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YAP1 and the Hippo Signaling Pathway Regulate Progenitor Proliferation

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YAP1 and the Hippo Signaling Pathway Regulate Progenitor Proliferation YAP1 and the Hippo Signaling Pathway Regulate Progenitor Proliferation Inaugural-Dissertation to obtain the academic degree Doctor rerum naturalium (Dr. rer. nat.) submitted to the Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin submitted by Dipl.-Biochem. Karin Schlegelmilch born in Berlin, Germany 2013 I conducted my doctoral studies from July 2009 until February 2013 at the Boston Children’s Hospital/ Department for Stem Cell and Regenerative Biology of Harvard University in Boston, USA under the supervision of Assistant Prof. Dr. Fernando D. Camargo. 1st Reviewer: Assistant Prof. Dr. Fernando D. Camargo, Harvard University, Boston, USA 2nd Reviewer: Prof. Dr. Petra Knaus, Freie Universität Berlin, Berlin, Germany Date of defense: Acknowledgements Most importantly, I would like to thank Assistant Professor Fernando Camargo for giving me the great opportunity to work in his laboratory, for always being there for stimulating discussions and providing guidance and support. I would also like to thank Professor Petra Knaus. Without her support and commitment, my PhD thesis abroad would not have been possible. I thank my whole family and in particular my parents, Sigrid and Walter Schlegelmilch, who have supported me in my decisions all my life. I am moreover truly grateful to my brother Ingo Schlegelmilch for all his encouragement. I am immensely grateful to Jan Riethmayer for supporting me in every possible way throughout my PhD, it means so much to me and made all the difference. I am especially thankful to have met my amiga Ingrid Carvacho during the time at Children’s Hospital. Thanks so much for always being there for me and finding the right words. You definitely brought sunshine into my days. I will miss our lunches. I am also truly grateful to the two other members of my “lunch-group”, Alexander von Gise and Mathias Pawlak for their friendship during my entire time in Boston, which means a lot to me, not to mention all the opportunities to laugh and great scientific support. I would also like to thank Grit Thurlow for her invaluable friendship and all the motivational support during the time of my PhD and especially during the time of writing. Great thanks goes also to all my Italian friends, for great culinary experiences and for making my time in Boston more fun and special. Thank you to all my friends all over the world, especially Cindy Bloch, Viola Rasch, Jasmina Murad, Sandra Stehling-Sun, Joanna Himmel and Stefanie Städtler, who make this life so much better. I would like to thank the members of the Camargo laboratory for fruitful discussions, in particular Jianlong Sun. And I am especially thankful for Azucena Ramos, Rosemarie de la Rosa and Basanta Gurung for bringing so much fun to the lab and always being immensely helpful. I would like to thank Thijn Brummelkamp, Jan Pruszak and Oktay Kirak for all the helpful discussions and a great collaboration. Furthermore, I would like to thank Alexander von Gise, Azucena Ramos, Rosemarie de la Rosa and Lindsay Herman for critical reading of this manuscript and valuable suggestions. Sincere gratitude goes to my grandmother, Agate Schlegelmilch, a truly outstanding person, for your boundless support throughout my life and sharing your wisdom with me. This is dedicated to you. Table of Contents 1. Introduction..................................................................................................................... 4 1.1 The Hippo Signaling Pathway ...............................................................................................4 1.1.1 The Hippo Signaling Pathway Core Kinase Cascade ........................................................5 1.1.2 YAP....................................................................................................................................8 1.1.3 Downstream Regulators.....................................................................................................9 1.1.4 Upstream Regulators........................................................................................................10 1.1.5 The Physiological Role of Mammalian Hippo Signaling ................................................11 1.2 The Skin .................................................................................................................................12 1.2.1 Structure of the Skin ........................................................................................................12 1.2.2 Epidermal Stem Cells ......................................................................................................15 1.2.2.1 Heterogeneity of Epidermal Stem Cells .....................................................................16 1.2.2.2 Independent Stem Cell Populations in Hair Follicle and Interfollicular Epidermis...18 1.2.3 Cell Adhesion in the Skin ................................................................................................19 1.2.3.1 Adherens Junctions.....................................................................................................19 1.2.3.2 Key Cytoplasmic Regulators at the Adherens Junctions............................................21 1.2.3.3 α-Catenin’s Function in Cell Proliferation and Carcinogenesis.................................22 1.2.4 Hippo Signaling in the Skin.............................................................................................24 2. Aims................................................................................................................................ 25 Aim 1: Investigate the Effect of Yap1 Activation in the Epidermis..............................................25 Aim 2: Investigate the Effect of Yap1 Deletion in the Epidermis .................................................26 Aim 3: Investigate the Function of the TEAD Transcription Factors in Epidermal Biology........26 Aim 4: Investigate the Function of the MST1/2 Kinases in Epidermal Biology ..........................27 3. MANUSCRIPT I........................................................................................................... 28 3.1 SCC-like Tumor Formation upon Yap1 activation is reversible .......................................51 3.2 Yap1 cKO skin grafts can be sustained ................................................................................52 4. Discussion........................................................................................................................ 53 4.1 YAP as a Critical Regulator of Epidermal Stem Cell Proliferation .................................53 4.2 YAP and Skin Cancers ..........................................................................................................55 4.3 A Connection of α-Catenin and the Hippo Pathway ..........................................................56 4.4 Regulation of YAP Activity by 14-3-3 and PP2A................................................................57 4.5 Crowd Control and the Hippo Pathway ..............................................................................57 4.6 YAP Regulates Cardiomyocyte Proliferation .....................................................................58 4.7 Tissue Specificity of the Hippo Pathway..............................................................................59 4.8 Future Directions ...................................................................................................................60 5. Summary......................................................................................................................... 64 6. Zusammenfassung.......................................................................................................... 66 7. Abbreviation List ........................................................................................................... 68 8. Eidesstattliche Erklärung.............................................................................................. 69 9. Bibliography ................................................................................................................... 70 Appendix ....................................................................................................................................i The Heart.............................................................................................................................................i MANUSCRIPT II....................................................................................................................iii Introduction 1. Introduction 1.1 The Hippo Signaling Pathway Looking at the different species of the animal kingdom, it is striking to see such an immense variation in organism size. An elephant, for example, grows to be a million times larger than a mouse. Additionally, the internal organs of an organism receive information telling them to grow proportionally to the overall body size. The mechanisms directing these growth regulatory processes of organisms and organs fascinate biologists all over the globe, however, they are still poorly understood. A better understanding of growth regulatory mechanisms might ultimately lead to the development of better medical treatments for human diseases associated with abnormal proliferation, such as cancer. An interesting organ in terms of growth potential is the liver, which is able to regenerate its original mass, even when two- thirds of it had been removed by hepatectomy. It is unclear, however, how it senses when to stop growing (Michalopoulos and DeFrances, 1997). Several
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