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Cell differentiation and the development of multicellular organisms are processes of self-assembly, controlled and driven by signaling molecules and cascades including redox regulation. These reactions may have provided the energy for the first metabolic steps in the evolution of life. Today, redox modifications are established as important regulatory events in cellular functions including differentiation and development. Redox modifications of single cysteines regulate differentiation of stem cells, formation of functioning organs, and de-differentiation such as formation of cancer cells. Current cancer therapy is based on redox events as well and regeneration often reactivates developmental pathways. Understanding differentiation and de-differentiation on a molecular level is therefore a prerequisite for the continuing development of new medical therapies. This book summarizes the roles of redox regulation in development by bringing together different concepts and comparing similarities and differences between various cell types and species. An international team of contributors presents several new aspects of redox-regulated differentiation and de-differentiation, including aspects of redox medicine.Key Features Provides the first summary on this important topic Reviews redox-dependent development of model organisms and single organs Highlights the redox-regulated pathways important for differentiation processes Illustrates the potential of redox medicine Combines state-of-the-art knowledge in differentiation/development, aging/longevity, and repair/regeneration Written by leading experts in the field Related TitlesAyyanathan, K., ed. Cancer Cell Signaling: Targeting Signaling Pathways Toward Therapeutic Approaches to Cancer (ISBN 978-1-77188-067-1)Clarke, M. & J. Frampton. Stem Cells: Biology and Application (ISBN 9780-8153-4511-4)Lim, W. & B. Mayer. Cell Signaling: Principles and Mechanisms (ISBN 978-0-8153-4244-1)Wong, E., ed. Autophagy and Signaling (ISBN 978-0-367-65772-7)

Protein phosphorylation via protein kinases is an inevitable process that alters physiological and pathological functions of the cells. Thus, protein kinases play key roles in the regulation of cell life or death decisions. Protein kinases are frequently a driving factor in a variety of human diseases including aging and cellular senescence, immune system and endothelial dysfunctions, cancers, insulin resistance, cholestasis and neurodegenerative diseases, as well as bacterial resistance in persistent infections. Recent developments in quantitative proteomics provide important opinions on kinase inhibitor selectivity and their modes of action in the biological context. Protein Kinase-mediated Decisions Between Life and Death aims to have the reader catch insights about up-to-date opinions on “Protein Kinases” related pathways that threaten human health and life. As “Protein Kinases” are related to many health problems, clinicians, basic science researchers and students need this information.Chapter “Signal Transduction in Immune Cells and Protein Kinases” is available open access under a Creative Commons Attribution 4.0 International License via link.springer.com.

Lipids are an integral part of cell membrane architecture, are intermediaries in cell metabolism, and are involved in transmitting cell signals from hormones, growth factors and nutrients. A number of lipases and phospholipases, lipid kinases, lipid phosphatases, sphingosine kinases, and their reaction products have been implicated in fundamental cellular processes including cell proliferation, division and migration. These enzymes and their products underlie the molecular mechanisms of numerous human diseases, in particular metabolic disease (diabetes), cancer, neurodegenerative disease and cardiovascular disease.Over the last decade, studies have advanced to the point that a number of inhibitors for these enzymes have been developed to attempt to ameliorate these conditions; some of the inhibitors are currently in human clinical trial. The need for this book is to review the current status of this field and the prospect for the inhibitors to be clinically important.

Rho GTPases control many aspects of cell physiology. This includes polarity, endo/exocytosis, adhesion, motility, transcriptional activation, cell cycle progression or apoptosis. In view of such pleiotropic activities, Rho-controlled signaling has proven to be of medical relevance, especially in tumorigenesis, disease-associated bone remodeling and infectiology.This book is divided into three parts. Part 1 gives an evolutionary perspective of the Rho family, its atypical members, and an overview of how Rho activity is regulated. Part 2 addresses two important aspects of multicellularity controlled by Rho-dependent pathways, namely, cell-cell interactions and mechanotransduction. It also describes how post-translational modifications control Rho activity and how this is exploited by pathogenic bacteria. Part 3 explores several examples of the variety of pathophysiological processes controlled by Rho signaling, and gives a successful example of translational research, from the inhibition of Rho activation to the development of new molecules against osteoporosis.This updated review on the biology of Rho GTPases is an essential read for molecular and cell biologists. It is also an invaluable guide to post-graduate and medical students who wish to deepen their knowledge in cell biology.

This open access book presents the roles and mechanisms of signal transduction triggered by nicotinic acetylcholine receptors (nAChRs) stimulation in neuroprotection against toxic effects of risk factors of neurodegenerative diseases. Accumulating evidence suggests that nAChRs in the CNS play important roles not only in excitatory neurotransmission but also in neuronal survival and related functions. Neuroprotection mediated by nAChRs in neurodegenerative diseases such as Alzheimer's disease is the major topic of this book. In response to rapidly evolving areas in clinical and laboratory neuropharmacology and neurochemistry, this volume provides in-depth coverage of neuroprotection in basic research and future developments in the clinical application of effective neuroprotective strategies in neurodegenerative diseases. This work appeals to both basic and clinical researchers in several fields, such as neuroscience, neurology, and pharmacology.

Latest research on Adhesion GPCRs has unearthed surprising revelations about the events that govern the signal transduction of these receptor molecules and the cellular and organ requirements for these signals. Unexpected and unprecedented findings suggest that Adhesion GPCRs constitute a group of receptors that sense mechanical stimuli and transcode them into metabotropic signals through the action of a novel activation paradigm. Interdisciplinary efforts transcending many areas of biomedical research including pharmacology, physiology, genetics, cell biology, structural biology, biochemistry and bioinformatics were necessary to unveil these fundamental properties. The scientific leaders in the field that carried this research effort have teamed up here to provide a comprehensive overview of our current understanding, how Adhesion GPCRs signal and how these receptors shape organ structure and function.

This book provides a simplified, yet comprehensive, overview of the signalling pathways operating between and inside cells, which will help younger oncologists find their way in the labyrinth of signalling pathways and in the multitude of signals and signal receptors, transducers and effectors that contribute to oncogenesis.This comprehensive reference text is based on the master's courses delivered by Prof. Jacques Robert to graduate students at the University of Bordeaux, France. It includes a large number of colour schemas and figures that have been improved year after year for educational purposes. Signalling pathways are described individually and in depth, but without ignoring the multiplicity of interconnections and crosstalk. The presentation of each pathway is followed by a brief description of the alterations found in cancers as well as of the targeted pharmacological approaches that can be used to prevent or overcome the consequences of these oncogenic alterations. The basic mechanisms of molecular biology at the DNA replication, RNA transcription and protein activity levels are presented in a series of didactic annexes, enabling readers to better understand the alterations in signalling pathways.

Platelets playa fundamental, life-saving role in hemostasis and blood clotting at sites of vascular injury. Unwanted platelet activation and arterial thombus formation are, however, implicated in the onset of myocardial infarction, stroke, and other cardiovascular diseases. Acceptance that platelets play a major role in the pathogenesis of atherosclerosis including coronary heart disease has revolutionized the pharmacological treatment of cardiovascular diseases, and aspirin is now an essential antiplatelet drug and the golden standard for future developments. Yet the search for better and perhaps safer antiplatelet drugs is one of the most active areas of investigation in both basic and clinical research. Platelets, especially human platelets, have also emerged as one of the major models for the study of inter- and intracellular signal transduction pathways. Many biochemists, cell biologists, pharmacologists, pathologists, hematologists, and cardiologists find platelets useful for studying processes such as adhesion, inside-out and outside-in signalling through the plasma membrane, channels, calcium homeostasis, protein kinases, the network of intracellular signal transduction cascades, and the release of vasoactive substances. The aim of the editors has been to compile chapters summarizing the current state-of-the-art information on the biochemistry, cell biology, pharmacology, and physiologic and pathophysiologic roles of human platelets. We hope that this volume represents the major aspects of current platelet research although it is perhaps inevitable that certain areas are covered less thoroughly than others. We would like to acknowledge the excellent help and support of the Springer-Verlag staff, in particular that of Ms. Doris Walker.

This book provides an overview of critical components of cell signaling machinery and its role in epithelial morphogenesis, proliferation, invasions and angiogenesis in human cancer and discusses novel types of protein kinase pathways.

In recent years, increasing evidence has suggested that abnormal activation of signaling pathways is a critical event in cancer pathogenesis. In particular, activation of these pathways can lead to inappropriate cellular survival, proliferation, pluripotency, invasion, metastasis, and angiogenesis. Thus, understanding the mechanisms by which signaling pathways become subverted in a cancer cell can provide insight into critical events in cancer pathogenesis. Furthermore, as our ability to target specific molecular interactions advances, we now have the ability to design small molecules, protein therapeutics, and other forms of targeted therapies. By focusing on the specific molecular abnormalities in a cancer cell, these agents hold the potential to be much more effective and much less toxic than current cytotoxic therapies.

Over the last decades cell biology and biological chemistry have increasingly turned their attention to the space between cells and revealed an elaborate network of macromolecules essential for structural support, cell adhesion and signaling. This comprehensive handbook of the extracellular matrix will give an overview of the current state of knowledge of matrix components (structure and function), their role in heath and disease (matrix pathobiology) and new aspects related to pharmacological targeting.It will provide an introduction to the extracellular matrix and detailed sections and chapters on: Importance of extracellular matrix in health and disease Matrix proteoglycans (aggrecan, versican, perlecan, SLRPs, syndecans, glypicans, serglycin) Matrix proteinases (remodeling, would healing, regulatory roles in health and disease, metalloproteinases, cystein proteases, plasmin and plasminogen activator system) Glycobiology (hyaluronan and sulfated glycosaminoglycans in cancer, inflammation and metabolic control) Collagens (supramolecular assembly, proteins binding collagen, scaffolds, bacterial and mutated collagens, procollagen proteinases) Cell surface receptors (integrins, syndecans, mechanical strain and TGFb, CD44 and DDR). Biotechnological and pharmacological outlook (matrix regulation by growth factors, hyaluronidases, pathobiology, disease targeting, delivery systems, EMT and proteomics).'The book Extracellular Matrix: Pathobiology and Signaling provides a comprehensive and up to date collection of very relevant topics for understanding the various facets of extracellular matrix and its interactions with cells in normal tissue as well as in disease. It represents the current front-line and will serve as a reference for extracellular matrix and posttranslational modifications.'Dick Heinegård, Department of Clinical Sciences Lund, Section Rheumatology, Lund University, Sweden

Main Question: G protein coupled receptors are involved in highly efficient and specific activation of signalling pathways. How do GPCR signalling complexes get assembled to generate such specificity? In order to answer this question, we need to understand how receptors and their signalling partners are synthesized, folded and quality-controlled in order to generate functional proteins. Then, we need to understand how each partner of the signalling complex is selected to join a complex, and what makes this assembly possible. GPCRs are known to be able to function as oligomers, what drives the assembly into oligomers and what will be the effects of such organization on specificity and efficacy of signal transduction. Once the receptor complexes are assembled, they need to reach different locations in the cell; what drives and controls the trafficking of GPCR signalling complexes. Finally, defects in synthesis, maturation or trafficking can alter functionality of GPCRs signalling complexes; how can we manipulate the system to make it function normally again? Pharmacological chaperones may just be part of the answer to this question.

Caveolins are important structural proteins of Caveolae, small invaginations of the membrane. They have been shown to play an important role in the pathogenesis of multiple cancers. In this volume, we will mainly focus on the importance of Caveolin-1 in breast, prostate, lung, skin, colon, pancreatic and brain cancers with also a mention of the novel role of Caveolin-3 in breast cancer.

Mitochondria have traditionally been associated with metabolic functions; however recent research has uncovered a central role for these organelles in cell signaling, cell survival, and cell death. Mitochondrial dysfunction is a factor in a myriad of pathophysiological conditions, including age-related neurodegenerative disorders, cancer, metabolic

Squamous epithelia form the lining surface of tissues in contact with the environment: the skin, oral mucosa, esophagus and respiratory tract, the genital tract, and several other specialized tissues. These tissues are at highest risk for exposure to environmental carcinogens such as UV, tobacco smoke and infectious agents. Cancers that form in squamous epithelia are among the most common human solid tumors and have high morbidity and mortality. These cancers include squamous cell carcinoma of the skin, oral cancer, head and neck and esophageal cancer, certain lung cancers and cervical cancer. We propose to organize the book so that the early chapters will focus on individual pathways and more specific mechanisms in both normal function and cancer, while the later chapters will be more integrative and include overviews of biomarkers and therapeutic development. This should increase interest for clinically oriented researchers. All authors will be encouraged to provide a balanced review in addition to highlighting their own work.

Inappropriate activation of the Wnt signaling pathway is observed in many human cancers and is sufficient to drive tumor initiation and progression in numerous contexts. Multiple mechanisms, such as overexpression of Wnt ligands, inactivation of the APC and Axin tumor suppressors, and mutation of -catenin, are responsible for pathway activation in tumor cells. The development of potent Wnt pathway antagonists for therapeutic use has been a major effort for investigators in both academia and industry in recent years. This book will provide an overview of the Wnt pathway as a therapeutic target for cancer, and discuss the preclinical development of inhibitors specifically directed to upstream and downstream components of the pathway.

This book attempts to analyze the latest discoveries in sphingolipid biology and how the alteration of their metabolism leads to altered signaling events and to the development of pathobiological disorders, such as cancer, cardiovascular diseases, asthma, diabetes, inflammation and infectious diseases.

Functional selectivity refers to the ability of different ligands acting at one receptor subtype to activate multiple signaling pathways in unique combinations; that is, one drug can be an agonist at pathway A and an antagonist or partial agonist at pathway B, and another drug can have the reverse profile. Functional selectivity has profound implications for drug development, for chemical biology, and for the design of experiments to characterize receptor function. In Functional Selectivity of G Protein-Coupled Receptors expert neuroscientists and pharmacologists review the work that demonstrated the existence of functional selectivity, placed it within a theoretical framework, and provided a mechanistic basis for the phenomenon. This exciting, comprehensive, and future-oriented volume includes chapters that focus on theoretical and mechanistic aspects of functional selectivity and that cut across subfamilies of GPCRs. Additional chapters focus on subfamilies of therapeutically relevant receptors where there is considerable evidence of ligand functional selectivity. Accessible and authoritative, Functional Selectivity of G Protein-Coupled Receptors is a valuable educational tool and reference source for students and scientists interested in drug development, chemical biology, and GPCR function.

Endocannabinoids control most of the body functions, and in the brain, they modulate neurotransmission, synaptic plasticity, confer neuroprotection, control metabolism, neuro- and neuritogenesis, survival, cognitive and motor functions as well as a plethora of other higher-order brain functions. Their fruitful therapeutic potential is recognized by cannabinoid researchers and pharmaceutical companies, respectively. The aim of this book is to help clinicians, neuroscientists, as well as students, understand the significance of the endocannabinoid system. This book, however, also will be very useful to those who already feel comfortable with the neuroscience of endocannabinoids. The book will introduce the reader to the “up-to-date” neurobiology of endocannabinoids and related systems, and will detail their pathophysiological role and therapeutic potential. Authors involved in clinical investigations present results of recent clinical trials, and the development of new therapeutic strategies and medicines.

A repertoire of 10 TLRs mediate the first response to all microbes that infect mammals. They are the long sought receptors for a wide range of microbial products. Notable examples include TLR4 which recognizes LPS from gram negative bacteria, TLR3 which recognizes viral double-stranded RNA and TLR9 which recognizes CpG DNA motifs, found commonly in both viruses and bacteria. TLRs are increasingly being implicated in both infectious and inflammatory diseases, notable examples being sepsis, inflammatory bowel disease, atherosclerosis and asthma. There is therefore great interest in targeting TLRs therapeutically since blocking TLRs will result in a decrease in the production of inflammatory mediators such as TNF. This volume covers our current understanding of TLRs, and their role in inflammation. Given the primacy of TLRs in the inflammatory process and their emerging role in inflammatory diseases the book is of great interest to researchers working in inflammation and immunology.

When introduced to the human body, bioactive metabolites produced by plants for self defense bind to particular biochemical targets, most notably to proteins involved in signaling by hormones and neurotransmitters. This, essentially, is the basis for the effects of herbal medicine. While herbal medicine preparations may act by complex synergistic i

Living cells are constantly sensing environmental changes, and their abilities to sense these changes and adapt to them are essential for their survival. In bacteria, histidine kinases are the major sensors for these environmental stresses, enabling cells to adapt to new growth conditions. Written by leading experts in the field, this book provides an up-to-date and comprehensive review on the structure and function of histidine kinases. It also provides extensive information on the physiological roles of histidine kinases in bacteria and eukaryotes. An an essential reference for cell biologists, microbiologists, molecular biologists, and biochemists interested in signal transduction. Experimental biologists and pharmacologists studying signal transduction systems in living organisms will also find it a valuable research tool. The first comprehensive book on the roles of histidine kinases in cells 23 in-depth chapters written by leading experts in the field Describes the most recent advances in the field of signal transduction

This thoroughly indexed book summarizes a wealth of information on the biochemical targets of plant defensive compounds, and is an an invaluable reference for all biomedical professionals.

Signal Transduction is a well-illustrated, coherent look at cellular signaling processes. Beginning with the basics, it explains how cells respond to external cues, hormones, growth factors, cytokines, cell surfaces, etc., and then shows how these inputs are integrated and coordinated. The extensive color artwork provides the reader with a clearer comprehension of key topics, and margin notes are incorporated to highlight milestones in the evolution of signal transduction. This book serves as an invaluable resource for advanced undergraduates, graduate researchers, and established scientists working in cell biology, pharmacology, immunology, and related fields. Coherent, precise text providing insight in depth to a subject that is central to cell biology and fundamental to many areas of biomedicine Extensive conceptual colour artwork assists with the comprehension of key topics Extensive referencing provides an invaluable link to the core and historical literature Margin notes highlighting milestones in the evolution of our understanding of signalling mechanisms

Henry Jay Forman, Jon Fukuto and Martine Torres'Research is to see what everybody else has seen and to think what nobody else has thought.'-- Albert Szent-Gyorgyi Several years ago, one of us put together a book that dealt with various aspects of oxidative stress and introduced the concept of signal transduction by oxidants. Since then, the interest in the mechanisms by which reactive oxygen and nitrogen species (ROS/RNS) can modulate the cell's response has tremendously grown, paralleling the intense efforts towards identifying new signaling pathways in which phosphorylation/dephosphorylation events take center stage. Evidence is now mounting that production of these species by the cells is required for their function from growth to apoptosis and numerous signaling pathways have been identified where the participation of ROS and RNS is apparent (see Chapters 11-14, 16 and 18). Thus, the field is no more limited to the group of free radical aficionados who have pioneered this area of research but has now gone mainstream. While it is satisfactory for those of us who have been working on this topic for a long time, it has the risk of becoming the “fashionable” motto where those molecules, still mysterious to some, become responsible for everything and anything.

Hormones and Signaling focuses on the mechanisms of gene regulation at the cellular level. It also describes the actions of hormones in modulating gene regulation and animal development. Glococorticoid and mineralcorticoid signaling Orphan nuclear receptors Nuclear receptor coactivators Cytokines and STAT signaling Coordination of cAMP signaling events through PKA anchoring G protein-coupled extracellular Ca2+ (Ca2+0)-sensing receptor (CaR) Pancreatic islet development Genetic analysis of androgen receptors in development and disease Antioprogestin regulable gene switch for induction of gene expression in vivo Steroid receptor knockout model

The last decade has witnessed a wealth of new information on the mechanisms underlying cell signaling. Molecular approaches have revealed the identity and structure of many of the receptor proteins which permit cells to respond to different chemical signals. An important mechanism regulating receptor function is desensitization, i.e. the suppression of a cellular response induced by the continuous presence of a constant agonist stimulus. This book features selected studies on receptor-mediated desensitization in various cells and tissues triggered by Ca2+. Post-receptor mechanisms are also considered. The contributions focus on muscarinic, histamine and adrenergic receptor systems as well as the phosphoinositidase C signaling pathway. The authoritative information compiled in this book will not only prove of great value to researchers interested in signal transduction but is also crucial for the development of new drugs.

This important new reference work offers an outstanding collection of articles devoted to the discussion of'intracellular messengers'. Extracellular stimuli ('first messengers') bind to receptors on the plasma membrane of cells to trigger changes in the concentration of intracellular messengers ('second messengers') which leads, in turn, to changes in cellular activity. However, the intracellular activities of so called'third messengers'may also be involved complicating the concept of a rigid sequence of events between receptor and response. The preference for the term'intracellular messengers', and, hence, the title of this volume, recognizes that a complex web of interactions between intercellular messengers determines the concentrations and ultimate effects of each.

Hormones and Signaling focuses on the mechanism of gene regulation at the cellular level. It also covers the way hormones act to modulate gene regulation and animal development.Key Features• Includes information on:• Nuclear receptors, coactivators, and corepressors• Membrane receptors, kinases, and phosphorylation on cascades• Hormonal regulation of development• Calcium channels and neurotransmitters• Chromatin, transcription factors, and regulation of gene expression• JAK/STAT pathways• Hormone-regulated development and gene'knock-out'