ADVANCES IN PROTEIN KINASES Edited by Gabriela Da Silva Xavier Advances in Protein Kinases Edited by Gabriela Da Silva Xavier 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. As for readers, this license allows users to download, copy and build upon published chapters 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. 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 Romina Skomersic Technical Editor Teodora Smiljanic Cover Designer InTech Design Team First published June, 2012 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from [email protected] Advances in Protein Kinases, Edited by Gabriela Da Silva Xavier p. cm. ISBN 978-953-51-0633-3 Contents Preface IX Chapter 1 Cross-Regulation of JAK-STAT Signaling: Implications for Approaches to Combat Chronic Inflammatory Diseases and Cancers 1 Claire Rutherford, Hayley D. Woolson and Timothy M. Palmer Chapter 2 Interactions of the Protein Kinase A Signaling Pathway: Implications for the Treatment of Endocrine and Other Tumors 41 Audrey J. Robinson-White Chapter 3 The Role of Tpl2 Protein Kinase in Carcinogenesis and Inflammation 81 Katie DeCicco-Skinner, Monika Deshpande and Jonathan Wiest Chapter 4 MEK1/2 Inhibitors to Treat Dilated Cardiomyopathy Caused by LMNA Mutations 97 Antoine Muchir Chapter 5 Signaling Pathways Coupled to Activation of the Kinin B1 Receptor 109 Pamela Ehrenfeld, Carlos D. Figueroa, Kanti D. Bhoola and Carola E. Matus Chapter 6 Multiple Kinase Involvement in the Regulation of Vascular Growth 131 Shaquria P. Adderley, Chintamani N. Joshi, Danielle N. Martin, Shayna Mooney and David A. Tulis Chapter 7 The Physiological Relationship of Endothelial Protein Kinase G with Endothelial Nitric Oxide Synthase 151 Theresa A. John and J. Usha Raj Chapter 8 The Role of Tyrosine Kinases in the Pathogenesis and Treatment of Lung Disease 181 Jonathan Lam and Stewart J. Levine VI Contents Chapter 9 Myotonic Dystrophy Protein Kinase: Structure, Function and Its Possible Role in the Pathogenesis of Myotonic Dystrophy Type 1 213 Jonathan J. Magaña, Rocío Suárez-Sánchez, Norberto Leyva-García, Bulmaro Cisneros and Oscar Hernández-Hernández Chapter 10 Protein Kinases in the Pathogenesis of Muscle Wasting 243 Fabio Penna, Domiziana Costamagna, Andrea Camperi, Maurizio Muscaritoli, Francesco M. Baccino and Paola Costelli Chapter 11 Mathematical Modeling of Syk Activation in Allergen-Stimulated Mast Cells and Basophils 271 Ambarish Nag, Michael I. Monine, Byron Goldstein, James R. Faeder and Michael L. Blinov Chapter 12 Roles of Kinases in Osteoblast Function 313 Tetsuya Matsuguchi Chapter 13 The Role of Mitogen-Activated Protein Kinase in Treatment Strategies for Fear and Drug Addiction 333 Robyn Mary Brown, Andrew J. Lawrence and Jee Hyun Kim Preface Proteins are the work horses of the cell. As regulators of protein function, protein kinases are involved in the control of cellular functions via intricate signalling pathways, allowing for fine tuning of physiological functions. This book is a collaborative effort, with contribution from experts in their respective fields, reflecting the spirit of collaboration ‐ across disciplines and borders ‐ that exists in modern science. Here, we review the existing literature and, on occasions, provide novel data on the function of protein kinases in various systems. We also discuss the implications of these findings in the context of disease, treatment, and drug development. Gabriela Da Silva Xavier Imperial College London, Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, London, UK 1 Cross-Regulation of JAK-STAT Signaling: Implications for Approaches to Combat Chronic Inflammatory Diseases and Cancers Claire Rutherford, Hayley D. Woolson and Timothy M. Palmer Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland, U.K. 1. Introduction The Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway is utilized by a range of cytokines (interferons, IL-2 and IL-6 amongst others) that control survival, proliferation and differentiation responses in diverse cell types. The realisation that unregulated activation of this pathway is a key driver of not only chronic inflammatory diseases such as rheumatoid arthritis, colitis and psoriasis, but also many cancers has identified its components as targets for therapeutic intervention by small molecule inhibitors and biologicals. In this article, we will discuss how an increased understanding of JAK-STAT pathway architecture, the basis for its dysfunction in pathological states, and its regulation by other intracellular signaling pathways are illuminating multiple strategies to manipulate this pathway in several disease arenas. 2. Basic architecture of the JAK-STAT pathway 2.1 Janus Kinases (JAKs) JAKs encompass a family of four of cytoplasmic tyrosine kinases (JAK1–JAK3, TYK2) that function as essential signaling components immediately downstream of receptors for many haematopoietic cytokines, such as granulocyte-macrophage colony-stimulating factor (GM- CSF), erythropoietin (Epo), interferons (IFNs), interleukins (e.g. IL-2, IL-6) as well as growth hormone and leptin. While JAK1, JAK2 and TYK2 are widely expressed, JAK3 expression is limited to haematopoietic cells where it is used by the receptors for a selected group of cytokines that are critical in T cell, B cell and natural killer cell development (Ghoreschi et al., 2009). Importantly, functional deficiencies in JAK3 have been shown to account for autosomal recessive “severe combined immunodeficiency” (SCID) syndrome (O’Shea et al., 2004). However, despite these differences, JAKs are thought to function downstream of individual cytokine receptors in a similar manner. 2 Advances in Protein Kinases Structurally JAKs comprise seven conserved domains (JAK homology (JH) domains 1-7) numbered from the carboxyl to the amino terminus (Fig. 1). The hallmark of the JAK family is the presence of JH1, which comprises a functional tyrosine kinase domain, and JH2, which was originally thought to be a catalytically inactive pseudokinase domain. However, it has recently been demonstrated that the JAK2 JH2 has dual-specificity protein kinase activity that phosphorylates Ser523 and Tyr570, which are critical negative regulatory sites, although the specific kinase activity of JH2 is approximately ten-fold less than that of JH1 (Ungureanu et al., 2011). It had long been established that JH2 has a negative regulatory function, as deletion of this domain has been shown to increase JAK2 and JAK3 phosphorylation and downstream activation of STATs. This is achieved via an intramolecular interaction between JH1 and JH2, which effectively suppresses basal kinase activity. Upon ligand binding, conformational changes relieve this interaction allowing activation of JH1 by phosphorylation of two activation loop Tyr residues (Tyr 1021/1022 in JAK1, Tyr 1007/1008 in JAK2, Tyr 980/981 in JAK3, Tyr 1054/1055 in TYK2) (Saharinen et al., 2000; Saharinen & Silvennoinen, 2002). Abrogation of JH2’s dual specificity kinase activity was found to be sufficient to increase basal JAK2 activity and downstream signaling to STAT1, suggesting that this is a key element of the JH2 domain’s suppressive effect on JH1. As described later in this chapter, this provides an essential “braking” function as mutations that disrupt the JH2 domain’s suppression of JH1 activity are found in several haematological disorders. Fig. 1. Domain structure of human JAK2. The crystal structure of the JAK2 JH1 domain bound to JAK inhibitor tofacitinib is reproduced from Williams et al. (2009) with permission. JH3-5 comprise an SH2 domain typically indicative of PTyr-dependent interactions with other signaling components but surprisingly partners for this domain have yet to be identified for any of the JAK family (Ingley & Klinken, 2006). Lastly, JH6-JH7 constitute a Cross-Regulation of JAK-STAT Signaling: Implications for Approaches to Combat Chronic Inflammatory Diseases and Cancers 3 Band 4.1, ezrin, radaxin, moesin (FERM) domain implicated in interactions with cytokine receptors required for cell surface expression (Huang et al., 2001) and also the JH1 domain to regulate its kinase activity (Zhou et al., 2001). JAKs have typically