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University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2016 Regulation of Protein Phosphatase One During Cell Cycle Nasa, Isha Nasa, I. (2016). Regulation of Protein Phosphatase One During Cell Cycle (Unpublished doctoral thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/27589 http://hdl.handle.net/11023/3446 doctoral thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY Regulation of Protein Phosphatase One During Cell Cycle by Isha Nasa A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GRADUATE PROGRAM IN BIOLOGICAL SCIENCES CALGARY, ALBERTA OCTOBER, 2016 © Isha Nasa 2016 Abstract Protein phosphatase 1 (PP1) is a highly conserved enzyme that controls the majority of serine/threonine (Ser/Thr) dephosphorylation reactions in eukaryotes. PP1 gains substrate specificity through binding to a large number (> 200) of regulatory proteins, which control PP1 localization, activity, and substrate interaction. PP1 recognizes the majority of these regulatory proteins via well-characterized RVxF binding motif generating hundreds of distinct PP1 holoenzymes. The main objective of this research was to uncover the regulatory mechanisms that govern the interaction of PP1 with its regulatory proteins during the cell cycle. The progression of cell cycle is largely governed by reversible protein phosphorylation. I showed that a subset of the RVxF binding motifs, in which x is a phosphorylatable amino acid (RV[S/T]F), are phosphorylated specifically during mitosis and that this phosphorylation event abrogates the interaction of PP1 with the regulatory protein. This phosphorylation is primarily governed by mitotic protein kinase Aurora B and is crucial to maintain phosphorylation of PP1 substrates during mitosis. In addition, I showed that PP1 itself dephosphorylates RVp[S/T]F motifs during mitotic exit, which allows the phosphatase to re-associate with the regulatory proteins and dephosphorylate other mitotic substrates. To gain further insight into the regulation of PP1 function in cell cycle, I characterized the novel cell cycle dependent interactome of PP1. Using quantitative mass spectrometry, I identified 113 novel RVxF containing potential PP1 binding partners including 17 mitosis-specific partners. Furthermore, using immunoblotting, I validated 9 of the PP1 interactions both in asynchronous and mitotic populations with proteins ii involved in cell cycle regulation (Aurora B, Aurora A, TPX2, CDCA2 (RM), TACC3, GCN2, DBC1, BRCA1 and RIF1). In addition, I demonstrated a novel interaction of PP1 with centrosomal protein, CEP192 via its ‘KHVTF’ motif. The work presented here expands our understanding of the regulation of PP1 in the cell cycle, and also suggests a novel regulatory mechanism by which the coordinated activities of Aurora B kinase and PP1 drive mitotic progression, which is crucial to maintain the genomic stability. iii Acknowledgements My Ph.D. journey would not have been the same without the support and encouragement of all the amazing people in my life. First and foremost, I offer my sincere gratitude to my supervisor and mentor, Dr. Greg Moorhead, for the continuous support and guidance throughout my Ph.D. research. His patience, motivation and knowledge, steered me through this journey. He was an exceptional supervisor who always inspired me to grow as a scientist by giving me intellectual and scientific freedom, engaging me in new ideas, and encouraging me to be a better version of myself in every aspect of student life. I would also like to thank my committee members Dr. Aaron Goodarzi and Dr. Carrie Shemanko, for fruitful discussions and insightful ideas which helped me carve my work into its present form. I truly appreciate their taking out time for all the committee meetings and discussions. I have been fortunate to be able to collaborate and be trained by excellent mentors throughout my graduate school journey. My sincere thanks to our collaborator Dr. Arminja Kettenbach, whose expertise and knowledge in the field of mass spectrometry were a great help for this project and my research. I owe my gratitude to Dr. Veerle de Wever, Dr. Pauline Douglas and Dr. Susan Lees-Miller, for their experimental advice, technical training and resources for microscopy experiments. All the past and present members of the Moorhead lab, who have always been truly helpful and have given me fond memories of my graduate school deserve a special mention. I would like to thank Anne-Marie Labandera, David Lloyd, Dr. Dylan Silver, Dr. Glen Uhrig, Sibapriya Chaudhuri, Brooke Rackel, Nic Sieben, Ahmad Vahab and Ryan Toth for all lunch-time and coffee conversations. In particular, I would like to extend my appreciation to Anne- iv Marie who has been a tremendous support, both in the lab and outside, and lifted up my spirit in days of frustration. I also owe thanks to all undergraduates and summer students who contributed to my research: Nic Sieben, Simon Hassan, Drishti Mannan, Brooke Rackel and Guneet Khosa. I am also grateful to the Samuel research group for their participation and fruitful discussions in our joint lab meetings, Prenner and Turner research groups for allowing me to use their equipment and supplies when I needed them. I would extend my gratitude to all the funding agencies who have kept me going in my research including Alberta Cancer Foundation, URGC Thesis Research Grant, URGC International Graduate Travel Award, University of Calgary Faculty of Graduate Studies Doctoral Scholarship, Chancellor’s Challenge Graduate Scholarship, Eyes High International Graduate Scholarship, and EMBO Conference Travel Award. Lastly, I would like to thank the most important people of my life, my family, who have supported me unconditionally throughout my journey. My Mom, Dad, Saurabh and Sakshi, who made it possible for me to follow my dreams away from home. A special thanks to my fiancée Rahul who has been a constant support through all these years and has virtually lived through all the ups and downs of this journey with me. Living away from my home, my friends became my family in Calgary through all these years. I would like to thank Bhairavi Sohoni, Navneet Randhawa, Neha Dawar, Rosy Dabas, and Tushar Sharma for their unyielding support and for always being there. v To my Family, for their endless love and support vi Table of Contents Abstract .............................................................................................................................. ii Acknowledgements .......................................................................................................... iv Dedication ......................................................................................................................... vi Table of Contents ............................................................................................................ vii List of Tables ................................................................................................................... xii List of Figures and Illustrations ................................................................................... xiii List of Symbols, Abbreviations and Nomenclature .................................................... xvi Epigraph ....................................................................................................................... xviii List of Manuscripts from Ph.D. thesis ......................................................................... xix Chapter 1. Introduction ...................................................................................... 1 1.1 Reversible protein phosphorylation and the cell cycle ...................................... 1 1.2 Mitotic entry and exit as controlled by phosphorylation .................................. 4 1.3 Protein phosphatases ............................................................................................ 6 1.3.1 Classification and function .............................................................................. 6 1.3.2 Phosphatases as mitotic guards ....................................................................... 9 1.4 Protein phosphatase one and its regulation ...................................................... 15 1.4.1 The catalytic subunit of protein phosphatase 1 (PP1) ................................... 15 1.4.2 Mechanism of dephosphorylation by PP1 ..................................................... 15 1.4.3 PP1 Regulatory proteins: Diversity and specificity ...................................... 17 1.5 Role of PP1 during mitosis ................................................................................. 20 1.5.1 Mitotic entry .................................................................................................. 20 1.5.2 Centrosomal splitting and spindle formation ................................................ 21 vii 1.5.3 Spindle assembly checkpoint ........................................................................ 23 1.5.4 Mitotic exit ...................................................................................................
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