PROTEIN PHOSPHORYLATION IN HUMAN HEALTH Edited by Cai Huang PROTEIN PHOSPHORYLATION IN HUMAN HEALTH Edited by Cai Huang Protein Phosphorylation in Human Health http://dx.doi.org/10.5772/2944 Edited by Cai Huang Contributors Elena Tchevkina, Andrey Komelkov, Andrei V. Budanov, Björn Stork, Sebastian Alers, Antje S. Löffler, Sebastian Wesselborg, Jing Pu, Pingsheng Liu, Olga Calvo, Alicia García, Martin Lützelberger, Norbert F. Käufer, Katrin Deinhardt, Freddy Jeanneteau, Andres Joaquin Lopez-Contreras, Oscar Fernandez-Capetillo, Dmytro Pavlov, John G. Mielke, Nina Kurrle, Bincy John, Melanie Meister, Ritva Tikkanen, Masataka Oda, Masahiro Nagahama, Keiko Kobayashi, Jun Sakurai, Yamuna D. Gandaharen, Rachel S. Welt, David Kostyal, Sydney Welt, Roberta Fraschini, Erica Raspelli, Corinne Cassani, C. Frazer, P.G. Young, Shuishu Wang Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2012 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. Notice Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book. Publishing Process Manager Vedran Greblo Typesetting InTech Prepress, Novi Sad Cover InTech Design Team First published September, 2012 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechopen.com Protein Phosphorylation in Human Health, Edited by Cai Huang p. cm. ISBN 978-953-51-0737-8 Contents Preface IX Section 1 Akt, mTOR and AMPK in Cancer and Metabolic Disorders 1 Chapter 1 Protein Phosphorylation as a Key Mechanism of mTORC1/2 Signaling Pathways 3 Elena Tchevkina and Andrey Komelkov Chapter 2 Sestrins Link Tumor Suppressors with the AMPK-TOR Signaling Network 51 Andrei V. Budanov Chapter 3 Regulation of Autophagy by Protein Phosphorylation 97 Björn Stork, Sebastian Alers, Antje S. Löffler and Sebastian Wesselborg Chapter 4 Fatty Acids Stimulate Glucose Uptake by the PI3K/AMPK/Akt and PI3K/ERK1/2 Pathways 129 Jing Pu and Pingsheng Liu Section 2 Protein Phosphorylation in Transcription, pre-mRNA Splicing and DNA Damage 149 Chapter 5 RNA Polymerase II Phosphorylation and Gene Expression Regulation 151 Olga Calvo and Alicia García Chapter 6 The Prp4 Kinase: Its Substrates, Function and Regulation in Pre-mRNA Splicing 195 Martin Lützelberger and Norbert F. Käufer Chapter 7 More Than Just an OFF-Switch: The Essential Role of Protein Dephosphorylation in the Modulation of BDNF Signaling Events 217 Katrin Deinhardt and Freddy Jeanneteau VI Contents Chapter 8 Signalling DNA Damage 233 Andres Joaquin Lopez-Contreras and Oscar Fernandez-Capetillo Section 3 Tyrosine Protein Kinases in Receptor Signaling and Diseases 263 Chapter 9 Tyrosine Phosphorylation of the NMDA Receptor Following Cerebral Ischaemia 265 Dmytro Pavlov and John G. Mielke Chapter 10 Function of Flotillins in Receptor Tyrosine Kinase Signaling and Endocytosis: Role of Tyrosine Phosphorylation and Oligomerization 307 Nina Kurrle, Bincy John, Melanie Meister and Ritva Tikkanen Chapter 11 Role of Tyrosine Kinase A Receptor (TrkA) on Pathogenicity of Clostridium perfringens Alpha-Toxin 343 Masataka Oda, Masahiro Nagahama, Keiko Kobayashi and Jun Sakurai Chapter 12 Modulation of HER2 Tyrosine/Threonine Phosphorylation and Cell Signalling 357 Yamuna D. Gandaharen, Rachel S. Welt, David Kostyal and Sydney Welt Section 4 Protein Kinases and Phosphatases in Cell Cycle Regulation 375 Chapter 13 Protein Phosphorylation is an Important Tool to Change the Fate of Key Players in the Control of Cell Cycle Progression in Saccharomyces cerevisiae 377 Roberta Fraschini, Erica Raspelli and Corinne Cassani Chapter 14 Phosphorylation Mediated Regulation of Cdc25 Activity, Localization and Stability 395 C. Frazer and P.G. Young Section 5 Histidine Kinases in Two-Component Systems 437 Chapter 15 Bacterial Two-Component Systems: Structures and Signaling Mechanisms 439 Shuishu Wang Preface Protein phosphorylation is a reversible posttranslational modification catalyzed by protein kinases and reversely by protein phosphatases. There are about 500 protein kinases and 25-30 phosphatases in human genome. Each kinase and phosphatase targets multiple substrates. Thus, protein phosphorylation is a most versatile signaling regulatory mechanism and constitutes a most complicated signaling network in living organisms. In fact, protein phosphorylation governs all aspects of physiological and pathological processes in human health. During last decades, more than 180,000 scientific papers on protein phosphorylation have been published. To handle and digest so much knowledge and information is a big challenge to our students, college teachers and investigators. Therefore, we invited expert scientists to write 15 chapters on specific fields of protein phosphorylation where their expertise lies. We also asked our authors to relate their protein phosphorylation pathways to human health. We hope that this book could be a good hand for our students, teachers and investigators who want to extend their knowledge on the role of protein phosphorylation in human health. Please also keep in mind that no any single book can cover all aspects of protein phosphorylation pathways. The chapters have been organized into 5 different sections, based on the similarity of protein phosphorylation pathways. The first section has 4 chapters summarizing on the role of Akt, mTOR and AMPK in cancer and metabolic disorders. The section focuses on the structure, function and regulation of mTOR1 and mTOR2 and their role in cancer, neurodegeneration, and diabetes, the role of Sestrins, a family of stress- responsive genes in regulating AMPK-mTOR pathway and their role in cardiovascular diseases, muscle- and neuro- degeneration, diabetes and cancer, the signaling pathways that regulate autophagy, including Akt, AMPK and mTOR, and the role of Akt/AMPK and PI3K/Erk pathways in fatty acids-stimulated glucose uptake. The second section has 4 chapters reviewing the role of protein phosphorylation in transcription, pre-mRNA splicing and DNA damage. The section emphasizes the regulation of RNA polymerase II sequentially by protein kinases and phosphatases in gene expression and therapeutically potentials, the genetic interactions, biochemical properties, and substrate specificity of Prp4 kinase and its role in pre-mRNA splicing, the regulation of Trk/Erk/CREB pathway by BDNF and the role in neuronal growth, synaptic plasticity and cell survival, and the signaling pathways in regulating DNA X Preface damage. The third section has 4 chapters covering the role of protein tyrosine kinases in receptor signaling and human diseases. This section accentuates the tyrosine phosphorylation of NMDA receptor by Src family kinases and its role in cerebral ischaemia, the role of flotillins in regulating receptor tyrosine kinase and in cancer, Alzheimer’s Disease and diabetes, the role of TrkA/PKCθ/Erk pathway in alpha-toxin- mediated inflammation, and distinct regulation of HER2 tyrosine/threonine phosphorylation by trastuzumab (anti-HER2 monoclonal antibody) and lapatinib (small molecule HER2/1 tyrosine kinase inhibitor). The fourth section has 2 chapters: one summarizes the regulation of cdc25 phosphatase by phosphorylation during cell- cycle and DNA damage, and another illustrates the role of protein phosphorylation in cell cycle regulation using Swe1, Kin4, Cyk3, Hof1 and Chs2 as examples. The fifth section has only 1 chapter describing the role of histidine kinases in the bacterium two- component system. The study on protein phosphorylation is one of most exciting fields in biomedical research. This book provides detailed and comprehensive review on 5 different areas of protein phosphorylation signaling pathways and their roles in human health. This book is our attempt to bridge the basic phosphorylation pathways with human health and diseases. We hope that this book will be of help to students, teachers and researchers who need to deepen their knowledge in these specific areas and promote progress in multi-disciplines of biomedical science. Cai Huang, Ph.D. Markey Cancer Center and Department of Molecular & Biomedical Pharmacology, University of Kentucky, USA [...]... regulates its function remains to be determined Regulation of the mRNA cap binding protein eIF4E is mediated mainly in two ways, firstly, through phosphorylation at S209 in its C-terminus by MAP kinase signaling integration kinases 1 and 2 (Mnk1/2) [156] and, secondly, through the sequestration by small, heat stable phosphoproteins termed 4E-binding proteins, 4E-BPs [153] belonging to the 4E-BPs translation... or -dependent mechanisms Hypoxia-inducible proapoptotic protein BNIP3 is reported to regulate mTOR by direct binding to Rheb, while PML can binds mTOR and inactivate it through sequestration in nuclear bodies 20 Protein Phosphorylation in Human Health 4 Signaling downstream of mTOR 4.1 TORC1 regulates translation machinery The protein synthesis stimulation and the inhibition of autophagy are two mostly... Human Health Therefore, while there is a requirement for GTP-bound Rheb to induct of mTORC1 by amino acids, amino acids probably do not affect Rheb activity – indicating that regulation of Rheb does not stimulate mTORC1 in response to amino acids Recently, Ste20-related kinase MAP4K3 (mitogen activated protein kinase kinase kinase kinase 3) and the class III PI3K hVps34 (human vacuolar protein sorting... translation initiation, mTOR signaling also regulates the translation elongation process through the phosphorylation of eukaryotic elongation factor 2 (eEF2) eEF2 is a GTP binding protein that mediates the translocation step of elongation [188] eEF2 is 24 Protein Phosphorylation in Human Health phosphorylated at T56 within the GTP-binding domain and this phosphorylation impedes its ability to bind the... calcium/calmodulin-dependent protein kinase eEF2K is an atypical enzyme since the sequence of its catalytic domain differs substantially from that of other protein kinases, and it is not a member, e.g., of the main Ser-Thr-Tyr kinase superfamily [191] The C-terminal half of the eEF2K polypeptide contains several sites of phosphorylation including the binding site for the substrate eEF2 at the C-terminus [192]... known protein kinase in the mTOR pathway Phosphorylation at this third site also causes the inactivation of eEF2 kinase, in this case by inhibiting the binding of CaM, which binds immediately C-terminal to S78 [193] eEF2K is thought to be a target of signaling from mTOR independently of other known targets of this pathway, which implies the existence of a novel (probably mTORcontrolled) protein kinase... rapamycin target genes titled TOR1 (the target of rapamycin 1) and TOR2 were discovered through the yeast genetic screens for mutations that counteract the growth inhibitory properties of rapamycin [10, 11] Further studies revealed that rapamycin forms the complex with its 4 Protein Phosphorylation in Human Health intracellular receptor, FK506-binding protein 12 kDa (FKBP12), This complex binds a region in. .. (rapamycin target 1), or SEP (sirolimus effector protein) , is a large 289 kDa atypical serine/threonine (S/T) kinase [1518] and is considered a member of the phosphatidylinositol 3-kinase (PI3K)-kinase-related kinase (PIKK) superfamily since its C-terminus shares strong homology to the catalytic domain of PI3K [19, 20] mTOR and yeast TOR proteins share > 65% identity in carboxyterminal catalytic domains... [150] Since the best characterized effectors of mTOR signaling are proteins controlling the translational initiation machinery it is important to understand how mTORC1 signal transduction pathways contribute to protein synthesis regulation (reviewed in [151]) The earliest identified and best-studied mTORC1 targets are S6K kinases (p70 ribosomal protein S6 kinase 1 and 2) and 4EBP1 (eIF4E binding protein. .. about 40% identity in overall sequence [21] At the amino-acid level, human, mouse and rat TOR proteins share a 95% identity [22, 23] The knockout of mTOR in mice is embryonic lethal, indicating its physiological importance [24, 25] Structurally, mTOR contains 2549 amino acids and the region of first 1200 N-terminal amino acids contains up to 20 tandem repeated HEAT (a protein- protein interaction structure . PROTEIN PHOSPHORYLATION IN HUMAN HEALTH Edited by Cai Huang PROTEIN PHOSPHORYLATION IN HUMAN HEALTH Edited by Cai Huang Protein Phosphorylation in Human Health. complex with its Protein Phosphorylation in Human Health 4 intracellular receptor, FK506-binding protein 12 kDa (FKBP12), This complex binds a region in the C-terminus of TOR kinase named FRB. investigators who want to extend their knowledge on the role of protein phosphorylation in human health. Please also keep in mind that no any single book can cover all aspects of protein phosphorylation