Signal Transduction

Signal Transduction

by Bastien D. Gomperts, Ijsbrand M. Kramer, Peter E.R. Tatham

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Signal Transduction, 2e, is a thorough, well-illustrated study in cellular signaling processes. Beginning with the basics, this book shows how cells respond to external cues, hormones, growth factors, cytokines, cell surfaces, etc., and further instructs how these inputs are integrated. Instruction continues with up-to-date, inclusive coverage of


Signal Transduction, 2e, is a thorough, well-illustrated study in cellular signaling processes. Beginning with the basics, this book shows how cells respond to external cues, hormones, growth factors, cytokines, cell surfaces, etc., and further instructs how these inputs are integrated. Instruction continues with up-to-date, inclusive coverage of intracellular calcium, nuclear receptors, tyrosine protein kinases and adaptive immunity, and targeting transduction pathways for research and medical intervention. Signal Transduction, 2e, serves as an invaluable resource for advanced undergraduates, graduate researchers, and established scientists working in cell biology, pharmacology, immunology, and related fields.

* Up-to-date, inclusive coverage of targeting transduction pathways for research and medical intervention
* In-depth coverage of nuclear receptors, including steps in isolation of steroid hormones and the discovery of intracellular hormone receptors; tyrosine protein kinases and adaptive immunity; and intracellular calcium
* Extensive conceptual color artwork to assist with comprehension of key topics
* Instrumental margin notes highlight milestones in signaling mechanisms

Editorial Reviews

5 Stars! from Doody
Michael B. Yaffe
The text is strikingly comprehensive...Written with a single voice, the chapters integrate elegantly with one another, and provide the reader with both broad and comprehensive viewpoints...Remarkably current and up-to-date, the book promises to be a core text for graduate and advanced undergraduate courses in cell signaling and molecular cell biology, and a valuable reference book for all scientists whose work involves mechanisms of cell communication.
From the Publisher
"Signal Transduction is indispensable for modern life sciences."

"...useful to senior undergrad and grad students entering the field, but will also provide a valuable reference for established researchers."

Doody's Review Service
Reviewer: Alvin Telser, PhD (Northwestern University Feinberg School of Medicine)
Description: This is a basic and comprehensive textbook on the subject of signal transduction.
Purpose: The authors intend the book to be used as a textbook in an advanced undergraduate or graduate course in this subject area. They also state that they hope and expect it will be interesting and useful to scientists at many levels. Signal transduction has become one of the most active and interesting areas of research in modern cell and molecular biology, which makes this book timely and extremely worthwhile. It is very well written and fully meets the author's objectives.
Audience: The major audience for this book are students who will use the book in a formal course on signal transduction, but it has a great deal of important and useful information and is sufficiently well written that many other scientists will find it useful. The authors are very knowledgeable in the subject area.
Features: The book begins with a very interesting historical perspective and proceeds to discuss all the major areas of signal transduction. The authors employ an excellent balance of experimental data and full color schematic diagrams that will greatly assist readers in understanding the material. There are a substantial number of explanatory margin notes that provide definitions, historical background, or points of general interest that add to the interest and understanding of material in the text.
Assessment: This book is an excellent addition to the line of textbooks that are useful for courses in modern cell and molecular biology. The abundant use of graphics is outstanding. The writing is excellent. This should become the standard textbook in the area of signal transduction.

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Signal Transduction

By Bastien D. Gomperts IJsbrand M. Kramer Peter E.R. Tatham

Academic Press

Copyright © 2009 Elsevier Inc.
All right reserved.

ISBN: 978-0-08-091905-8

Chapter One

Prologue: Signal Tranduction, Origins, and Ancestors

Transduction, the word and its meaning: one dictionary, different points of view

The expression signal transduction first made its mark in the biological literature in the 1970s and appeared as a title word in 1979. Physical scientists and electronic engineers had earlier used the term to describe the conversion of energy or information from one form into another. For example, a microphone transduces sound waves into electrical signals. The widespread use of the term in bio-speak was triggered by an important review by Martin Rodbell, published in 1980 (Figure 1.1). He was the first to draw attention to the role of GTP and GTP-binding proteins in metabolic regulation and he deliberately borrowed the term to describe their role. By the year 2000, 12% of all papers using the term cell also employed the expression signal transduction.

Hormones, evolution, and history

These chemical messengers ... or 'hormones' (from the Greek [TEXT NOT REPRODUCIBLE IN ASCII), meaning excite or arouse), as we may call them, have to be carried from the organ where they are produced to the organ which they affect, by means of the bloodstream, and the continually recurring physiological needs of the organism must determine their repeated production and circulation throughout the body.

The plasma membrane barrier

In the main, when we consider signal transduction we are concerned about how external influences, particularly the presence of specific hormones, can determine what happens inside their target cells. There is a difficulty, since the hormones, being mostly hydrophilic (or lipophobic) substances, are unable to pass through membranes, so that their influence must somehow be exerted from outside. The membranes of cells, although very thin (3–6nm) are effectively impermeable to ions and polar molecules. Although K+ ions might achieve diffusional equilibrium over this distance in water in about 5ms, they would take some 12 days (280h) to equilibrate across a phospholipid bilayer (under similar conditions of temperature, etc.). Likewise, the permeability of membranes to polar molecules is low. Even for small molecules such as urea, membrane permeability is about 104 times lower than that of water. So for a hormone such as adrenaline (epinephrine), the rate of permeation is too low to measure. The evolution of receptors has accompanied the development of mechanisms which permit external chemical signalling molecules, the first messengers, to direct the activities of cells in a variety of ways with high specificity and precise control in terms of extent and duration. With some important exceptions (the steroid hormones, thyroid hormone), they do this without ever needing to penetrate their target cells.


The first messengers (which include the hormones), and their related intracellular (second) messengers, are of great antiquity on the biological timescale. It is interesting to consider which came first: the hormones or the receptors that they control. Substances exhibiting the actions of hormones in animals first made their appearance at early stages of evolution (Figure 1.2). Chemical structures closely related to thyroid hormones have been discovered in algae, sponges, and many invertebrates. Steroids such as estradiol are present in microorganisms and also in ferns and conifers. Catecholamines have been found in protozoa, and ephedrine, which is closely related, can be isolated from the stems and leaves of the Chinese herb Ma Huang (Ephedra sinica). Ephedrine is still in use as an oral stimulant in the treatment of hypotension (low blood pressure) and in the relief of asthma. There are claims, based on immunological detection, for the presence of peptides related to insulin and the endorphins in protozoa, fungi, and even bacteria, although no messenger-like function has been discerned and it is likely that the receptors that mediate their effects in animals evolved much later.

The a- and α-type mating factors of yeast, which certainly act as messengers, are very similar in structure to gonadotropin-releasing hormone (GnRH) which controls the release of gonadotropins from the anterior pituitary in mammals. Factors resembling mammalian atrial natriuretic factor (ANF) are present in the cytosol of the single-cell eukaryote Paramecium multimicronucleatum and in the leaves of many species of plants, where they act as regulators of solvent and solute flow and of the rate of transpiration. ACTH and β-endorphin are present in protozoa. These organisms also contain high molecular mass precursors of these peptides, reminiscent of the vertebrate pro-opiomelanocortin (POMC). It is striking that pathways for the biosynthesis of these 'protohormones', often complex, were established early on, well before the evolution of membrane receptors.

Receptor-like proteins in non-animal cells have been much harder to identify. A recently described example is a protein expressed in the plant Arabidopsis that shares extensive sequence homology with the ionotropic glutamate receptor of mammalian brains. A corollary is the possibility that the potent neurotoxins thought to be generated in defence against herbivores may have their origin as specific agonists, and were only later selected and adapted in some species as poisons. Molecules having a close relationship to the receptors for epidermal growth factor (EGF) and insulin apparently evolved in sponges before the Cambrian Explosion (more than 600 million years ago) and it has been proposed that they may have contributed to the rapid development of the higher metazoan phyla.

Although invertebrates express some members of the nuclear receptor family (such as the receptors for thyroid hormone and vitamin D), nuclear receptors for adrenal and sex steroid hormones (cortisol, aldosterone, testosterone, estradiol, progesterone, etc.) are absent. The ancestral steroid hormone receptor probably made its first appearance in a cephalochordate such as Amphioxus. Receptors for estradiol, progesterone, and cortisol have been cloned from lamprey. From this point in evolution onwards, the steroid hormones would have allowed for a ligand-based mechanism for the regulation of gene transcription and this could have promoted the complex processes of differentiation and development found in the higher vertebrates. Thus, the hox genes that are critical for development and differentiation, including the brain of Amphioxus, are regulated by oestrogens and progestins.

In general, it appears that many of the molecules that we regard as hormones arose long before the receptors that they control. An important consequence of this is that the responses to a given hormone can vary widely across different species and even within species. Numerous actions of prolactin have been identified. It is the regulator of mammary growth and differentiation and of milk protein synthesis in mammals. In birds, it acts as a stimulus to crop milk production and in some species as a controlling factor for fat deposition and as a determinant of migratory behaviour. It is a regulator of water balance in urodeles (newts and salamanders) and of salt adaptation and melanogenesis in fish. Serotonin (5-hydroxytryptamine), a neurotransmitter that controls mood in humans, is reported to stimulate spawning in molluscs, probably as a consequence of its conversion to melatonin (naturally, one wonders whether it affects their mood as well).


Despite excellent anatomical descriptions, almost nothing was known about the functions of the various organs which constitute the endocrine system (glands) until the last decade of the 19th century. Indeed, in the standard textbook of the period (Foster's Textbook of Physiology, 3 volumes and more than 1200 pages), consideration of the thyroid, the pituitary, the adrenals ('suprarenal bodies'), and the thymus is confined to a brief chapter of less than 10 pages, having the title 'On some structures and processes of an obscure nature'.

The initial impetus prompting the systematic investigations which led to the discovery of the hormones can be ascribed to a series of papers that were much misunderstood. However, here we are confronted with the work of Charles Edouard Brown-Séquard, the successor to Claude Bernard at the Collège de France and also a member of leading scientific academies in England and the USA. He had held professorial appointments at both Harvard and Virginia; in London he was appointed physician at the National Hospital for the Paralysed and Epileptic (now the National Hospital for Neurology and Neurosurgery). He was an associate of Charles Darwin and Thomas Huxley. He wrote over 500 papers relating to many diverse fields such as the physiology of the nervous system; the heart, blood, muscles, and skin; the mechanism of vision; and much more. He was an outstanding experimentalist making fundamental contributions. Starting with his doctoral thesis, he described the course of motor and sensory fibres in the spinal cord, a field to which he returned many times. He was in constant demand as lecturer, teacher, and physician on both sides of the Atlantic, crossing the ocean on more than 60 occasions. Of direct relevance to us must be his demonstration that the adrenal glands are essential to life.

In view of all this, it is curious that Brown-Séquard is now all but forgotten. On the rare occasions when he is recalled, it is generally in connection with a series of brief reports, published in 1889, in which he described the self-administration by injection, of testicular extracts, which he considered had the effect of reinforcing his bodily functions. Some brief quotations from his paper in the Lancet must suffice:

I am seventy-two years old. My general strength, which has been considerable, has notably and gradually diminished during the last ten or twelve years. Before May 15th last, I was so weak that I was always compelled to sit down after about half an hour's work in the laboratory. Even when I remained seated all the time I used to come out of it quite exhausted after three or four hours of experimental labour ...

The day after the first subcutaneous injection, and still more after the two succeeding ones, a radical change took place in me, and I had ample reason to say and to write that I had regained at least all the strength I possessed a good many years ago ...

My limbs, tested with a dynamometer for a week before my trial and during the month following the first injection, showed a decided gain of strength ...

I have measured comparatively, before and after the first injection, the jet of urine in similar circumstances – i.e. after a meal in which I had taken food and drink of the same kind and in similar quantity. The average length of the jet during the ten days that preceded the first injection was inferior by at least one quarter of what it came to be during the twenty following days. It is therefore quite evident that the power of the spinal cord over the bladder was considerably increased ...

I will simply say that after the first ten days of my experiments I have had a greater improvement with regard to the expulsion of faecal matters than in any other function. In fact a radical change took place, and even on days of great constipation the power I long ago possessed had returned.


Excerpted from Signal Transduction by Bastien D. Gomperts IJsbrand M. Kramer Peter E.R. Tatham Copyright © 2009 by Elsevier Inc.. Excerpted by permission of Academic Press. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
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Meet the Author

IJsbrand Kramer is a professor at the University of Bordeaux, working in the European Institute of Chemistry and Biology (IECB). He holds a Bachelors and Masters degree in BioMedicine from the University of Utrecht, The Netherlands, with a one year research-excursion in the Department of Cell Biology at the University of Liverpool, UK. He did his Ph.D. at the University of Amsterdam, in the Central Laboratory of Blood transfusion services (Stichting Sanquin) and worked as a post-doctoral fellow at the Hubrecht Laboratory in Utrecht and at the University of Washington in Seattle. He then took a lecturer position at the Department of Pharmacology at University College London, where he taught Signal Transduction (with Bastien Gomperts and Pether Tatham) and Pharmacology. Both teaching activities have been documented in textbooks: Signal Transduction (3 editions) and Receptor Pharmacology (CRC Press/Taylor Francis Group, 3 editions). Most of his research centers on the theme of inflammation, starting with neutrophils and the NADPH oxidase, synovial fibroblasts and destruction of the joint and more recently podosomes formation and extracellular matrix destruction in vascular endothelium. He moved to the University of Bordeaux for family reasons and switched from Pharmacology to Cell Biology, with a strong contribution to an introductory course for 1st year university students. Given the important teaching load and the general low level of student engagement in higher education he started to investigate the reasons for student failure (finding out about their expectations and attitudes) and the role of images and animations in comprehension. Scientific publications, web-based multimedia resources and dramatically enhanced retention rates (from 33 to 85%) are the fruits of these activities. At the same time he organized with University College London and Universitat Pompeu Fabra, Barcelona, summer schools on Receptor and Signalling Mechanism. He has been co-director of two European Programmes (Interbio and Transbio) that aimed at enhancing industrial innovation in the biomedical sector in the South West European Region (SUDOE).
For book/publicity purposes, image of the author by © Maarten Kramer

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