Table Of ContentSIGNAL
TRANSDUCTION
THIRD EDITION
IJ M. K
sbrand ramer
University of Bordeaux
European Institute of Chemistry and Biology, INSERM U1045
Talence, France
AMSTERDAM • BOSTON • HEIDELBERG • LONDON
NEW YORK • OXFORD • PARIS • SAN DIEGO
SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO
Academic Press is an imprint of Elsevier
Academic Press is an imprint of Elsevier
125 London Wall, London EC2Y 5AS, UK
525 B Street, Suite 1800, San Diego, CA 92101-4495, USA
225 Wyman Street, Waltham, MA 02451, USA
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK
Copyright © 2016 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any
means, electronic or mechanical, including photocopying, recording, or any information
storage and retrieval system, without permission in writing from the publisher. Details on
how to seek permission, further information about the Publisher’s permissions policies
and our arrangements with organizations such as the Copyright Clearance Center and the
Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under
copyright by the Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research
and experience broaden our understanding, changes in research methods, professional
practices, or medical treatment may become necessary.
Practitioners and researchers may always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds, or experiments described
herein. In using such information or methods they should be mindful of their own safety
and the safety of others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or
editors, assume any liability for any injury and/or damage to persons or property as a
matter of products liability, negligence or otherwise, or from any use or operation of any
methods, products, instructions, or ideas contained in the material herein.
ISBN: 978-0-12-394803-8
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
For information on all Academic Press publications
visit our website at http://store.elsevier.com/
Acquisition Editor: Janice Audet
Editorial Project Manager: Fenton Coulthurst
Production Project Manager: Karen East and Kirsty Halterman
Designer: Mark Rogers
Typeset by TNQ Books and Journals
www.tnq.co.in
Printed and bound in United States of America
Biography
IJsbrand Kramer is a professor at the Univer-
sity 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, the UK. He did
his PhD at the University of Amsterdam, in
the Central Laboratory of Blood Transfusion
Services (Stichting Sanquin) and worked as
a postdoctoral fellow at the Hubrecht Labo-
ratory 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 Peter Tatham) and pharmacology.
Both teaching activities have been documented in textbooks: Signal Trans-
duction (three editions) and Receptor Pharmacology (CRC Press/Taylor
Francis Group, three 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 for-
mation 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 introduc-
tory course for first-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 Signaling Mechanism. He has been codirector of two Euro-
pean Programmes (Interbio and Transbio) that aimed at enhancing indus-
trial innovation in the biomedical sector in the South West European region
(SUDOE). More information about his teaching and pedagogical-research
activities can be found at www.cellbiol.net.
xiii
Preface
The third edition differs considerably from the earlier editions in that
the book is no longer separated in two parts, the first providing the nuts
and bolts of what might be termed classical signal transduction. In fact,
this classification does not really apply for two reasons. First, for students
everything is as new as the latest scientific article is for a teacher and
dividing between classical or nonclassical is not really making the subject
clearer and might even pretend that cells employ classical (important) and
not-so classical (less important) mechanisms that bring about changes in
their metabolism, gene expression, secretion rate, contraction state, and
so on. Second, with the recent structural revelations of G protein-coupled
receptor and the action of biased agonists, classical signal transduction has
suddenly lost its classical touch and has become very modern. Instead, an
introductory chapter has been added in which a number of principles are
outlined common to many signal transduction events, and these are placed
in the context of the most “Nobel”, the most classic, of all pathways: adren-
aline to glycogen phosphorylase. While the previous editions were written
by three authors and rewritten by Bastien Gomperts, so that it appeared
as written by one mind, one hand, this edition also differs in that it has
been written by one hand only (or, less poetically, typed by two hands on
a keyboard). The two “greybeards” have pulled out after publication of
the second edition and, very sadly, Bastien Gomperts has passed away
in October 2013. If, from the previous editions, you appreciate the writ-
ing style, the wit, and the anecdotes, bearing from some unusual sources,
much of the credit goes to him. He was an inspiring mentor indeed.
With a few exceptions, for instance the chapter on protein phosphatases,
each chapter now has a theme of its own, around which specific aspects
of signal transduction pathways are developed. For teaching purposes,
Table 1-1 attempts to give a short overview of each chapter’s subjects and
highlights, so that, depending on the pathway to be explored, a relevant
(suitable) context can be selected. Although there still is a gradual build-
up of the subject, where later chapters make reference to earlier chapters,
each chapter could stand on its own. Naturally, the signaling aspects
highlighted are not necessarily unique to the context in which they are
developed, but it allows teachers (and students) to tell a story rather than
just listing a sequence of signaling events (Kramer and Thomas, 2006).
As a consequence, this edition contains more on cell biology, physiology,
pathology, and immunology. By providing precise examples, embedded
in precise contexts, the book offers the possibility to integrate signaling
xv
xvi PREFACE
knowledge into the above-mentioned disciplines and, therefore, facilitates
a constructive approach to teaching (for more information, see http://www.
cellbiol.net/docs/Constructive_teachingKramer.pdf).
Again, there has been no attempt to be comprehensive and certain
important topics that well qualify for inclusion in this book, such as signals
initiated by damaged DNA or unfolded proteins, are conspicuous only by
their absence. Although the book touches the leading edges of the sub-
ject, it also endeavors to provide an elementary basis with some historical
background to all the topics covered. The “prologue” has been extended
considerably with new information about the first observations of “irrita-
bility,” a phenomenon that qualifies as “an essential element of the living”
(besides template replication and metabolism). Historical background not
only provides a broader insight into the subject and pays tribute to the
wisdom of our forebears, whose freedom of thought and sometimes ser-
endipitous discoveries in the nineteenth and early twentieth centuries led
to the creation of the modern sciences, for certain people it may also pro-
vide meaning to the numerous odd names, abbreviations, and acronyms
(collectively named symbols) that riddle the book. For unexplained sym-
bols the reader is encouraged to consult UniProt (paragraphs “function”
and “names & taxonomy”) or relevant Wikipedia articles. Besides the
chapter about intracellular calcium, the book does not reveal a good deal
of experimental techniques. A lack of time and a growing complexity of
technology are to blame. Moreover, experience tells that explaining tech-
nology is revealing for learners who already master the cellular context
and signaling events but tend to mystify matters, because of a substantial
increase in cognitive burden, when learners are still struggling with the
molecular mechanisms that drive the pathways.
In preparing the book, I have had the benefit of advice and opin-
ions from many friends and colleagues. These include (in order of their
first name) Alan Hall (New York), Alasdair Gibb (London), Bob Wein-
berg (Cambridge, USA), Bob Lefkowitz (Durham, USA), Bruno Klaholz
(Illkirch), Carsten Hoege (Dresden), Chris de Graaf (Amsterdam), Chris-
topher Glass (San Diego), David Armstrong (Durham, USA), David Strutt
(Sheffield), Filip van Petegem (Vancouver), Geerten Vuister (Leicester),
George Mosialos (Thessaloniki), Graham Dunn (London), Jean Des-
solin (Bordeaux), Jeff Saucerman (Charlottesville), Jennifer Lippincott-
Schwartz (Bethesda), Jürgen Knoblich (Vienna), Karin Rittinger (London),
Karl Matter (London), Maria Schumacher (Durham, USA), Marian Joëls
(Utrecht), Marina Gloukova (Paris), Mark Dell’Acqua (Aurora), Matthew
Gold (London), Michel Laguerre (Bordeaux), Miho Lijima (Baltimore),
Mingjie Zhang (Hong Kong), Peter van Haastert (Groningen), Purna Joshi
(Toronto), Roel Sterckx (Cambridge, UK), Romuald Nargeot (Bordeaux),
Sander van den Heuvel (Utrecht), Shiva Malek (South San Francisco),
Stuart Firestein (New York), Yohanns Bellaiche (Paris), Vadim Asharvsky
(Durham, USA), Wai Leong (Singapore), and Wei-Min Shen Los Angeles.
Special gratitude also goes to all authors, curators, Website developers, and
PREFACE xvii
technicians who contributed and continue to contribute to an increasing
number of outstanding annotated databases (UniProt, PubMed, OMIM,
UniGene, GenomeNet, HGNC, PhosphoSite, and so on) and Wikis. These
databases have become key sources of information for research as well as
education. I encourage students to go out on the web!
In acknowledgment of their contribution I offer the following quota-
tion by one of the pioneers of signal transduction (Figure 1-1; Ringer and
Murrell, 1878).
FIGURE 1-1
xviii PREFACE
Of course, the authors of this paper would themselves never have recog-
nized the expression signal transduction, and it would be a further 100 years
before it made its appearance in the biological literature. The sensations
brought about by pituri, an alkaloid that Ringer and Murrell described as
sharing some of the pharmacological properties of atropine (courage, infu-
riation, frustration, and headaches), are not dissimilar to those experienced
in the writing of this book. Indeed, they will be familiar to many students
and investigators in this and other fields of research. However, we should
not take this too far. When Ringer (1879) tested the effects of the applica-
tion of pituri on four men, he noted that it also causes drowsiness, faint-
ness, pallor, giddiness, hurried and superficial breathing, dilates the pupil,
produces general weakness with convulsive twitchings, and antagonizes
the action of muscarin on the heart. Unlike atropine, it produces sickness
and increases the salivary secretion in large doses copiously, the breathing
becomes quick and shallow, and general weakness ensues. Reading all this,
it leads one to wonder who, among their students, colleagues, and servants,
may have offered themselves up as willing, or less than willing, guinea pigs
in the furtherance of scientific research. Ringer and his friends apparently
preferred to eschew membership of the very honorable brotherhood of self-
experimenters, of which the more famous members include Sir, Humphry
Davey, who breathed nitrous oxide as well as other more noxious gases,
John Scott Haldane, who too inhaled lethal gases; and more recently Barry
Marshall, who has swallowed a culture of Helicobacter pylori to show that it
caused stomach ulcers and who with Robin Warren was awarded the Nobel
Prize in Physiology or Medicine in 2005. Another member of this fraternity,
Charles Eduard Brown-Sequard, figures prominently in “prologue” chapter.
NOTES
For web-support of this book
See the companion website: http://booksite.elsevier.com/9780123948038
For protein structural data we have made use of
The Protein Data Bank: Berman et al. (2000).
Protein structures have been generated using PyMol (education ver-
sion), a molecular visualization system on open source foundation, main-
tained and distributed by Schrodinger.
References
We have tried to provide original text sources to nearly all the state-
ments, experiments, and discoveries discussed. The main reason for this
PREFACE xix
is that we ourselves have necessarily had to extend the treatment of nearly
all the topics presented far beyond the areas of our own experience or
expertise. Thus, comprehensive lists are there to provide us with some
sort of reassurance that what we have written has not simply been con-
jured out of the air. Also, because we have made a particular feature of
presenting original historical source material by quotation, which nec-
essarily required referencing, it seemed logical also to include literature
references to modern sources as well. Thus we hope that this book may
serve as a valuable resource, in the manner of a basic literature review, for
anyone wanting to explore further.
Protein symbols (gene products)
We have named proteins according to the symbols agreed upon in the
HUGO gene nomenclature database (HGNC) (www.genenames.org).
Similar symbols have been adopted by protein databases such as UniProt.
Some of the new symbols are simply awkward, so different from conven-
tional names that they are even not recognized by scientists who made
major contributions to the field, and when they really are uncommon
alternative more conventional names are provided, but from a pedagogi-
cal point of view it is vital that students can search the web with unique
(unambiguous) symbols and find out about the relevant proteins (and
genes) themselves. And remember, certain symbols may be more familiar
to experts in the field, for students they are all the same: new and often
gruesome.
References
Kramer, I.M., Thomas, G., Spring 2006. Meeting report: teaching signal transduction. CBE
Life Sci. Educ. 5, 19–26.
Ringer, S., Murrell, W., 1878. On pituri. J. Physiol. 377–383.
Ringer, S., 1879. On the action of pituri on man. Lancet 290–291.
Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N.,
Bourne, P.E., 2000. The protein data bank. Nucleic Acids Res. 28, 235–242. http://www.
rcsb.org/pdb/.
TABLE 1-1 Contexts, pathways, subjects, and proteins/molecules elaborated in different chapters x
x
Highlights on molecules, proteins,
Title/context/main pathway Subjects and personalities
1. P rologue: Signal transduction from An account of how the term “signal transduction” • A lfred Gilman
an historical perspective entered biomedical research and how stimulus– • M artin Rodbell
response coupling, hormones, neurotransmitters, • T homas Henry Huxley
growth factors, and their receptors were brought to • S teve Grand
light • C harles Edouard Brown-Séquard
• H enry Hallett Dale
• O tto Loewi
• G eorge Oliver
• E dward Scharpey-Schäfer
• E rnest Henry Starling
• W illam Maddock Baylis
• C ONRO, a self-reconfigurable robot
• P aul Ehrlich
• J ohn Newport Langley
• F rancis Peyton Rous
• R ita Levi-Montalcini
• S tanley Cohen
• A lexis Carrel
• H oward Temin
• R enato Dulbecco
2. A n introduction to signal • S ignaling pathways serve to create symbolic • A ph(2′)-Ib, aminoglycoside-2
transduction representations of the cellular environment phosphotransferase, Escherichia coli (ancient)
Context: • F irst messengers, description of hormones, protein kinase fold, structural composition,
Adrenalin-mediated activation of growth and differentiation factors, cytokines, conserved residues, αC helix
glycogen phosphorylase in striated inflammatory mediators, vasoactive agents, • D ocking site, substrate-binding motifs in
muscle neurotransmitters MAPKinase, D motif, and DEF motif, examples
of substrates, sequence of the transcription factor
ELK1
• S ignaling in context, the signal itself is ambiguous • E dmond Fischer and Edwin Krebs, Nobel
but context, cell type, and cell condition, Laureates 1992 (protein phosphorylation,
determine the outcome glycogen phosphorylase)
• R eceptor–ligand concept, classic pharmacology, • E icosanoids, molecular composition,
different receptor types prostaglandin, prostacyclin, thromboxane,
• S ignaling mechanisms, the sequence of receptor– leukotriene, anandamide
transducer–effector–second messenger • G NAI1, Gαi subunit of heterotrimeric G-protein,
• A drenaline to glycogen phosphorylase, structural composition, conserved residues,
pioneer studies in signal transduction, detailed GTP-binding pocket, GαRAS and alpha-helical
transcription of the pathway as operated in segment
muscle • H 3F3A, histone-3.3, posttranslational
• N obel laureates associated with the adrenaline to modifications, acetylation, crotonylation,
glycogen phosphorylase pathway methylation, and phosphorylation
• W ired allostery, signal integration, and thoughtful • H RAS, monomeric G-protein, molecular
decisions structure, position of conserved residues,
• P osttranslational modifications, a broad overview mechanism of nucleotide exchange and GTP
• F eedback mechanisms, modeling of EGFR- hydrolysis, GTPase cycle, switch regions,
mediated activation of MAP-kinase farnesylation
• C ellular communication, modes of, endocrine,
paracrine, juxtacrine, synaptic, and autocrine
• P harmacology, agonist, antagonist, inverse
agonist, receptor–ligand interaction, affinity,
dose–response curve, receptor number, and
signal sensitivity
• P hosphoenolpyruvate-dependent
phosphotransferase system in bacteria
• P hosphorylation, consequences for activity and
subcellular localization of proteins, potential
phosphate donors, ATP favorite but not
exclusive
x
Continued x
i
