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With No Lysine (WNK) Family Proteins and Their Interaction With WITH NO LYSINE (WNK) FAMILY PROTEINS AND THEIR INTERACTIONS WITH DOWNSTREAM KINASES APPROVED BY SUPERVISORY COMMITTEE Melanie Cobb, Ph.D. Joseph Albanesi, Ph.D. Chou-Long Huang, M.D., Ph.D. Michael White, Ph.D. DEDICATION I would like to thank my family for all of the support to get me to this point in my life; my girlfriend, Pooja Paranjpe, for putting up with the vagaries of my path through endless education; the Medical Scientist Training Program and all of my friends for taking this route with me; members of the Cobb lab for a great experience these past four years; and most especially, Melanie Cobb, for being an amazing mentor who has had incredible faith in me, and without whom this dissertation would not be possible. WITH NO LYSINE (WNK) FAMILY PROTEINS AND THEIR INTERACTIONS WITH DOWNSTREAM KINASES by KYLE EDWARD WEDIN DISSERTATION Presented to the Faculty of the Graduate School of Biomedical Sciences The University of Texas Southwestern Medical Center at Dallas in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY The University of Texas Southwestern Medical Center at Dallas Dallas, Texas November, 2009 Copyright by KYLE EDWARD WEDIN, 2009 All Rights Reserved WITH NO LYSINE (WNK) FAMILY PROTEINS AND THEIR INTERACTION WITH DOWNSTREAM KINASES KYLE EDWARD WEDIN, Ph.D. The University of Texas Southwestern Medical Center at Dallas, 2009 Working in the laboratory of MELANIE H. COBB, Ph.D. With no lysine (WNK) kinases are a family of protein kinases characterized by unusual kinase domain architecture. These large proteins, divergent outside of a kinase core and protein-protein interaction motifs, have been associated with pseudohypoaldosteronism 2, a form of Mendelian-inherited hypertension, and numerous downstream effectors that regulate vesicle trafficking, membrane protein localization, and ion handling. This study shows that WNK2 is also a functioning protein kinase with the same unusual kinase domain architecture and regulation by an autoinhibitory region. Like WNK1, WNK2 is able to signal to the extracellular-signal regulated kinase 5 v (ERK5) pathway. One effector for WNK1 is oxidative stress responsive 1 (OSR1), a sterile20-like kinase. All four WNKs are able to phosphorylate OSR1 and stimulate its activity toward an ion transporter substrate, to roughly a similar degree. The WNKs have similar kinetic properties, with K m toward OSR1 in the micromolar range and k cat near 1 min -1. No significant differences in activity toward OSR1 were seen for a mutant kinase domain at a site divergent among the WNKs that shows differential binding to substrate. Analysis of the phosphorylation sites of OSR1 reveals multiple sites along the activation loop that can promote increased activation if carrying a negative charge. It is unknown if these sites are phosphorylated in vivo. However, a second site of WNK1 phosphorylation just outside of the OSR1 kinase domain does not seem to affect WNK-OSR interactions. Further studies of interactions of the WNKs with their downstream effectors will reveal unusual functions for this unique family of proteins. vi TABLE OF CONTENTS Abstract ............................................................................................................................. v Prior Publications ............................................................................................................. ix List of Figures ................................................................................................................... x List of Tables .................................................................................................................. xii List of Abbreviations ..................................................................................................... xiii Chapter One – Introduction: WNKs and their Interactions with OSR1............................. 1 WNKs and OSR1 ......................................................................................................... 1 WNK2 characterization................................................................................................ 2 WNKs activate OSR1................................................................................................... 3 Analysis of OSR1 possible phosphorylation sites........................................................ 4 Chapter Two – A Review of the Literature......................................................................... 6 Cloning and Characterization of the WNK Kinases..................................................... 6 Disruptions of WNK Function Lead to Human Disease............................................ 12 Pleiotropic actions of WNKs...................................................................................... 16 Activation and modification of WNKs................................................................ 16 WNKs and cell cycle regulation.......................................................................... 17 WNKs – regulators of membrane trafficking ...................................................... 20 Association of WNKs with ion handling............................................................. 22 WNKs and the TGF β pathway............................................................................. 25 OSR1 and SPAK, Important WNK Effectors ............................................................ 26 Interactions of WNKs and OSR1/SPAK.................................................................... 30 Chapter Three – Comparisons of WNK Isoform Interactions with OSR1 ....................... 39 vii Introduction................................................................................................................ 39 Methods...................................................................................................................... 43 Results........................................................................................................................ 46 Discussion .................................................................................................................. 56 Chapter Four – Functional Analysis of Putative Phosphorylation Sites on OSR1/SPAK 62 Introduction................................................................................................................ 62 Methods...................................................................................................................... 64 Results........................................................................................................................ 66 Discussion .................................................................................................................. 68 Chapter Five – Initial Characterization of WNK2............................................................ 73 Introduction................................................................................................................ 73 Methods...................................................................................................................... 73 Results........................................................................................................................ 77 Discussion .................................................................................................................. 85 Chapter Six – A View Toward the Future ........................................................................ 91 Bibliography ................................................................................................................... 101 Figure permissions.......................................................................................................... 110 viii PRIOR PUBLICATIONS Lenertz, L.Y., Lee, B.H., Min, X., Xu, B.E., Wedin, K., Earnest, S., Goldsmith, E.J., Cobb, M.H. (2005). Properties of WNK1 and implications for other family members. 280 , 26653-26658. ix LIST OF FIGURES FIGURE 2-1 Crystal structure of WNK1 .......................................................................... 7 FIGURE 2-2 Domain structure of WNK kinases .............................................................. 9 FIGURE 2-3 Domain structure of OSR1.......................................................................... 26 FIGURE 2-4 RFXV bound to OSR1 PF2 domain............................................................ 28 FIGURE 2-5 SPAK kinase domain crystal structure........................................................ 29 FIGURE 2-6 WNK1 immunoprecipitates with OSR1...................................................... 32 FIGURE 3-1 Alignment of RFXV motifs......................................................................... 40 FIGURE 3-2 RFXV motif in WNK kinase domain.......................................................... 41 FIGURE 3-3 WNK1 vs. WNK4 phosphorylation of OSR1 ............................................. 48 FIGURE 3-4 WNK phosphorylation of OSR1 K46R....................................................... 49 FIGURE 3-5 WNK isoform activation of OSR1.............................................................. 51 FIGURE 3-6 Determination of kinetics constants of WNKs toward OSR1..................... 52 FIGURE 3-7 WNK1 wild type vs. V318E phosphorylation of OSR1 K46R................... 54 FIGURE 3-8 WNK1 wild type vs. V318E activation of OSR1........................................ 55 FIGURE 3-9 WNK1 kinase domain replacement of WNK1 shows no difference........... 57 FIGURE 4-1 Phosphorylation site on OSR1/SPAK activation loop ...............................
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