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Regulation of Erk Signal Transduction by Signal-Induced Cysteine Oxidation

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Regulation of Erk Signal Transduction by Signal-Induced Cysteine Oxidation REGULATION OF ERK SIGNAL TRANSDUCTION BY SIGNAL-INDUCED CYSTEINE OXIDATION By JEREMIAH D. KEYES A Dissertation submitted to the Graduate Faculty of WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY In Biochemistry and Molecular Biology August 2016 Winston-Salem, North Carolina Approved By: Leslie Poole, Ph.D., Advisor Cristina Furdui, Ph.D., Chair Doug Lyles, Ph.D. Larry Daniel, Ph.D. W. Todd Lowther, Ph.D. ACKNOWLEDGMENTS This has been an extremely challenging and rewarding project, and I could not have brought it to this point without the help of several individuals. I’d like to first thank my advisor, Dr. Leslie Poole, for encouraging me to pursue my interest in this project despite the fact that it diverged from her normal areas of study. Dr. Poole fostered a rich atmosphere for study and collaboration and helped me to get to an unusual number of conferences to push my project forward. The last couple months she has especially put forth a heroic effort to see me to this point. I would also like to thank Dr. Kimberly Nelson, who taught critical thinking through every day discussions over experimental design and analysis. Dr. Derek Parsonage was an essential element in my study by teaching and performing molecular biology and protein purification. I need to especially thank LeAnn Rogers, who taught me cell culture and, along with Rama Yammani who came in at just the right time, heroically helped in key discoveries to enable me to finish my project. I would also like to thank Gao, Laura Soito, and Chelsea Kesty who all contributed to my training and progress in this project. I thank Dr. Julie Reisz and Dr. Cristina Furdui for advice and analysis on mass spectrometry experiments. I need to give a special thank you to Dr. Rob Newman, who not only aided in his kinase signaling expertise, but encouraged me at a time when I was discouraged, which led me to an exciting post-doctoral opportunity. I also could not have made the progress I have without the help of Dr. Rony Seger, who gave critical and encouraging feedback on my studies, and Dr. Natalie Ahn who provided several established plasmids for ERK and MEK purification. I i would also like to acknowledge Dr. Richard Watt, who introduced me to a love of research as an undergraduate student at Brigham Young University. I would like to thank each member of my committee, Dr. Doug Lyles, Dr. Todd Lowther, Dr. Larry Daniel, and Dr. Cristina Furdui. Not only did they guide me throughout my graduate school tenure, but they helped me learn that consistent results are the truth – even if those results don’t match initial results. I would like to especially thank members of my family. My mom, who helped me with my homework every day when I was young. My dad, who took me to science centers and taught me to cherish learning and always keep my doors open. My children, Porter, Hazel, and Nora, who have kept my imagination young by turning Eppendorf tubes into spaceships and allowing me to play with them almost every day. My brother Nathan, who reminded me at critical times of disappointment that science is more than failed experiments; it is enrapturing, fun, and wondrous. But most especially, my wife Samantha, who has by far been my greatest support and believer. She reminded me of my potential during my most difficult times. Her strength the past several years is unmatched as my attention has been siphoned into completing this project. ii TABLE OF CONTENTS Page ACKNOWLEDGEMENTS………………………………………………… i LIST OF ABBREVIATIONS………………………………………………. iv LIST OF ILLUSTRATIONS………………………………………..……… vii ABSTRACT……………………………………………………………..….. x 1. INTRODUCTION…………………………………………………….... 1 2. ENDOGENOUS SULFENYLATION OF ERK IN RESPONSE TO PROLIFERATIVE SIGNALS…………………………………….. 47 3. MODIFICATION OF rERK2 ACTIVITY IN RESPONSE TO IN VITRO OXIDATION BY H2O2………………………………………… 90 4. CONCLUSIONS……………………………………………………….. 121 SCHOLASTIC VITAE……………………………………………………… 137 iii LIST OF ABBREVIATIONS ATP adenosine triphosphate BCA bicinchoninic acid CDK Cyclin Dependent Kinase CK2 Casein Kinase 2 Clk Cell Division Cycle-like-kinase DMEM Dulbecco's Modified Eagle Medium DRS D-recruitment site DTT Dithiothreitol EDTA Ethylenediaminetetraacetic acid EGF Epidermal Growth Factor ELISA Enzyme-linked immunosorbent assay EMEM Eagle's minimal essential medium ERK Extracellular signal-regulated kinase FBS Fetal Bovine Serum FRET fluorescence resonance energy transfer FRS F-recruitment site GDP Guanosine diphosphate iv GPCR G-protein couple receptor GSK3 glycogen synthase kinase 3 GSNO S-Nitrosoglutathione GTP Guanosine triphosphate HR Hormone receptor IAM iodoacetamide JNK c-Jun N-terminal kinase KO knock-out LPA Lysophosphatidic acid MAPK Mitogen Activated Protein Kinase MEF Mouse Embryonic Fibroblast MEK MAPK/ERK kinase MKP Mitogen activated protein kinase phosphatase MW Molecular Weight NEM N-ethylmaleimide NO Nitric Oxide NTS Nuclear Translocation Signal PDGF Platelet Derived Growth Factor v PDGFR platelet-derived growth factor receptor PEG-Catalase Polyethylene Glycol-Catalase PKC protein kinase C PTP Protein Tyrosine Phosphatase RNS Reactive Nitrogen Species ROS Reactive Oxygen Species RSS Reactive Sulfur Species RTK Receptor Tyrosine Kinase SDS-PAGE Sodium dodecyl sulfate – polyacrylamide gel electrophoresis SNP Sodium Nitroprusside SOS Son of Sevenless TIRF Total internal reflection fluorescence microscopy VEGF Vascular Endothelial Growth Factor VSMC Vascular Smooth Muscle Cells vi LIST OF ILLUSTRATIONS AND TABLES TABLES PAGE 1-I Redox Sensitive Kinase 21 1-II MAPK oxidation in literature 22-23 3-I Cysteine Modifications Observed on rERK2 103 3-II List of proteins on function protein array 108 FIGURES PAGE 1-1 MAPK Signaling Cascades 4 1-2 MAPK Alignment 5 1-3 Signal-specific context to induce distinct cellular responses through ERK1/2 signal cascade 8 1-4 Rat ERK2 and human ERK1/2 alignment with secondary structure assignments 10 1-5 Structural analysis of ERK1/2 docking sites and NTS 12 1-6 Cysteine oxidation chemistry 27 2-1 Sulfenic acid trapping of cellular proteins during lysis 51 2-2 ERK1/2 cysteines are oxidized to sulfenic acid in response to PDGF in NIH-3T3 cells 61 vii 2-3 ERK1/2 oxidation is caused by H2O2 generated in response to PDGF in NIH-3T3 cells 62 2-4 Serum-depleted WI38 fibroblasts exhibit distinct temporal patterns of sulfenic acid formation in response to PDGF compared to serum-replete WI38 cells 64 2-5 Endogenous ERK1/2 oxidation inhibits kinase activity towards Elk1 67 2-6 Potential modes of ERK regulation 76 2-S1 ERK1/2 biotinylation is due to labeling by DCP-Bio1 84 2-S2 Oxidation of ERK1/2 in prostate cancer-derived PC3 cells in response to LPA 85 2-S3 ERK1/2 oxidation in ovarian-cancer derived SKOV3 cells 86 2-S4 Observed oxidation of ERK in HeLa cells treated with EGF 87 2-S5 Observed oxidation of total and TEY-phosphorylated ERK1/2 in response to Androgen agonist R1881 in prostate-epithelium derived RWPE-1 cells 88 2-S6 Endogenous ERK1/2 oxidation from SKOV3 cells inhibits activity towards Elk1 89 viii 3-1 rERK2 activity towards Elk1 is inhibited by adventitious and H2O2-dependent oxidation 99 3-2 ERK1/2 oxidized during cell signaling events does not make inter- or intramolecular disulfide bonds with itself or other proteins 101 3-3 Identification of rERK2 cysteine sensitivity to sulfenylation by H2O2 102 3-4 C159/252S (C2xS) double mutant rERK2 responds to H2O2 differently than WT rERK2 104 3-5 C159S responsible for observed inhibition of ERK2 kinase activity towards DRS-binding substrates 106 3-6 Dose-dependent, global changes in ERK2 kinase activity 113 ix ABSTRACT The ERK1/2 pathway plays roles across eukaryotic biology by transducing extracellular signals into cell-fate decisions. One conundrum is in understanding how disparate signals induce specific responses through a common, ERK- dependent kinase cascade. While studies have revealed intricate modes to control ERK1/2 through spatiotemporal localization and phosphorylation dynamics, additional details of ERK1/2 signaling remain elusive. We hypothesized that fine-tuning of ERK1/2 signaling could occur by cysteine oxidation. We report that ERK1/2 is actively and directly oxidized by signal- generated H2O2 during proliferative signaling, and that oxidation occurs downstream of a variety of receptor classes tested in six cell lines. Furthermore, within the tested cell lines and proliferative signals, we observed that both phosphorylated and non-phosphorylated ERK1/2 undergo sulfenylation in cells, that there is a difference in the consistency of ERK1/2 oxidation between transformed and non-transformed cells, and that dynamics of ERK sulfenylation is dependent on whether or not cells are serum starved prior to stimulus. We also tested the effect of endogenous ERK1/2 oxidation on kinase activity and report that phospho-transfer reactions are drastically inhibited by oxidation, underscoring the importance of considering this alternative modification when assessing ERK1/2 activation. In light of these paradoxical results, we undertook a series of in vitro analyses to elucidate how oxidation could modulate ERK2 activity in a cellular environment. We identified one cysteine residue that is sensitive to in vitro oxidation by H2O2. C159 (Rat ERK2 numbering) was found to x be highly sensitive to sulfenylation. We also have evidence that C252 undergoes sulfenylation at moderately higher concentrations of H2O2. Interestingly, neither of these cysteines are near the active site, indicating that observed inhibition by oxidation must occur by another mechanism than by direct inhibition of the kinase’s phospho-transfer activity. Indeed, both of these cysteines are part of important regulatory regions of ERK1/2, and their oxidation will likely affect protein-protein interactions with regulatory proteins and substrates and alter the spatiotemporal dynamics of ERK1/2 within cells. Finally, preliminary results indicate that oxidation of ERK1/2 actually activates kinase activity towards some substrates while inhibiting activity towards others, bolstering our hypothesis that oxidation is a more complex mode of ERK1/2 regulation than a simple switch to control ERK1/2 activity.
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