Signal Transduction

ljsbrand M. Kramer

• Publisher: Academic Press
• Year: 2015
• eBook ISBN: 9780123948199
• Edition: 3
• Topic: Biological Sciences
• Subtopic: Biochemistry
• Index: Biological Sciences

A reference on cellular signaling processes, the third edition of Signal Transduction continues in the tradition of previous editions, in providing a historical overview of how the concept of stimulus-response coupling arose in the early twentieth century and shaped our current understanding of the action of hormones, cytokines, neurotransmitters, growth factors and adhesion molecules. In a new chapter, an introduction to signal transduction, the book provides a concise overview of receptor mechanisms, from receptor – ligand interactions to post-translational modifications operational in the process of bringing about cellular changes. The phosphorylation process, from bacteria to men, is discussed in detail. Signal transduction third edition further elaborates on diverse signaling cascades within particular contexts such as muscle contraction, innate and adaptive immunity, glucose metabolism, regulation of appetite, oncogenic transformation and cell fate decision during development or in stem cell niches. The subjects have been enriched with descriptions of the relevant anatomical, histological, physiological or pathological condition. - In-depth insight into a subject central to cell biology and fundamental to biomedicine, including the search for novel therapeutic interventions - Essential signaling events embedded in rich physiological and pathological contexts - Extensive conceptual colour artwork to assist with comprehension of key topics - Special emphasis on how molecular structure determines protein function and subcellular localization - Employment of unambiguous protein names (symbols) in agreement with leading protein- and gene databases, allowing the learner to extend his/her exploration on the web

Chapter 1

Prologue

Signal Transduction from an Historical Perspective

Abstract

An historical account of how the term “signal transduction” entered biomedical research and how stimulus-response coupling, hormones, neurotransmitters, growth factors, and their receptors were brought to light. It pays tribute to the wisdom of our forebears, whose freedom of thought and sometimes serendipitous discoveries in the nineteenth and early twentieth centuries led to the creation of the modern sciences. Personalities highlighted are, in order of appearance, Alfred Gilman, Martin Rodbell, Thomas Henry Huxley, Steve Grand, Charles-Edouard Brown-Séquard, Henry Hallett Dale, Otto Loewi, George Oliver, Edward Sharpey-Schäfer, Ernest Henry Starling, William Maddock Bayliss, Paul Ehrlich, John Newport Langley, Francis Peyton Rous, Rita Levi-Montalcini, Stanley Cohen, Alexis Carrel, and the robot CONRO whose control of functionalities is based on the principles of hormone action.

Keywords

Discovery; Growth factors; Hormones; Neurotransmitters; Receptors; Stimulus-response coupling

Transduction, the word and its meaning

The expression signal transduction first made its mark in the biological literature in the 1970s (Hildebrand, 1977) and appeared as a title word in 1979 (Springer et al., 1979; Koman et al., 1979; Kenny et al., 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 term implies two related activities: one concerns transmission and the other translation of the original signal (a sound wave). Its widespread use in bio-speak was triggered by an important review by Martin Rodbell, published in 1980. 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 transducer to describe their role in the relay of the receptor signal to the effector (Figure 1-1).

Alfred G Gilman and Martin Rodbell were awarded the Nobel Prize in 1994 “for their discovery of G-proteins and the role of these proteins in signal transduction in cells.”

In the year 2010, 12.6% of all papers using the term cell also employed the expression signal transduction and 16.6% also employed the expression signaling (the American spelling of signalling) (information from PubMed). The explosion in signal transduction research corresponds with the episode in which it became apparent that oncogenes disrupt ordinary, well-controlled, signaling processes. In particular Ras, the product of the oncogene ras leading to the formation of rat sarcoma, and its role in growth factor signaling has been the subject of intense investigation. It occurs that signaling mechanisms are an important research domain in biological sciences (Figure 1-2).

Figure 1-1 The transducer. Introduction of the concept of a transducer in the relay of the receptor signal to the effector. A transducing GTP-binding protein relays the receptor signal, we speak of signal transduction. Adapted from Rodbell (1980). Image of Rodbell from http://www.nobelprize.org/.

Figure 1-2 Occurrence of the term signal transduction. The left-hand axis records all papers using the term cell traced through the PubMed database. The right-hand axis records the proportion of papers using the term cell that also use the term signal transduction. Major discoveries that have boosted signal transduction research are shown underneath the time axis.

Below follows a description of personalities and experiments, during the transition from the nineteenth to the twentieth century, that have paved the way to our current understanding of how different parts of the body communicate with one another (hormones, neurotransmitters, growth factors). Naturally, major discoveries gave rise to controversy (as they challenged hegemony of ideas and personalities) and, as a consequence, a good dose of (persistent) anxiety for those who deviated from the trodden path. Our account also shows that in many instances, scientists did not really know what to look for and thus what to expect from their experiments. Only through the course of their experimentations did they develop a sense of direction and importantly, understanding. Had they been confronted with current grant application forms, the section “expected outcome” would be manifested by its blankness.

Transduction entries in the Oxford English Dictionary (Figures 1-3 and 1-4)

Irritability, a vital phenomenon

The origin of life is often considered as fundamentally a problem of the origin of template replication. However, replication itself is not sufficient, metabolism was another important property right from the beginning (Dyson, 1999). According to Thomas Henry Huxley (Figure 1-5), a third essential element for the living comprises a stimulus-response system. Ultimately, this system became the basis of how organisms respond to the environment, and how parts of an organism (or whole organisms) communicate with one another. In his lecture on “the physical basis of life” (Edinburgh, on the evening of Sunday November 8, 1868), Huxley argues that all living things, ranging from Amoebae to Homo sapiens, are substantially similar in kind with respect to elementary functions and substance (which he named “protoplasm”). Irritability, Huxley’s description of stimulus-response coupling, takes an essential place among the list of “vital phenomena.”

Figure 1-3 From the Shorter Oxford English Dictionary (3rd edition, 1994, with corrections 1977, © Oxford University Press).

Figure 1-4 From the Oxford English Dictionary (2nd edition, 2008 © Oxford University Press online).

Figure 1-5 Irritable medusa and Thomas Henry Huxley. On the left, Rhizostoma pulmo, one of the species studied by Huxley. On the right, Thomas Huxley around 1857, 10 years after his journey on the HMS Rattlesnake. Image of Rhizostoma pulmo from Willy Couard (www.souslemers.fr) and image of Huxley from the Royal Society (www.darwininlondon.com).

In physiological language this means that all the multifarious and complicated activities of man are comprehensible under three categories: either they are immediately directed towards the maintenance and development of the body (“metabolism”), or they effect transitory changes in the relative positions of parts of the body (“stimulus-response”), or they tend towards the continuance of the species (“template replication”). Even those manifestations of intellect, of feeling, and of will, which we rightly name the higher faculties, are not excluded from this classification, inasmuch as to everyone but the subject of them, they are known only as transitory changes in the relative positions of parts of the body. Speech, gesture, and every other form of human action are, in the long run, resolvable into muscular contraction, and muscular contraction is but a transitory change in the relative positions of the parts of a muscle. But the scheme which is large enough to embrace the activities of the highest form of life, covers all those of the lower creatures. The lowest plant, or animalcule, feeds, grows, and reproduces its kind. In addition, all animals manifest those transitory changes of form which we class under irritability and contractility; and, it is more than probable, that when the vegetable world is thoroughly explored, we shall find all plants in possession of the same powers, at one time or other of their existence.

Irritability

Perhaps it were the medusa that he studied during his voyage on the HMS Rattlesnake (around 1846), that led Huxley to employ the word “irritability” and “contractility” (rather than stimulus-response coupling). Describing the stomach, situated under the disc of Rhizostoma he writes: “From this ‘common canal’ a series of parallel diverticula are given off at regular intervals, and run to the edge of the branch, where they terminate by rounded oblique openings. It is not always easy to see these apertures, but I have repeatedly satisfied myself of their presence by passing a needle or other delicate body into them. The difficulty in seeing the openings arises in great measure from the presence of a membrane which surrounds and overlaps them, and being very irritable, contracts over them on being touched” (Huxley, 1849).

Cellular theory and protoplasm

The initial microscopic observations of cellular structures by Robert Hooke (around 1653) and Anthony van Leeuwenhoek (around 1682) obtained full recognition when in 1832 the German botanist Matthias Schleiden proclaimed that cells were the elementary structures of plants. A few years later, Theodore Schwann showed that the animal tissues were also made up of cells, and that they owed their beginning and development to the activity of cell elements; thus originated the “cellular theory.” Until 1888, the composition of the brain remained, however, an enigma. In that year Santiago Ramon y Cajal, using Camillo Golgi’s silver nitrate impregnation staining, convincingly demonstrated that even the soft, near homogeneous, gray matter was made up of distinctive structures, the nerve cells.

In his “Manual of Physiology” (1889) Gerald Yeo, from King’s College, describes the characteristics of the cell as follows: “The first idea which was conveyed by the term cell varied much from that which we now accept as a proper definition of such an organic unit. Fully developed veget...

Table of contents

• Signal Transduction
• Chapter 1 Prologue
• Chapter 2 An Introduction to Signal Transduction
• Chapter 3 Regulation of Muscle Contraction by Adrenoceptors
• Chapter 4 Cholinergic Signaling and Muscle Contraction
• Chapter 5 Sensory Signal Processing; Visual Transduction and Olfaction
• Chapter 6 Intracellular Calcium
• Chapter 7 Bringing the Signal into the Nucleus
• Chapter 8 Nuclear Receptors
• Chapter 9 Protein Kinase C in Oncogenic Transformation and Cell Polarity
• Chapter 10 Regulation of Cell Proliferation by Receptor Tyrosine Protein Kinases
• Chapter 11 Signal Transduction to and from Adhesion Molecules
• Chapter 12 WNT Signaling and the Regulation of Cell Adhesion and Differentiation
• Chapter 13 Activation of the Innate Immune System
• Chapter 14 Chemokines and Traffic of White Blood Cells
• Chapter 15 Activating the Adaptive Immune System
• Chapter 16 Signaling through the Insulin Receptor
• Chapter 17 TGFβ and Signaling through Receptor Serine/Threonine Protein Kinases
• Chapter 18 Protein Phosphatases
• Chapter 19 Cell Fate Determination by Notch
• Index