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INVESTIGATION of the ROLE of the SCAFFOLD PROTEIN SHC in ERK SIGNALING Kin Man Suen

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INVESTIGATION of the ROLE of the SCAFFOLD PROTEIN SHC in ERK SIGNALING Kin Man Suen The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 5-2015 INVESTIGATION OF THE ROLE OF THE SCAFFOLD PROTEIN SHC IN ERK SIGNALING kin man suen Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Biochemistry, Biophysics, and Structural Biology Commons, and the Medicine and Health Sciences Commons Recommended Citation suen, kin man, "INVESTIGATION OF THE ROLE OF THE SCAFFOLD PROTEIN SHC IN ERK SIGNALING" (2015). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 549. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/549 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. INVESTIGATION OF THE ROLE OF THE SCAFFOLD PROTEIN SHC IN ERK SIGNALING by Kin Man Suen, B.Sc. APPROVED: ______________________________ Dr. John E. Ladbury ______________________________ Dr. Swathi Arur ______________________________ Dr. Carmen W. Dessauer ______________________________ Dr. Jessica K. Tyler ______________________________ Dr. Naoto T. Ueno APPROVED: ____________________________ Dean, The University of Texas Graduate School of Biomedical Sciences at Houston INVESTIGATION OF THE ROLE OF THE SCAFFOLD PROTEIN SHC IN ERK SIGNALING A DISSERTATION Presented to the Faculty of The University of Texas Health Science Center at Houston and The University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY by Kin Man Suen, B.Sc. Houston, Texas May, 2015 Dedication This work is dedicated to the Creator of this beautiful and harmonized world. Without His love and assurance that He will never leave me nor forsake me, I would not have pursued my passion in biomedical research. iii ACKNOWLEDGEMENTS I have always known that I am the most fortunate person on earth to be my parents’ child. They have made enormous and numerous sacrifices in order to provide me with the best opportunity in life. Their strength and courage when faced with serious illnesses and financial difficulties taught me that all hardships can be overcome as long as you work hard, persevere and stay positive – which turn out to be life-saving qualities in scientific research. Therefore, even though my parents know nothing about science, my deepest gratitude and respect must go to them because they have helped me most in my study simply by living their lives. I would also like to thank Dr. Thomas Lin – without his companionship this journey would have been much harder both in life and in the laboratory. His steadfastness has been a much-needed anchor in the uncertain nature of biomedical research. I would like to thank my advisor Professor John Ladbury for his trust in me and the freedom he has given me to be adventurous in my work. Even when my experiments failed, he never failed to encourage me to march on. I will never forget the warmth he and his family provided for those of us who were far away from home. I would also like to thank my advisory committee members Dr. Swathi Arur, Dr. Carmen Dessauer, Dr. Jessica Tyler and Dr. Naoto Ueno. Without their gentle guidance, my study would have taken more wrong turns. In particular, I would like to express my gratitude towards Dr. Arur, who for some reasons has more faith in me than I have in myself. Her constant mentorship in the last few years has been inspiring. I am very much indebted to her generous help in the writing of this dissertation. iv The necessity to work as part of a team in academic science has always been a major attraction to me. I have learnt so much throughout the years from my colleagues in the Ladbury and Arur laboratories. I will not mention everyone by name because the list is endless. However, I would like to express my gratitude towards a few Ladbury lab members specifically. Dr. Roger George patiently taught me about biochemistry, which I have come to love. Much of the work in this dissertation is based on his initial interesting finding. Dr. Zamal Ahmed and Dr. Paul Leonard have shown me the ropes in cell biology and structural biology, respectively. Dr. Ann-Marie Cimo went out of her way to help me with my candidacy examination. I would like to thank the administrative staff at GSBS, which has been most efficient and kind. I would like to thank the Rosalie B. Fellowship for their generous support of my research. I would also like to thank my fellow graduate students Le and Mehrnoosh. Complaining about student life as a group was much more fun than doing it on your own. Last but not least, I would like to thank my dear brothers and sisters in Christ for their love, understanding and support. The pride they have in me gives me great comfort and confidence as I move onto my postdoctoral training. v INVESTIGATION OF THE ROLE OF THE SCAFFOLD PROTEIN SHC IN ERK SIGNALING Kin Man Suen, B.Sc. Advisor Professor: John E. Ladbury, Ph. D. Cells respond to environmental changes by converting extracellular signals into intracellular events. Scaffolding proteins play important roles in generating specificity in intracellular signaling through the combinatorial use of protein domains and posttranslational modifications. Using the scaffold protein Shc (Src-homology collagen- like) as a model system, we explored novel mechanisms whereby this class of protein shapes signaling output. In the present work, we focused on the role of Shc in the MAP kinase Erk signaling both prior to and post -growth factor stimulation. Prior to growth factor stimulation, we found Erk to be a direct interacting partner of Shc. The two proteins associate through a non-canonical interface. This interaction blocks the phosphorylation of Erk and restricts its nuclear translocation. Post -growth factor stimulation, Erk is released from Shc through an allosteric mechanism facilitated by the binding between Shc and the activated growth factor receptor. Furthermore, fully activated Erk phosphorylates Shc on three threonine residues. These phosphorylated residues on Shc subsequently serve as platforms to mediate both a positive feedforward loop in prolonging Erk activity and crosstalk with Akt signaling through protein recruitment. vi Table of Contents Approval sheet……………………………………………………………………………………………………………….i Title page………………………………………………………………………………………………………………………ii Dedication……………………………………………………………………………………………………………………iii Acknowledgements………………………………………………………………………………………………………iv Abstract………………………………………………………………………………………………………………………..vi Table of contents………………………………………………………………………………………………………….vii List of figures……………………………………………………………………………………………………………...xiii List of tables……………………………………………………………………………………………………………….xvi Chapter 1: Introduction ..................................................................................................................................... 1 1.1 Signal Transduction ................................................................................................................................... 1 1.2 Shc - General……………………………………………………………………………………………………………5 1.3 ShcA .................................................................................................................................................................. 6 1.3.1 Isoforms ....................................................................................................................................................... 6 1.3.2 Domain architecture ............................................................................................................................... 6 1.3.2.1 PTB domain ............................................................................................................................................ 6 1.3.2.2 CH1 domain ............................................................................................................................................ 8 1.3.2.3 SH2 domain ............................................................................................................................................ 9 1.3.2.4 CH2 domain ......................................................................................................................................... 10 1.3.2.5 Cytochrome C binding region ....................................................................................................... 11 vii 1.4 ShcA in signaling ....................................................................................................................................... 11 1.4.1 Mitogen-activated protein kinase (MAPK) signaling .............................................................. 11 1.4.1.1 Extracellular signal-regulated kinase (Erk) pathway ......................................................... 11 1.4.1.2 c-Jun N-terminal kinase pathway………………………………………………………………………13 1.4.2 Phosphatidylinositol-4,
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