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Investigating the Role and Regulation of the AMPK-Related Kinase NUAK1

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Investigating the Role and Regulation of the AMPK-Related Kinase NUAK1 Investigating the role and regulation of the AMPK-related kinase NUAK1 Duncan Richard Bull A thesis submitted to Imperial College London for the degree of Doctor of Philosophy October 2013 Cellular Stress Group Medical Research Council, Clinical Sciences Centre Imperial College London Declaration of Originality I hereby certify that I am the sole author of this thesis and that no original part of this thesis has been published previously. I declare that any material or information from the work of others that is included in my thesis, published or otherwise, is fully acknowledged in the text and in the list of references. I confirm that this thesis has not been submitted for a higher degree to any other university or institution. Signed: Date: 2nd October 2013 Copyright Declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. 2 Abstract AMP-activated protein kinase (AMPK) is a well characterised central regulator of energy homeostasis with many downstream substrates and potential therapeutic targets. Recently several kinases related to AMPK have been identified which are activated by the same upstream kinase, LKB1, and share significant sequence homology with the catalytic α subunit of AMPK. Previous studies have implicated NUAK1, one of these related kinases, in cell cycle regulation and other studies have identified various partner proteins but as yet there is no consensus model of its regulation or physiological role. This aim of this study was to investigate the regulation and interactions of NUAK1 using an in vitro system and also use an in vivo tissue specific mouse knockout system to investigate its function in two different tissues. The results of these studies reveal new insights into the regulation of NUAK1 in vitro and suggest that the kinase is capable of activation by autophosphorylation, in the absence of LKB1. NUAK1 is shown to interact with 14-3-3 proteins and evidence that this interaction may be important for the function of the kinase is presented. Cell based studies in mouse embryonic fibroblasts (MEFs) lacking NUAK1 show that it is involved in proliferation and there are suggestions of pathways involved in regulating this effect. NUAK1 liver-specific knockout mice were generated and extensive metabolic phenotyping analyses were carried out. In young animals deletion of NUAK1 in liver did not lead to any obvious changes in whole body metabolism. However, preliminary studies revealed a possible role for NUAK1 in metabolic regulation in older mice and in response to liver damage. Mice with heart-specific deletion of NUAK1 were generated and these mice were found to have a cardiac hypertrophy phenotype in response to angiotensin II treatment. Potential signalling pathways downstream of NUAK1 in the heart were then investigated in this model. 3 Acknowledgments I would like to thank my supervisors Dave Carling and Naveenan Navaratnam for all their help and guidance throughout my project, especially Nav for watching over me in the lab and giving me some invaluable support! Thanks to David Carmena for his assistance and his early work on this project. Thank you also to everyone else in the Cell Stress group, past and present, for all their help and for making my time in the lab so fun. Many thanks to Phill Muckett for his incredible help with the animal work and to Zoe Webster and the Transgenic Facility for re-deriving the mouse lines. Thanks to Anna Slaviero and Olga Boruc for their assistance with the CLAMS and echocardiography. Thanks to Mahrokh Nohadani for her work with the histology. Thanks to Luke Boulter and the group in Edinburgh for their work on the panCK staining. I acknowledge the financial support of the Medical Research Council which allowed me to carry out my PhD. Finally, thanks to my parents for supporting me for twenty-seven years and to everyone who has kept me sane throughout the past four years, especially those who helped drag me across the finishing line! 4 Abbreviations ACC Acetyl-Coenzyme-A carboxylase ACE Angiotensin converting enzyme ACTH Adrenocorticotropic hormone ADP 5’adenosine diphosphate AICAR 5-aminoimidazole-4-carboximide ribonucleoside AID Autoinhibitory domain ALT Alanine aminotransferase AMARA Synthetic peptide, AMARAASAAALARRR AMP 5’adenosine monophosphate AMPK 5’adenosine monophosphate-activated protein kinase aPKC Atypical protein kinase C AST Aspartate aminotransferase ATP 5’adenosine triphosphate AUC Area under curve BK Bradykinin BRSK Brain-specific kinase BSA Bovine serum albumin BSEP Bile salt export pump C. elegans Caenorhabditis elegans CaM Calmodulin CaMKK Ca2+/calmodulin-dependent protein kinase kinase CAPS 3-[cyclohexylamino]-1-propanesulfonic acid CBM Carbohydrate binding module CBS Cystathionine β-synthase CDE Choline-deficient ethionine supplemented diet CK Cytokeratin CK2 Casein kinase 2 CLAMS Comprehensive Laboratory Animal Monitoring System Cox6b Cytochrome c oxidase subunit VIb CREB cAMP-response element binding protein CRTC2 CREB-regulated transcription co-activator 2 CV Calorific value DAK Death-associated kinase DDC Diethyl 1,4-dihydro-2,4,6,-trimethyl-3,5-pyridinedicarboxylate DMEM Dulbecco’s Modified Eagle’s Medium DMSO Dimethyl Sulphoxide DTT Dithiothreitol E. coli Escherichia coli ECAR Extracellular acidification rate ERK Extracellular-signal regulated kinase et al. et alia FAS Fatty acid synthase g Acceleration due to gravity GAPDH Glyceraldehyde 3-phosphate dehydrogenase 5 GLUT Glucose transporter GSK-3β Glycogen synthase kinase-3β GTP Guanosine triphosphate H&E Haematoxylin & Eosin HCC Hepatocellular carcinoma HDL High density lipoprotein HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid ILK Integrin-linked kinase IP3 Inositol trisphosphate ipGTT Intra-peritoneal glucose tolerance test IPTG Isopropyl-1-thio-b-D-galactopyranoside IRS Insulin receptor substrate IVC Individually ventilated cage KO Knockout KOMP Knockout Mouse Project KSR1 Kinase suppressor of Raf-1 LATS Large tumour suppressor LB Luria broth LDL Low density lipoprotein LKB1 Liver kinase B1/serine threonine kinase 11 LNR Synthetic peptide, KKLNRTLSFAEPG MAP Microtubule associated protein MAPK Mitogen-activated protein kinase MARK Microtubule affinity-regulating kinase MCK Muscle creatine kinase MEF Mouse embryonic fibroblast MELK Maternal embryonic leucine zipper kinase MHC Myosin heavy chain MLC Myosin regulatory light chain MLCK Myosin light chain kinase MO25 Mouse protein 25 MRCK Myotonic dystrophy protein kinase-related cdc42-binding kinase mTOR Mammalian target of rapamycin MYPT Myosin phosphatase targeting NDR Nuclear Dbf2-Related Kinase Ndufs4 NADH dehydrogenase protein 4 NMR Nuclear magnetic resonance NUAK Nua (novel) kinase OCR Oxygen consumption rate PAGE Polyacrylamide gel electrophoresis PAK p21-activated protein kinase PAR Partitioning defective mutant PAS Periodic Acid Schiff PBS Phosphate-buffered saline PCR Polymerase chain reaction PFA Paraformaldehyde PFKFB 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 6 PGC1α Peroxisome proliferator-activated receptor-γ co-activator 1α PI3K Phosphoinositide 3-kinase PJS Peutz-Jeghers syndrome PKA Cyclic AMP-dependent protein kinase PKC Protein kinase C PMSF Phenylmethylsulphonyl fluoride PP1C Protein phosphatase 1C PVDF Polyvinylidene difluoride qPCR Quantitative polymerase chain reaction RAB-GAP RAB family GTPase activating protein RAPTOR Regulatory-associated protein of mTOR RER Respiratory exchange ratio RHEB RAS homologue enriched in brain ROCK Rho-associated protein kinase ROS Reactive oxygen species S.E.M Standard error of the mean SAD Synapses of the amphid defective SAMS Synthetic peptide, HMRSAMSGLHLVKRR SDS Sodium lauryl sulfate SIK Salt-inducible kinase SILAC Stable Isotope Labelling by Amino Acids in Cell Culture SNF1 Sucrose non-fermenting protein 1 SREBP1C Phosphorylate sterol regulatory element-binding protein 1C STRAD STE20-related adaptor protein TAB TGFβ-activated kinase binding protein TAE Tris-acetate-EDTA buffer TAK1 Transforming growth factor-β activated kinase-1 TAZ Transcriptional coactivator with PDZ-binding motif TBS-T Tris buffered saline with Tween TCEP Tris(2-carboxyethyl)phosphine TGFβ Transforming growth factor-β UBA Ubiquitin associated domain USP9X Ubiquitin-specific protease 9X 7 Table of Contents Declaration of Originality ........................................................................................................... 2 Abstract ...................................................................................................................................... 3 Acknowledgments...................................................................................................................... 4 Abbreviations ............................................................................................................................. 5 Table of Contents ....................................................................................................................... 8 List of Figures ........................................................................................................................... 13 List of Appendices ...................................................................................................................
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