TG2 IN CELL MOTILITY PROCESSES: CELL ADHESION, SPREADING, MIGRATION .................................................................................... 83 4.1 Introduction ...................................................................................................... 83 4.1.1 The fibroblast and the extracellular matrix .......................................... 83 4.1.2 Cell motility: from adhesion to spreading to migration ....................... 86 4.1.3 TG2 in cell motility processes .............................................................. 92 4.2 Results .............................................................................................................. 96 4.2.1 TG2+/+ or TG2-/- MEF growth curves ................................................... 96 4.2.2 Cell adhesion assay ..............................................................................
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