**Meet the editor**

My research interest is in the fuel sensing protein kinases - AMP-activated protein kinase (AMPK) and PAS-domain containing protein kinase (PASK)- and their roles in pancreatic endocrine cell function and development. I completed my PhD in Biochemistry at the University of Bristol in 2001. After two postdoctoral positions at the University of Bristol, I moved to Imperial College in 2006

where I was appointed lecturer in 2008 and have been involved in collaborative efforts to elucidate how the Type 2 Diabetes genes identified by Genome Wide Association Studies - TCF7L2, SLC30A8, WFS1, and HHEX - may affect beta-cell function and development. My work has been funded by the Juvenile Diabetes Research Foundation and European Foundation for the Study of Diabetes.

Contents

**Preface IX** 

Chapter 2 **Interactions of the Protein** 

Audrey J. Robinson-White

Chapter 4 **MEK1/2 Inhibitors to Treat Dilated** 

Antoine Muchir

Chapter 5 **Signaling Pathways Coupled** 

Chapter 6 **Multiple Kinase Involvement** 

Chapter 3 **The Role of Tpl2 Protein Kinase** 

Chapter 1 **Cross-Regulation of JAK-STAT Signaling: Implications for Approaches** 

**Kinase A Signaling Pathway: Implications** 

**in Carcinogenesis and Inflammation 81** 

**to Combat Chronic Inflammatory Diseases and Cancers 1**  Claire Rutherford, Hayley D. Woolson and Timothy M. Palmer

**for the Treatment of Endocrine and Other Tumors 41** 

Katie DeCicco-Skinner, Monika Deshpande and Jonathan Wiest

**Cardiomyopathy Caused by** *LMNA* **Mutations 97** 

**to Activation of the Kinin B1 Receptor 109** 

**in the Regulation of Vascular Growth 131**  Shaquria P. Adderley, Chintamani N. Joshi,

Danielle N. Martin, Shayna Mooney and David A. Tulis

**Protein Kinase G with Endothelial Nitric Oxide Synthase 151** 

**the Pathogenesis and Treatment of Lung Disease 181** 

Pamela Ehrenfeld, Carlos D. Figueroa, Kanti D. Bhoola and Carola E. Matus

Chapter 7 **The Physiological Relationship of Endothelial** 

Jonathan Lam and Stewart J. Levine

Theresa A. John and J. Usha Raj

Chapter 8 **The Role of Tyrosine Kinases in** 

## Contents

### **Preface XI**



## 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:** 

Claire Rutherford, Hayley D. Woolson and Timothy M. Palmer

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

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

**1. Introduction** 

**2.1 Janus Kinases (JAKs)** 

manipulate this pathway in several disease arenas.

individual cytokine receptors in a similar manner.

**2. Basic architecture of the JAK-STAT pathway** 

**Implications for Approaches to** 

**Combat Chronic Inflammatory** 

**Diseases and Cancers** 

*University of Glasgow,* 

*Scotland, U.K.* 

*Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences,* 
