The Annexins is focused on a specific family of calcium and membrane-binding proteins, annexins, ubiquitously spread within living organisms, including animals, plants and fungi. The volume covers important areas of annexinology. The characterization of structural-functional relationship within the annexin family of proteins, together with emerging transgenic animal models, provides an up-to-date overview of potential physiological roles of annexins. Growing evidence of participation of annexins in human diseases, called annexinopathies, related to disturbances in signal transduction, vesicular traffic, ion homeostasis and energy metabolism within the cell.
The book will attract a broad scientific audience, not only scientists interested in annexins, but also others involved in multidisciplinary studies, as well as undergraduate and postgraduate students. It can be used in courses relating to special topics such as calcium homeostasis, calcium-binding proteins, membrane structure and transport properties, various signal transduction pathways, and membrane trafficking.

The knowledge of Th17 cells and other cell populations which secrete IL-17A, and/or IL-22 has expanded tremendously since the publication of the first edition "Th17 Cells: Role in Inflammation and Autoimmune Disease" in 2008. The present volume has been completely revised with the addition of new chapters on the IL-17 receptor family and signaling, and an in-depth review of IL-22 and innate lymphoid cells. The differentiation of na ve T cells into regulatory T cells and Th17 cells as well as the plasticity of Th17 cells is discussed. The role of IL-22 in cutaneous inflammation including psoriasis has been reviewed. In addition, the volume contains critical updates on autoimmunity, organ transplantation, tumor immunology and genetic mouse models for mechanistic studies. Lastly, the latest clinical progress in neutralizing antibodies to IL-17A, IL-17RA not only confirms the therapeutic promise foreseen in 2008, but also improves our knowledge of the pathogenesis of autoimmune diseases. In summary, this is a timely update and important review of the clinical and experimental aspects of IL-17, IL-22 and their producing cells.

The second volume continues to fill the gap in protein review and protocol literature. It does this while summarizing recent achievements in the understanding of the relationships between protein misfoldings, aggregation, and development of protein deposition disorders. The focus of Part B is the molecular basis of differential disorders.

Lipid peroxidation is an important cellular process which can lead to detrimental effects if it is not regulated efficiently. Lipid hydroperoxide is formed in an initial step of lipid peroxidation. Lipid hydroperoxide is also known as a potential source of singlet oxygen. Harmful aldehydes are formed when the lipid hydroperoxide is degraded. The formed aldehyde has high reactivity against thiol or amine moieties. Therefore, it could act as a signaling molecule, which might induce the changing of gears inside a cell. Recent studies have shown that lipid hydroperoxide or a slightly modified product of the lipid hydroperoxide reacts with biomolecules such as proteins and aminophospholipids, which leads to formation of amide-type adducts. Amide-type adducts could be one of markers for oxidative stress and could also be an important player in some diseases. In this book, the chemistry and biochemistry of lipid hydroperoxide along with their conjugates with biomolecules are described.

The main purpose of this volume is to provide a focused analysis of the function of the G protein-coupled signaling pathways that operate in the interconnected network of retinal neurons as they detect and encode the information carried by light. The organization of this volume will generally follow the path of signal flow in the retina. First we will describe recent advances in understanding the phototransduction cascade of rod and cone photoreceptors, which use signaling cascade based on the GPCR rhodopsin to transduce incident light into neural activity. Chapters will be devoted to unique specializations of the two major types of photosensitive cells that comprise the predominant input for our spatial and color vision. Subsequently, the mechanisms of synaptic information encoding by retinal ON bipolar cells will be described, where the GPCR mGluR6 plays a fundamental role. Chapters in this section will examine macromolecular organization of the mGluR6 signaling pathway as well as current understanding of its function. The functional characteristics of this signaling mechanism will be explored in detail. Additionally, this section will cover the role of dopamine receptors in modulating signal transmission between photoreceptors and ON-bipolar cells. Finally, chapters will be focused on the output neurons of the inner retina, ganglion cells, where the components of the emerging GPCR melanopsin cascade in intrinsically photosensitive ganglion cells will be detailed. Collectively these mechanisms allow the retina to represent visual space over a wide range of light intensities.

The incentive for putting together Volume 4 of this series was to review the wealth of new information that has become available in prokaryotic organisms in protein export and membrane biogenesis. Just in the last several years, protein translocation has now been efficiently reconstituted using defined components and the mechanism by which proteins are moved across membrane bilayers is now being examined at a higher resolution. In addition, because of a new technical breakthrough using osmolytes, it is now possible to reconstitute a number of channel proteins, ATPase, receptors, and transporters. In many cases, it is possible to successfully predict the membrane topology of these types of proteins using both "hydrophobicity analysis" and the "positive inside" rule.
In this volume, two chapters focus on protein translocation across membranes ("Biochemical Analyses of Components Comprising the Protein Translocation Machinery of E. Coli; Protein Translocation Genetics"), while several others on how proteins assemble into the ineer membrane of E. Coli ("Membrane Protein Assembly; Membrane Insertion of Small Proteins: Evolutionary and Functional Aspects; Pigment-Protein Complex Assembly in Rhodobacter sphaeroides and Rhodobacter Capsulatus"). Other sections review recent progress on transporters ("Identification and Reconstitution of Anion Exchange Mechanisms in Bacteria; Helic Packing in the C-Terminal Half of Lactose Permease") and signal transduction ("Mechanism of Transmembrane Signaling in Osmoregulation") as well as the assembly of prints into the outer membrane ("Export and Assembly of Outer Membrane Proteins in E. coli"). Although the emphasis of the book is on proteins, the role of phospholipids in controlling various cell surface processes is reviewed ("Role of Phospholipids in coli Cell Function"). I should point out the reason for the rapid progress in bacteria research is because of the possibility to apply biochemistry and genetics in this organism.

Protein Glycosylation provides clear, up-to-date, and integrated coverage of key topics in this field. Particular emphasis is placed on the biosynthetic pathways that result in a wide variety of identified protein-bound oligosaccharides. Protein Glycosylation begins with an overview of the chemical structures of mono- and oligosaccharides, to provide a scientific basis for the later chapters. The book includes discussions on the purification, function, and enzyme kinetics of selected glycosidases and glycotransferases, as well as a review of the roles of oligosaccharides in glycoprotein function and the in vivo role of glycoproteins themselves. Finally, the in vitro synthesis of glycoproteins is presented, together with future directions in glycobiology. Protein Glycosylation serves as an excellent text for upper-level undergraduate and graduate students as well as a reference for those scientists whose training is not in glycobiology but who are moving into this field.

In "Single Molecule Studies of Proteins," expert researchers discuss the successful application of single-molecule techniques to a wide range of biological events, such as the imaging and mapping of cell surface receptors, the analysis of the unfolding and folding pathways of single proteins, the analysis interaction forces between biomolecules, the study of enzyme catalysis or the visualization of molecular motors in action. The chapters are aimed at established investigators and post-doctoral researchers in the life sciences wanting to pursue research in the various areas in which single-molecule approaches are important; this volume also remains accessible to advanced graduate students seeking similar research goals.

Proteins are the functional units of the cellular machinery and they provide significant information regarding the molecular basis of health and disease. Therefore, techniques to separate and isolate the various proteins are critical to studying and understanding their functional characteristics. One of the widely used techniques for this purpose is electrophoresis. In Protein Electrophoresis: Methods and Protocols, contributions from experts in the field have been collected in order to provide practical guidelines to this complex study. Each chapter outlines a specific electrophoretic variant in detail so that laboratory scientists may perform a technique new to their lab without difficulty. Written in the successful Methods in Molecular Biology (TM) series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible protocols, and notes on troubleshooting and avoiding known pitfalls. Authoritative and accessible, Protein Electrophoresis: Methods and Protocols seeks to serve laboratory scientists with well-honed, detailed methodologies in an effort to further our knowledge of this essential field.

Presents methods for determining the secondary and tertiary structure of proteins. The issues covered here involve theoretical/empirical approaches for predicting protein structure; a review using protein ligand interactions to study surface properties of proteins; use of fluorescence techniques to study structure and dynamics of proteins; and limited proteolysis with monoclonal antibodies to understand how specific structural features confer biological function.

After the identification of a potential protein drug, the next critical step is the production of sufficient authentic material for testing, characterization, and clinical trials, which, when successful, leads to the need for robust methodologies for large-scale production, purification, characterization, viral inactivation, and continued testing of the final protein product. Building on the valuable first edition, Therapeutic Proteins: Methods and Protocols, Second Edition aims to cover each of these key aspects of protein drug production through the contributions of authors from highly esteemed industrial and academic institutions around the world. Emphasizing the newest developments in the field, this second edition also includes additional emphasis on discovery, including new display and screening methods as well as the design and engineering of new types of therapeutic proteins. There is also discussion of computational and bioinformatics methods, and chapters on safety aspects of therapeutic protein development. Written in the highly successful Methods in Molecular Biology (TM) format, protocol chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Fully updated and practical, Therapeutic Proteins: Methods and Protocols, Second Edition provides an essential resource to all scientists working in the field of therapeutic proteins.

This volume presents established bioinformatics tools and databases for function prediction of proteins. Reflecting the diversity of this active field in bioinformatics, the chapters in this book discuss a variety of tools and resources such as sequence-, structure-, systems-, and interaction-based function prediction methods, tools for functional analysis of metagenomics data, detecting moonlighting-proteins, sub-cellular localization prediction, and pathway and comparative genomics databases. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, step-by-step instructions of how to use software and web resources, use cases, and tips on troubleshooting and avoiding known pitfalls. Thorough and cutting-edge, Protein Function Prediction: Methods and Protocols is a valuable and practical guide for using bioinformatics tools for investigating protein function

This book highlights key technologies and identifies areas for further development in proteogenomics. The utility and usefulness of very large Omics data sets (Next Gen Sequencing of DNA, RNA-seq, ribosome profiling, mass spectrometry- and antibody-based proteomics) is discussed and opportunities and challenges of related bioinformatics applications are outlined. The reader will be able to appreciate the interdisciplinary nature of the continuously evolving area of proteogenomics, which has already grown beyond its original concept of verifying gene annotations by proteomics. The chapters presented in this book are arranged to offer a general overview, rather than to provide detailed descriptions of technologies. The selected applications will provide useful insight into the level of detail that can be obtained in relation to certain diseases areas, including cancer biology and personalized medicine. The readers will find that each chapter delivers a comprehensive approach to proteogenomics, each from the point of view of a specific application. Research scientists interested in innovative processes that can offer a unique and at the same time a more complete access to technological developments and concepts that in turn can contribute to a better understand biological functions should read this book.

Cancerremainstobeoneofthemostdevastatingdiseasesworldwidesincelong ago. Thepoorprognosisofcancerislargelyduetometastasis. Metastasisisoften depictedasamultistageprocessinwhichmalignantcellsspreadfromtheprimary locustodistantorgansviacirculation. Whereasgeneticalterationsweresuggested tobeessentialfortransformationofprimarytumorcellsintometastaticphenotype, epigeneticeventsareequallyimportant,whichmaybetriggeredbymetastaticf- torswhereverintheprimarytumorlocus,bloodcirculationandthesecondaryloci. Signaltransductionsinitiatedbythemetastaticfactorsareresponsibleformediating themolecularandcellularprocessesleadingtometastasis. Blockadeoftherelevant molecularpathwaysisoneofthemosteffectivestrategiesforpreventionoftumor metastasis. Clinicaltrialsareunderwaywithpromisingoutcome. Inthisbook, wetakecomprehensive review inregard withthisexciting eld ofcancerresearch. Chapter1takesabriefoverviewofrecentlyidenti edsignal mechanismsforeachstepoftumormetastasisincludingtheinitiationstage,intra- sation,anti-anoikisinbloodcirculation,homing,extravasationand nalsurvivalin themetastaticsite. Chapter2makesacompletedreviewforthemolecularandcel- lareventsinvolvedininitiationofmetastasis. Especially,thesignalingmechanisms formediatingtumorprogressioninducedbysomeimportantmetastaticfactorsare described. InChapters3and4,thecentralrolesofMAPKanditsdownstreameff- torsMAPKAPKplayineachstepoftumormetastasisarewelldelineated. Chapter5 furtherdescribesdetailedlyabouthowGrb2andotheradaptorproteins,upstreamof MAPK cascade, contribute tometastasis. InChapter 6, therole ofreactive o- genspecies(ROS)intumorprogressionarehighlighted. Moreover,thepotential contribution of ROS to cross talk between major signaling cascades that lead to sustainedMAPKactivationareproposedinChapter7. Chapter8takesaninsight intothesignalingmechanismsfordynamictraf ckingandturnoveroffocalad- sionproteinsinregulationoftractionandretractionforces,whichareneededfor celllocomotionandinvasion. Chapter9describestheinvolvementofNotchsign- ingpathwaywhichisnotonlyessentialforembryonicdevelopmentbutalsoplays importantroleintumorprogression. Chapter10reviewedtherecentlyidenti ed cancer- and metastasis-initiating cells involved in tumor progression. Especially, signal pathways that are frequently deregulated in cancer stem/progenitor cells v vi Preface duringcancerprogressionarehighlighted. Chapter11describestheroleoflipid rafts, a special component within membrane lipid domain, in signal transd- tion triggered by growth factor receptors leading to tumor metastasis. Finally, Chapters12,Chapters13,andChapters14presentthesignalingpathwaysresp- sibleformetastaticprogressionofspeci ctumorsincludingovariancancer,uveal melanomaandhepatoma,respectively. WethankallthecontributorsofeveryChapterinthebookincludingJia-RuWu, Chi-TanHu,LaureVoisin,StephanieDuhamel,SylvainMeloche,AlexeyShiryaev, MarijkeVanGhelue,UgoMoens,AlessioGiubellino,PraveenR. Arany,Moulay A. Alaoui-Jamali, Krikor Bijian, Panagiota Toliopoulos, Pingyu Zhang, Patrick A. Zweidler-McKay,MurielleMimeault,SurinderK. Batra,SamirKumarPatra, LydiaW. T. Cheung,CarmanK. M. Ip,AliceS. T. Wong,CecileLaurent,Jerome Couturier,XavierSastre-Garau,LaurenceDesjardins,EmmanuelBarillot,Sophie Piperno-Neumann,SimonSauleandRajagopalN. Aravalli. Wehopethisbookmightstimulatemorecancerbiologiststoemphasizethis eld whichbene tsdevisingmoreeffectivemoleculartargetingstrategiesforprevention ofcancermetastasis. Hualien,Taiwan Wen-ShengWu Chi-TanHu Contents 1 Overview of Signal Transduction in Tumor Metastasis...1 Wen-ShengWuandJia-RuWu 2 Microenvironment Triggers EMT, Migration and Invasion of Primary Tumor via Multiple Signal Pathways ...9 Wen-ShengWuandChi-TanHu 3 The ERK1/2 MAP Kinase Signaling Pathway in Tumor Progression and Metastasis ...25 LaureVoisin,StephanieDuhamel,andSylvainMeloche 4 Mitogen-Activated Protein Kinase-Activated Protein Kinases and Metastasis...41 AlexeyShiryaev,MarijkeVanGhelue,andUgoMoens 5 Grb2 and Other Adaptor Proteins in Tumor Metastasis ...77 AlessioGiubellinoandPraveenR. Arany 6 The Role of ROS Signaling in Tumor Progression...103 Wen-ShengWuandJia-RuWu 7 Signal Cross Talks for Sustained MAPK Activation and Cell Migration Mediated by Reactive Oxygen Species: The Involvement in Tumor Progression...

The biological interactions of living organisms, and protein-protein interactions in particular, are astonishingly diverse and present numerous challenges to modern biomolecular research because of their complexity. Analysis of patterns and principles governing these interactions has prompted a rapid development of computational methods to identify protein interaction partners and to understand the roles of individual components of protein interaction networks in cell functions.

This book integrates different approaches from bioinformatics, biochemistry, computational analysis and systems biology to offer the reader a comprehensive global view of the diverse data on protein-protein interactions and protein interaction networks. It brings together the descriptions of experimental techniques and expounds on different computational algorithms for protein network analysis and prediction of protein and domain interactions, with each chapter containing a description of the problem, a review of methods and algorithms, a list of resources and current conclusions.

Features

a [ Reviews experimental techniques for identification of protein interactions

a [ Discusses protein interaction databases and methods of integrating data from diverse sources

a [ Describes computational methods to predict protein and domain interaction partners

a [ Explores the properties of interaction interfaces and highlights approaches to model the assembly of protein complexes

a [ Examines the topological and dynamical properties of protein interaction networks and presents the tools for comparative analysis of these networks

Written by leading experts, Protein-protein Interactions and Networksprovides a broad, thorough and multidisciplinary coverage of this field. It will be invaluable to researchers from academia and the bioinformatics industry, as well as an excellent auxiliary text for graduate students studying the topic.

This volume focuses on the structure, function and regulation of plant signaling G proteins and their function in hormonal pathways, polarity, differentiation, morphogenesis and responses to biotic and abiotic stresses.

Plants are sessile organisms that need to continuously coordinate between external and internal cues. This coordination requires the existence of hubs to allow cross-talk between different signaling pathways. A single family of Rho GTPases, termed either ROPS or RACs, and heterotrimeric G proteins have emerged as the major molecular switches in a multitude of signal transduction pathway in plants.

This volume covers a wide spectrum of techniques and approaches that are used in the upstream and downstream processing for recombinant glycoprotein production. Chapters guide the reader through state-of-art of therapeutic recombinant glycoproteins, explores the patent literature, expression systems used for glycoproteins production, methods employed in the downstream processing of different glycoproteins, and information about analytical tools and formulation strategies. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and cutting-edge, Recombinant Glycoprotein Production: Methods and Protocols aims to ensure successful results in the further study of this vital field

The purpose of Calpain Methods and Protocols is quite straightf- ward: it is to present the actual experimental methods used in many different laboratories for the study of calpain. It will provide the vital experimental detail, and the discussion of possible pitfalls, for which the standard journals no longer provide space. This will make it as easy as possible for investi- tors interested in calpain to adopt established methods without repeating old mistakes, and to adapt and apply these methods in novel approaches to the many outstanding calpain questions. These questions range from purely biochemical problems of protein structure and enzyme regulation at the molecular level, through large areas of cell biology, to applied and clinical aspects of calpain function in human d- ease. Within this panoply of topics, a wide range of investigators will find many fascinating and as yet unanswered questions about calpain. Calpain Methods and Protocols will provide instant access to many essential te- niques, while saving them the time and effort involved in developing a new method. In addition to questions relating to the normal physiological roles of the calpains, there is considerable evidence that inappropriate calpain activity may have pathological effects in many tissues, for example, following ischemia. This provides a major stimulus for the development of specific calpain inhi- tors for therapeutic purposes, and for the development of methods to evaluate such inhibitors.

Knowledge of cholesterol and its interaction with protein molecules is of fundamental importance in both animal and human biology. This book contains 22 chapters, dealing in depth with structural and functional aspects of the currently known and extremely diverse unrelated families of cholesterol-binding and cholesterol transport proteins. By drawing together this range of topics the Editor has attempted to correlate this broad field of study for the first time. Technical aspects are given considerable emphasis, particularly in relation cholesterol reporter molecules and to the isolation and study of membrane cholesterol- and sphingomyelin-rich "raft" domains. Cell biological, biochemical and clinical topics are included in this book, which serve to emphasize the acknowledged and important benefits to be gained from the study of cholesterol and cholesterol-binding proteins within the biomedical sciences and the involvement of cholesterol in several clinical disorders. It is hoped that by presenting this topic in this integrated manner that an appreciation of the fact that there is much more that needs to be taken into account, studied and understood than the widely discussed "bad and good cholesterol" associated, respectively, with the low- and high-density lipoproteins, LDL and HDL. Content Level Professional/practitioner

Chemical and Functional Properties of Food Proteins presents the current state of knowledge on the content of proteins in food structures, the chemical, functional, and nutritive properties of food proteins, the chemical and biochemical modification of proteins in foods during storage and processing, and the mutagenicity and carcinogenicity of nitrogenous compounds. It emphasizes the structure-function relationship as well as the effects of practical conditions applied in food processing on the biochemical and chemical reactions in food proteins and food product quality.

The first ten chapters discuss structure-function relationships, methods of analysis of nitrogenous compounds, chemical and enzymatic modifications, nutritive roles, and mutagenicity and carcinogenicity of food proteins. The following six chapters describe the proteins of meat and fish, milk, eggs, cereals, legumes, oilseeds and single cell organisms, and present detailed information on the effects of conditions applied in storage and processing on the reactions in proteins and their impact on quality attributes of food products.

This book contains 14 original review chapters each yielding new, exciting and intriguing data about the emerging understanding of nucleolar structure and function in normal, stressed and diseased cells. The goal of this work is to provide special insight into the nucleolus of the past, present and future, as well its regulation, translocation, and biomedical function. A multitude of topics are introduced and discussed in detail, including nucleologenesis, nucleolar architecture, nucleolar targeting, retention, anchoring, translocation, and the relationship between the nucleolus and cancer. This book also brings together work from several different species, from human to Drosophila to Dictyostelium and other eukaryotic microbes. The final chapter summarizes some of the issues brought up in the various chapters with a view to future research. This book supports the continued emergence of the nucleolus as a dynamic intranuclear region that oversees a vast diversity of events.

SELDI is distinct from other TOF-MS technologies in that it couples features of chromatography and mass spectrometry, facilitating analyte enrichment and sample cleanup on an array surface. In the growing field of proteomics, SELDI technology has been widely used for biomarker discovery and characterization in diverse applications including diagnostics, drug development, and basic research. SELDI-based biomarker studies can typically be divided into four phases: discovery, validation, purification and identification, and assay development. SELDI-TOF Mass Spectrometry: Methods and Protocols provides an overview of the current applications of SELDI-TOF MS (surface enhanced laser desorption/ionization time-of-flight mass spectrometry), with an emphasis on study and experimental design, data analysis and interpretation, and assay development. Written in the highly successful Methods in Molecular Biology (TM) series format, chapters contain introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and notes on troubleshooting and avoiding known pitfalls. Authoritative and accessible, SELDI-TOF Mass Spectrometry: Methods and Protocols will provide information on optimizing study design, experimental protocols, and data analysis and interpretation to yield robust biomarkers and biomarker assays, using examples from different disease areas.

This book provides a comprehensive survey of recent developments and applications of high performance capillary electrophoresis in the field of protein and peptide analysis with a distinct focus on the analysis of intact proteins. With practical detail, the contents cover different modes of capillary electrophoresis (CE) useful for protein and peptide analysis, CZE, CIEF, ACE, CGE, and different types of application such as the quality control of therapeutic proteins and monoclonal antibodies, clinical analyses of chemokines in tissues, qualitative and quantitative analysis of vaccine proteins, and determination of binding constants in complexes involving peptides or proteins. Written for the highly successful Methods in Molecular Biology series, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and exhaustive, Capillary Electrophoresis of Proteins and Peptides: Methods and Protocols serves both beginners and experts with a collection of the current and most active topics in this vital field of study.

Protein Folding Protocols presents protocols for studying and characterizing protein folding from the unfolded to the folded state. Covering experiment and theory, bioinformatics approaches, and state-of-the-art simulation protocols for better sampling of the conformational space, this volume describes a broad range of techniques to study, predict, and analyze the protein folding process.
Protein Folding Protocols also provides sample approaches toward the prediction of protein structure starting from the amino acid sequence, in the absence of overall homologous sequences. These approaches have tremendous implications, ranging from drug design, functional assignment, comprehension of the nature of regulation, understanding molecular machines, viral entry into cells, and putting together cellular pathways and their dynamics.

"Theoretically, one should obtain essentially the same clinical picture from failure of an end-organ to respond to a hormone as from a decreased production or absence of said hormone. " With these words, Fuller Albright began his now classic paper describing a novel disease, pseudo hypoparathyroidism (PHP), and a novel concept, hormone resis- tance as a cause of disease. Soon, other hormone resistance disorders such as nephrogenic diabetes insipidus (NDI) were recognized, and the concept was extended to resistance to other substances such as calcium ions in familial hypocalciuric hypercalcemia (FHH). Later, diseases characterized by excess rather than deficient hormone action such as McCune-Albright syndrome (MAS) and familial male precocious puberty (FMPP) were recognized to be caused by autonomous endocrine hyperfunction. Although many i!!vestigators provided careful and detailed descriptions of the clinical features of these and other related endocrine disorders, an understanding of pathogenesis proved elusive for many years. In just the past few years, we have gone from clinical description to a molecular understanding of these interesting disorders. This remarkable progress reflects a synthe- sis of three distinct, but now overlapping, areas of biomedical research: the aforemen- tioned recognition and careful clinical description of specific diseases, the elucidation of the basic mechanisms of signal transduction, and the application of the powerful tools of molecular biology and genetics. Fundamental studies on the mechanisms of hormone action by Rodbell and colleagues at NIH culminated in the discovery of a major signal transduction pathway involving heterotrimeric G proteins.