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 CELL
SIGNALING
principles and mechanisms

CellSig_FM.indd i 12/05/14 7:18 PM

CellSig_FM.indd ii 12/05/14 7:18 PM
 CELL
SIGNALING
principles and mechanisms

Wendell Lim
Bruce Mayer
Tony Pawson

CellSig_FM.indd iii 12/05/14 7:18 PM

 Garland Science Wendell Lim is at the University of California, San Francisco,
Vice President: Denise Schanck where he is Professor of Cellular and Molecular Pharmacology.
Senior Editor: Michael Morales The principal focus of his research is the structure and
Production Editor: Natasha Wolfe mechanism of protein interaction domains and the logic by which
Development Editor: Mary Purton these components are used to build complex cellular signaling
Editorial Assistants: Lamia Harik and Alina Yurova systems.
Copy Editor: Jo Clayton
Proofreader: Sally Huish Bruce Mayer is at the University of Connecticut Health
Illustrations and Design: Matthew McClements, Blink Studio, Ltd. Center, where he is a Professor of Genetics and Developmental
Indexer: Medical Indexing Ltd. Biology. Current work in his group focuses on characterizing
Typesetter: Thomson Digital and manipulating tyrosine kinase-mediated signal transduction
pathways.

Tony Pawson, deceased, was Senior Investigator and Director of

Research in the Department of Medical Genetics and Microbiology
© 2015 by Garland Science, Taylor & Francis Group, LLC
at the University of Toronto where his research focused on the
molecular dissection and functional significance of protein–
protein interactions in signal transduction.
Front Cover: Cover painting and chapter-opening images by the
British artist and architect Victor Pasmore (1908–1998). Used
with permission of The Victor Pasmore Estate. Copyright is with
the Estate of the Artist.

This book contains information obtained from authentic and

highly regarded sources. Every effort has been made to trace
copyright holders and to obtain their permission for the use of
copyright material. Reprinted material is quoted with permission,
and sources are indicated. A wide variety of references are
listed. Reasonable efforts have been made to publish reliable
data and information, but the author and the publisher cannot
assume responsibility for the validity of all materials or for the
consequences of their use.

All rights reserved. No part of this book covered by the copyright

hereon may be reproduced or used in any format in any form
or by any means—graphic, electronic, or mechanical, including
photocopying, recording, taping, or information storage and
retrieval systems—without permission of the publisher.

Library of Congress Cataloging-in-Publication Data

ISBN 978-0-8153-4244-1
Lim, Wendell, author.
Cell signaling: principles and mechanisms /Wendell Lim, Bruce
Published by Garland Science, Taylor & Francis Group, LLC, Mayer, Tony Pawson.
an informa business, 711 Third Avenue, New York, NY, 10017, pages cm
USA, and 3 Park Square, Milton Park, Abingdon, OX14 4RN, UK. ISBN 978-0-8153-4244-1 (paperback)
1. Cell interaction. 2. Cellular signal transduction. I. Mayer,
Bruce, author. II. Pawson, T., author. III. Title.
Printed in the United States of America QH604.2.L56 2014
571.7’4--dc23
15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 2014010851

Visit our Web site at http://www.garlandscience.com

CellSig_FM.indd iv 12/05/14 7:18 PM

 This book is dedicated to the memory of Tony Pawson (1952–2013). Tony was a
towering figure in the field of cell signaling, and he will be sorely missed. The photo
was taken at the Gerstle Park Inn in San Rafael, CA, where we often met to work on
the book under the spreading branches of this ancient live oak tree.

CellSig_FM.indd v 12/05/14 7:18 PM

CellSig_FM.indd ii 12/05/14 7:18 PM
 vii

Preface

The ability to sense one’s environment and respond to it which our understanding is growing exponentially and
is one of the most fundamental properties common to all our viewpoint is constantly changing. While the rapid
living organisms. Single-celled organisms are able to seek growth and change in this field makes writing a textbook
out nutrients, avoid toxins, and change their shape, gene on cell signaling challenging, it is also a particularly
expression, and metabolism depending on conditions. In exciting time to try to lay out the core molecular concepts
multicellular animals and plants, even more subtle and and principles that have emerged in this young field.
sophisticated interactions between cells and the out-
Memorizing the details of “who did what to whom and
side environment are needed. Individual cells are able
when” for a number of specific pathways, especially
to sense and integrate vast amounts of information and
where most of the players have similar-sounding three-
use it to make decisions about whether to grow, divide,
letter acronyms, can be a recipe for confusion. It is our
migrate, adopt a particular shape, or even die. Without
hope that by focusing on the common themes and con-
these decisions, a multicellular organism could neither
cepts that underlie all signaling pathways, students will
develop nor maintain its integrity as a coherent living
better see the beauty and logic of the system, and be able
entity. Cell signaling is everywhere we look.
to apply this understanding to any signaling problem
For most of its relatively brief history, cell signaling (or they encounter. This is particularly relevant in our era of
signal transduction, as it is often termed) was typically superabundant information where manifold details are
taught from the perspective of individual, top-down phys- readily available at a few keystrokes. We hope the book
iological stories—for example, understanding how a cell conveys the deeper principles of the subject that cannot
responds to a particular type of hormone, such as insu- be encapsulated in a Wikipedia entry.
lin or epinephrine. However, this approach has become
increasingly untenable as we attempt to understand and
explain how thousands of signaling proteins interact with ORGANIZATION OF THE BOOK
each other in vast interconnected networks. Fortunately,
The first major section of the book (Chapters 2–9) focuses
it is now apparent that diverse signaling processes are
on the molecular parts and molecular principles used
often executed by very similar sets of molecular compo-
in cell signaling. These chapters introduce the types of
nents, which in turn often interact in common network
molecular players, including catalytic domains, protein
patterns. We can now consider a more bottom-up view—
interaction domains, and receptor molecules. They also
that there are hierarchical building blocks for signaling
introduce the core currencies that are used to store and
often used in archetypical ways to achieve particular
transmit signaling information at the molecular level,
classes of cellular behaviors. The overarching theme of
including molecular conformation, interaction, localiza-
this book is that signaling is best understood by focusing
tion, modification, and degradation. In this section, we
on the common design principles, components, and logic
hope the reader will gain a deep understanding of how
that drive all signaling.
these molecular players can be used to conditionally mod-
We have written this book embracing this new, bottom- ulate the core information-storage currencies. The second
up view of cell signaling, and focus on the principles and major section of the book (Chapters 10–12) moves gradu-
mechanisms that underlie many, if not all, cell signal- ally toward understanding cell signaling systems—how
ing processes. Therefore, we emphasize the commonality these components and currencies can be used to make
of underlying mechanisms rather than the diversity of more complex devices and networks that are capable of
individual examples. As we enter the postgenomic era, executing higher-level physiological decisions. The last
research is shifting away from the discovery of specific chapter of this section (Chapter 12) is organized as a set of
signaling molecules and toward understanding how such exploratory, visual panels. Here, we return to a more clas-
cellular components can execute nuanced, complex regu- sical view of signaling—focusing on four physiologically
latory behaviors. Understanding how simple molecules important pathways (vision, mitogen response, the cell
specifically interact to form a system with emergent cycle, and T cell activation)—and describe their molecu-
response properties is very much at the heart of cellular lar components from top to bottom. We attempt to illus-
signaling, as is understanding how such a diversity of trate how the components discussed in previous sections
response behaviors has evolved. Signaling is a field in of the book are used to solve key physiological problems in

CellSig_FM.indd vii 12/05/14 7:18 PM

 viii Preface

these model pathways. The goal of this unique chapter is but rather integrates exploratory questions throughout
to integrate a top-down physiological perspective with a each panel set.
bottom-up perspective of central principles and molecular
We also include a short list of references at the end of
components. Finally, the last chapter of the book (Chap-
the chapters. The intent is to provide a starting point for
ter 13) is a compendium of experimental methods and
readers who wish to delve more deeply into the topics
approaches used to study cell signaling. It provides an
covered. These references are by no means comprehen-
overview of “how we know” what we know and of impor-
sive, and in a field as rapidly moving as cell signaling,
tant tools of the trade.
it would be impossible to cover fully the most recent
Although our aim in organizing the book is to provide developments. Therefore we sincerely apologize to the
a conceptual framework for understanding signaling many valued colleagues whose publications deserved to
mechanisms, we understand that some readers may also be included, but were omitted due to space constraints or
wish to use it to provide an introduction to specific sig- inadvertent oversight.
naling pathways. For this reason, we use many specific
examples throughout the book (mostly but not exclusive-
ly from multicellular animals) to illustrate the broader
STUDENT AND INSTRUCTOR
principles. In this way, most major signaling pathways RESOURCES
and families of signaling molecules are explained and
Every copy of the book includes a two-sided “Signal
illustrated in some detail. However, we imagine that
Transduction Pathways” poster created by Cell Signal-
many instructors using this book may choose to supple-
ing Technologies®. The poster details forty important
ment it with readings selected from recent experimental
signaling pathways.
papers, in order to provide greater depth in specific areas
of interest. Online resources for students and instructors can be
found at www.garlandscience.com/cellsignaling.
The end of each chapter includes a set of study questions.
These questions are designed to encourage students to For qualified instructors:
think more concretely about the concepts covered in
each chapter, to extract and synthesize this informa- • Artwork in JPEG and PowerPoint® formats
tion in new ways, and to think about signaling from For students:
an experimental perspective. Some questions have one
clear answer, whereas others are more open-ended and • Online flashcards and glossary
have multiple possible answers. Answers to the ques-
• Answers to end-of-chapter questions
tions are available online from the publisher’s Web site.
Chapter 12 does not contain end-of-chapter questions, • PDF of “Signal Transduction Pathways”

CellSig_FM.indd viii 12/05/14 7:18 PM

 ix

Acknowledgments
This book is the product of nearly a decade of thinking, prod- We would also like to thank the many scientists who made a
ding, procrastination, and hard work. It owes its inception to special effort to provide us with high-resolution figures for the
Miranda Robertson, who was our first editor, and originally book, including Susumu Antoku, Jonathon Ditlev, Vsevolod V.
proposed a cell signaling textbook as part of the New Science Gurevich, Mark Hollywood, Evi Kostenis, Marco Magalhaes,
Press “Primer” series. Miranda recruited and cajoled this Michiyuki Matsuda, Holger Stark, and Yi Wu.
team of authors and guided them until the “Primer” project
Through these past several years, much of the writing and
was discontinued. Without Miranda’s keen insight and shop-
discussion occurred at retreats held at the Gerstle Park Inn,
ping bags full of ginger biscuits, this book would never have
San Rafael, California, and we thank Jim and Judy Dowling
taken flight. At that point, the project was brought to Garland
for their warm hospitality and delicious omelets. We would
Science thanks to Denise Schanck and Adam Sendroff. Here,
also like to thank the current owners, Gail S. Jones and David
our second editor, Janet Foltin, deftly shepherded us through
W. Pettus, for allowing us to take the dedication photograph
this transition and the writing of the core chapters. Finally,
at their beautiful home. Thanks also to Mary Collins for wel-
our last editor, Mike Morales, took over the immense chal-
coming us into her San Francisco home for writing sessions,
lenge of pulling us over the finish line and keeping us on task.
and for supplying us with delicious scones and biscotti. This
We would also like to thank Natasha Wolfe, our production
book also owes much of its inception to discussions held at
editor, for guiding us through the copyediting and typeset-
the FEBS Protein Modules meeting at the Hotel Veronika in
ting processes. We are indebted to Mary Purton, our devel-
Seefeld im Tirol, Austria, where the authors would gather
opmental editor, who read, edited, and formatted every word
every other year to meet with our wonderful colleagues.
of the book. Special thanks for keeping track of constantly
shifting figures while we rearranged the order of chapters. The art on the cover of this book and chapter introductions
Our illustrator, Matt McClements, has been with us since the is by the British artist, Victor Pasmore (1908–1998). W.L.
beginning, and has been invaluable in translating our ideas discovered Pasmore’s paintings and prints while wander-
to pictures, while at the same time developing a coherent and ing through Tate Modern in London, and realized how his
consistent style for the book that fits perfectly with its con- abstract but organic forms matched the grace and magic of
ceptual organization. We also thank Kenneth Xavier Probst signaling molecules. We are grateful to the Estate of Victor
who generated the molecular structure images in the book, Pasmore, especially the photographer John Pasmore, and
along with Lore Leighton and Tiago Barros. Many thanks their representatives at the Marlborough Gallery, for grant-
to other Garland Science staff that worked on this project, ing us permission to use these remarkable images.
including Monica Toledo, Alina Yurova, and Lamia Harik, as WAL: I am deeply grateful to my wife, Karen Earle-Lim, and
well as Joanna Miles from New Science Press. my children, Emilia, Nadia, and Jasper, for their constant love
We also want to thank Jesse Zalatan and Brian Yeh, who and support, and their patience in allowing me to undertake
contributed to several chapters in the book, as well as col- this important project. I am also grateful to my parents, Ramon
leagues who read chapters at various stages, including Steve and Victoria Lim, for their encouragement and support. I would
Harrison, Henry Bourne, Jim Ferrell, David Foster, David also like to thank my mentors, Jeremy Knowles, Bob Sauer,
Morgan, Chao Tang, and Art Weiss. We are grateful for the and Fred Richards, as well as the many members of my labora-
instructors and content experts who read draft chapters tory, who have consistently filled my life with interesting ideas.
of the manuscript and provided detailed, formal reviews: BJM: I will always be thankful for my wife, Rita Malenczyk,
Johannes L. Bos, University Medical Center Utrecht; who has been unfailingly supportive throughout this seem-
Andrew Bradford, University of Colorado School of Medicine; ingly interminable project, despite a busy career of her own
Adrienne D. Cox, The University of North Carolina at Chapel and three growing boys at home. I am also grateful for the
Hill; Madhusudan Dey, University of Wisconsin, Milwau- many colleagues and members of my lab who helped when
kee; Julian Downward, London Research Institute of Cancer needed and didn’t complain when The Book pushed other
Research UK; Yanlin Guo, The University of Southern Mis- obligations aside. And finally, I owe an enormous debt to Jim
sissippi; Tony Hunter, Salk Institute; Do-Hyung Kim, Univer- Donady, who introduced me to the sheer joy of research in
sity of Minnesota; Low Boon Chuan, National University of biology, and especially to Saburo Hanafusa and David Bal-
Singapore; Shigeki Miyamoto, University of Wisconsin, Madi- timore, who presided over the wonderful playpens where I
son; and Henry Hamilton Roehl, The University of Sheffield. found my love for cell signaling.

CellSig_FM.indd ix 12/05/14 7:18 PM

 x

Brief Contents

Chapter 1: Introduction to Cell Signaling 1

Chapter 2: Principles and Mechanisms of Protein Interactions 21

Chapter 3: Signaling Enzymes and Their Allosteric Regulation 43

Chapter 4: Role of Post-Translational Modifications in Signaling 85

Chapter 5: Subcellular Localization of Signaling Molecules 115

Chapter 6: Second Messengers: Small Signaling Mediators 135

Chapter 7: Membranes, Lipids, and Enzymes That Modify Them 155

Chapter 8: Information Transfer Across the Membrane 177

Chapter 9: Regulated Protein Degradation 217

Chapter 10: The Modular Architecture and Evolution of Signaling Proteins 243

Chapter 11: Information Processing by Signaling Devices and Networks 275

Chapter 12: How Cells Make Decisions 305

Chapter 13: Methods for Studying Signaling Proteins and Networks 345

Glossary 375

Index 385

CellSig_FM.indd x 12/05/14 7:18 PM

 xi

Detailed Contents

Chapter 1 The affinity and specificity of an interaction

Introduction to Cell Signaling 1 determine how likely it is to occur in the cell 24
WHAT IS CELL SIGNALING? 1 The strength of a binding interaction is defined
by the dissociation constant (Kd) 25
All cells have the ability to respond to their environment 2
The dissociation constant is related to the
Cells must perceive and respond to a wide range of signals 3
binding energy of the interaction 27
Signaling systems need to solve a number of
The dissociation constant is also related
common problems 4
to rates of binding and dissociation 28
THE FUNDAMENTAL ROLE OF SIGNALING
PROTEIN INTERACTIONS IN THEIR
IN BIOLOGICAL PROCESSES 6
CELLULAR AND MOLECULAR CONTEXT 30
Work in many different fields converged to reveal the
The apparent dissociation constant can be
underlying mechanisms of signaling 6
strongly affected by the local cellular
Despite the diversity of signaling pathways and environment and other binding partners 30
mechanisms, fundamental commonalities have emerged 7
Ideal affinity and specificity depends on biological
Signaling must operate at multiple scales in space and time 9 function and ligand concentrations 31
THE MOLECULAR CURRENCIES OF There are functional constraints on
INFORMATION PROCESSING 11 interaction affinities and specificities 32
Information is transferred by changes in Interaction affinity and specificity can be
the state of proteins 11 independently modulated 34
There is a limited number of ways in Cooperativity involves the coupled binding of
which the state of proteins can change 12 multiple ligands 35
Most changes in state involve simultaneous Diverse molecular mechanisms underlie
changes in several different currencies 14 cooperativity 36
LINKING SIGNALING NODES INTO Cooperative binding has a variety of
PATHWAYS AND NETWORKS 15 functional consequences 36
Information transfer involves linking different Protein assemblies differ in their stability
changes of state together 15 and homogeneity 37
Multiple state changes are linked together to Summary 38
generate pathways and networks 16 Questions 38
Cellular information-processing systems References 40
have a hierarchical architecture 17
Summary 18 Chapter 3
Signaling Enzymes and Their Allosteric
Questions 18
Regulation 43
References 19
PRINCIPLES OF ENZYME CATALYSIS 44
Chapter 2 Enzymes have a number of properties that make
Principles and Mechanisms of them useful for transmitting signals in the cell 44
Protein Interactions 21 Enzymes use a variety of mechanisms to
PROPERTIES OF PROTEIN–PROTEIN enhance the rate of chemical reactions 45
INTERACTIONS 22 Enzymes can drive reactions in one direction
by energetic coupling 46
Changes in protein binding have both direct
and indirect functional consequences 22 ALLOSTERIC CONFORMATIONAL CHANGES 47
Protein binding can be mediated by broad Conformational flexibility of proteins enables
interaction surfaces or by short, linear peptides 23 allosteric control 47

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 xii Detailed Contents

Signaling proteins employ diverse classes of Questions 80

conformational rearrangements 48 References 82
PROTEIN PHOSPHORYLATION AS
A REGULATORY MECHANISM 49
Chapter 4
Role of Post-Translational
Phosphorylation can act as a regulatory mark 49
Modifications in Signaling 85
Phosphorylation can either disrupt or
induce protein structure 50 THE LOGIC OF POST-TRANSLATIONAL
REGULATION 85
PROTEIN KINASES 52
Proteins can be covalently modified by
The structure and catalytic mechanism of protein
the addition of simple functional groups 86
kinases are conserved 52
Proteins can also be covalently modified by the
The activation loop and C-helix are conserved
addition of sugars, lipids, and even proteins 87
molecular levers that conformationally
control kinase activity 54 Post-translational modifications can alter
protein structure, localization, and stability 88
Insulin receptor kinase activity is controlled
via activation-loop phosphorylation 54 Post-translational control machinery often
works as part of “writer/eraser/reader” systems 90
Phosphorylation mediates long-range
conformational regulation of Src family kinases 55 Post-translational modifications allow very rapid
signaling and transmission of spatial information 92
Multiple binding interactions regulate
protein kinase substrate specificity 56 INTERPLAY BETWEEN POST-TRANSLATIONAL
Protein kinases can be divided into nine families 58 MODIFICATIONS 92
PROTEIN PHOSPHATASES 60 A post-translational modification can
promote or antagonize other modifications 93
Serine/threonine phosphatases are metalloenzymes 60
p53 is tightly regulated by a wide variety
Most tyrosine phosphatases utilize a catalytic
of post-translational modifications 95
cysteine residue 62
The level and activity of p53 are regulated
Tyrosine phosphatases are regulated by modular
by ubiquitylation and acetylation 96
domains while serine/threonine phosphatases
often associate with regulatory accessory subunits 64 Additional modifications further fine-tune p53 activity 96

G PROTEIN SIGNALING 65 PROTEIN PHOSPHORYLATION 97

G proteins are conformational switches Phosphorylation is often coupled with protein
controlled by two opposing enzymes 65 interactions 97
The presence of the GTP γ-phosphate determines Kinases and phosphatases vary in their
the structure of G protein switch I and II regions 66 substrate specificity 99
There are two major classes of signaling G proteins 67 Multiple phosphorylation of proteins can
Subfamilies of small G proteins regulate arise by different mechanisms 100
diverse biological functions 67 Histidine and other amino acids can be
Many upstream receptors feed into a small set of phosphorylated, especially in prokaryotes 101
common heterotrimeric G proteins 68 Two-component systems and histidine
phosphorylation are also present in eukaryotes 103
REGULATORY ENZYMES FOR G PROTEIN
SIGNALING 70 ADDITION OF UBIQUITIN AND RELATED
G-protein-coupled receptors act as GEFs PROTEINS 104
for heterotrimeric G proteins 71 Specialized enzymes mediate the addition
Distinct GEF and GAP domains regulate and removal of ubiquitin 104
specific small G protein families 71 E3 ubiquitin ligases determine which proteins
GEFs catalyze GDP/GTP exchange by will be ubiquitylated 105
deforming the nucleotide-binding pocket 73 Ubiquitin-binding domains read ubiquitin-mediated
GAPs order the catalytic machinery for hydrolysis 74 signals in diverse cellular activities 106
Regulators of G protein signaling (RGS) proteins HISTONE ACETYLATION AND METHYLATION 107
act as GAPs for heterotrimeric G proteins 75 Chromatin structure is regulated by post-
Additional mechanisms are used to translational modification of histones
fine-tune the activity of G proteins 75 and associated proteins 108
SIGNALING ENZYME CASCADES 75 Two writer/eraser/reader systems are based on
The three-tiered MAP kinase cascade forms protein methylation and acetylation 109
a signaling module in all eukaryotes 76 Chromatin modification in transcription is dynamic
Scaffold proteins often organize MAPK cascades 77 and leads to highly cooperative interactions 110
G protein activity can also be regulated by Summary 112
signaling cascades 79 Questions 113
Summary 80 References 114

CellSig_FM.indd xii 12/05/14 7:18 PM

 Detailed Contents xiii

Chapter 5 Small signaling mediators are controlled by an

Subcellular Localization of Signaling interplay of their production and elimination 136
Molecules 115 Small signaling mediators exert their effects
by binding downstream effectors 136
LOCALIZATION AS A SIGNALING CURRENCY 115
Small signaling mediators can lead to fast,
Changes in subcellular localization can
distant, and amplified signal transmission 137
transmit information 116
Small signaling mediators can generate
Subcellular localization can be regulated
complex temporal and spatial patterns 138
by a variety of mechanisms 117
CONTROL OF NUCLEAR LOCALIZATION 117 CLASSES OF SMALL SIGNALING MEDIATORS 139
Short, modular peptide motifs direct nuclear Small signaling mediators have a wide range of
import and export 118 physical properties 140
Nuclear transport is controlled by shuttle The cyclic nucleotides cAMP and cGMP are
proteins and the G protein Ran 118 produced by cyclase enzymes and destroyed
by phosphodiesterases 140
Phosphorylation of transcription factor Pho4
regulates nuclear import and export 119 Cyclic nucleotides regulate diverse cellular activities 141
Nuclear import of STATs is regulated by The regulatory (R) subunit of protein kinase
phosphorylation and conformational change 120 A is a conformational sensor of cAMP binding 142
Localization of MAP kinases is regulated Some small signaling mediators are
by association with nuclear and cytosolic derived from membrane lipids 143
binding partners 121 PLC generates two signaling mediators,
Notch nuclear localization is regulated by IP3 and DAG 144
proteolytic cleavage 122 Activation of protein kinase C is regulated
by IP3 and DAG 144
CONTROL OF MEMBRANE LOCALIZATION 122
Proteins can span the membrane or be CALCIUM SIGNALING 145
associated with it peripherally 122 Activation of Ca2+ channels is a common
Proteins can be covalently modified with means of regulation 146
lipids after translation 123 Ca2+ influx is rapid and local 147
Modular lipid-binding domains are important for Calmodulin is a conformational sensor of
regulated association of proteins with membranes 124 intracellular calcium levels 147
Some lipid-modified proteins can reversibly Signaling can lead to propagating Ca2+ waves 148
associate with membranes 125 SPECIFICITY AND REGULATION 149
Coupling effector protein activation to Scaffold proteins can increase input and output
membrane recruitment is a common theme specificity of small-molecule signaling 150
in signaling 126 AKAP scaffold proteins can also regulate dynamics
Akt kinase is regulated by membrane recruitment of cAMP signaling 150
and phosphorylation 126
Summary 152
MODULATION OF SIGNALING BY Questions 152
MEMBRANE TRAFFICKING 127
References 153
Proteins can be internalized by a variety
of mechanisms 127 Chapter 7
Internalization of receptors can modulate Membranes, Lipids, and Enzymes
signal transduction 128 That Modify Them 155
TGFβ signaling output depends on the
BIOLOGICAL MEMBRANES AND THEIR
mechanism of receptor internalization 129
PROPERTIES 155
Retrograde signaling allows effects distant
Biological membranes consist of a variety of polar lipids 156
from the site of ligand binding 130
Structural properties of membrane lipids favor
Ras isoforms in distinct subcellular locations
the formation of bilayers 157
have different signaling outputs 130
The composition of the membrane determines
Summary 132 its physical properties 158
Questions 132 There are fundamental differences between
References 132 biochemistry in solution and on the membrane 160
LIPID-MODIFYING ENZYMES USED
Chapter 6 IN SIGNALING 161
Second Messengers: Small Signaling Cleavage of membrane lipids by phospholipases
Mediators 135 generates a variety of bioactive products 161
PROPERTIES OF SMALL SIGNALING A variety of lipid kinases and phosphatases
MEDIATORS 135 are involved in signaling 163

CellSig_FM.indd xiii 12/05/14 7:18 PM

 xiv Detailed Contents

EXAMPLES OF MAJOR LIPID SIGNALING The voltage-gated potassium channel provides clues
PATHWAYS 164 to mechanisms of gating and ion specificity 200
Phosphoinositides can serve as membrane binding Ligand-gated ion channels play a central
sites and as a source of signaling mediators 164 role in neurotransmission 202
Phosphoinositide species provide a set of membrane MEMBRANE-PERMEABLE SIGNALING 204
binding signals 166 Nitric oxide mediates short-range signaling
Phospholipase D generates the important in the vascular system 204
signaling mediator, phosphatidic acid (PA) 168 O2 binding regulates the response to hypoxia 205
Phospholipase D plays a role in mTOR signaling 169 The receptors for steroid hormones are
The metabolism of sphingomyelin generates transcription factors 206
a host of signaling mediators 170
DOWN-REGULATION OF RECEPTOR SIGNALING 208
Phospholipase A2 generates the precursor for
Ubiquitylation regulates the endocytosis, recycling,
a family of potent inflammatory mediators 172
and degradation of cell-surface receptors 209
Summary 174
G protein coupled receptors are desensitized
Questions 174 by phosphorylation and adaptor binding 211
References 174 Summary 213
Chapter 8 Questions 213
Information Transfer Across the Membrane 177 References 215
PRINCIPLES OF TRANSMEMBRANE SIGNALING 177 Chapter 9
The cell must process and respond to a Regulated Protein Degradation 217
diversity of environmental cues 178
GENERAL PROPERTIES AND EXAMPLES OF
Three general strategies are used to SIGNAL-REGULATED PROTEOLYSIS 217
transfer information across the membrane 179
Proteases are a diverse group of enzymes 218
Many drugs target receptors 180
Blood coagulation is regulated by a
TRANSDUCTION STRATEGIES USED BY cascade of proteases 219
TRANSMEMBRANE RECEPTORS 180 Regulated proteolysis by metalloproteases
Receptors with multiple membrane-spanning can generate signaling molecules and
segments undergo conformational changes alter the extracellular environment 220
upon ligand binding 180 ADAMs regulate signaling pathways
Receptors with a single membrane-spanning segment by cleaving membrane-associated proteins 221
form higher-order assemblies upon ligand binding 181 MMPs participate in remodeling the
Receptor clustering confers advantages for extracellular environment 222
signal propagation 182 Proteolysis activates the thrombin receptor 223
G-PROTEIN-COUPLED RECEPTORS 184 Regulated intramembrane proteolysis (RIP) is
G-protein-coupled receptors have intrinsic an essential step in signaling by some receptors 224
enzymatic activity 184 UBIQUITIN AND THE PROTEASOME
Signaling by GPCRs can be very fast and DEGRADATION PATHWAY 225
lead to enormous signal amplification 186 The proteasome is a specialized molecular machine
TRANSMEMBRANE RECEPTORS ASSOCIATED that degrades intracellular proteins 225
WITH ENZYMATIC ACTIVITY 186 The cell cycle is controlled by two large
Receptor tyrosine kinases control important cell fate ubiquitin-conjugating complexes 226
decisions in multicellular eukaryotes 186 SCF recognizes specific phosphorylated proteins,
TGFβ receptors are serine/threonine targeting them for destruction 227
kinases that activate transcription factors 187 Two APC species act at distinct points in
Some receptors have intrinsic protein the cell cycle 228
phosphatase or guanylyl cyclase activity 189 NF-κB is controlled by regulated
Noncovalent coupling of receptors to protein degradation of its inhibitor 230
kinases is a common signaling strategy 189 CASPASE-MEDIATED CELL DEATH PATHWAYS 232
Some receptors use complex activation Apoptosis is an orderly and highly regulated form
pathways that involve both kinase activation of cell death 232
and proteolytic processing 193 The activity of caspases is tightly regulated 233
Wnt and Hedgehog are two important The extrinsic pathway links cell death receptors
signaling pathways in development 194 to caspase activation 235
A variety of receptors couple to proteolytic activities 197 Mitochondria orchestrate the intrinsic cell death
GATED CHANNELS 199 pathway 238
Gated channels share a similar overall structure 199 Summary 241

CellSig_FM.indd xiv 12/05/14 7:18 PM

 Detailed Contents xv

Questions 241 Certain plant protein kinases are regulated by

References 242 modular light-gated domains 267
Regulation of the neutrophil NADPH oxidase
Chapter 10 by modular interactions 268
The Modular Architecture and CREATING NEW FUNCTIONS THROUGH
Evolution of Signaling Proteins 243 DOMAIN RECOMBINATION 269
MODULAR PROTEIN DOMAINS 244 Some modular domain rearrangements can lead
Protein domains usually have a globular structure 244 to cancer 269
Bioinformatic approaches can identify protein domains 244 Modules can be recombined experimentally
Domains can be composed of several smaller repeats 245 to engineer new signaling behaviors 270
Protein domains often act as recognition modules 246 Summary 272
INTERACTION DOMAINS THAT RECOGNIZE Questions 272
POST-TRANSLATIONAL MODIFICATIONS 249 References 273
SH2 domains bind phosphotyrosine-containing sites 249
Chapter 11
Some SH2 domains are elements of larger binding Information Processing by Signaling
structures 252
Devices and Networks 275
Several different types of interaction domains
recognize phosphotyrosine 252 SIGNALING SYSTEMS AS INFORMATION-
Multiple domains recognize motifs phosphorylated
PROCESSING DEVICES 276
on serine/threonine 254 Signaling devices can be considered as state machines 276
14-3-3 proteins recognize specific phosphoserine/ Signaling devices are organized in a hierarchical
phosphothreonine motifs 254 fashion 277
Interaction domains recognize acetylated and Signaling devices face a variety of challenges in
methylated sites 255 input detection 278
Ubiquitylation regulates protein–protein interactions 256 Proteins can function as simple signaling devices 279

INTERACTION DOMAINS THAT RECOGNIZE INTEGRATING MULTIPLE SIGNALING INPUTS 281

UNMODIFIED PEPTIDE MOTIFS OR PROTEINS 257 Logic gates process information from multiple inputs 281
Proline-rich sequences are favorable Simple peptide motifs can integrate multiple
recognition motifs 257 post-translational modification inputs 282
SH3 domains bind proline-rich motifs 258 Cyclin-dependent kinase is an allosteric
PDZ domains recognize C-terminal peptide motifs 258 signal-integrating device 283
Protein interaction domains can form dimers Modular signaling proteins can integrate multiple
or oligomers 259 inputs 284
Transcriptional promoters can integrate input from
INTERACTION DOMAINS THAT RECOGNIZE
multiple signaling pathways 285
PHOSPHOLIPIDS 260
PH domains form a major class of phosphoinositide- RESPONDING TO THE STRENGTH OR
binding domains 260 DURATION OF AN INPUT 286
FYVE domains are phospholipid-binding domains Signaling systems can respond to signal amplitude
found in endocytic proteins 261 in a graded or a digital manner 288
BAR domains bind and stabilize curved membranes 262 An enzyme can behave as a switch through
cooperativity 289
CREATING COMPLEX FUNCTIONS BY
Networks can also yield switchlike activation 290
COMBINING INTERACTION DOMAINS 262
Signaling systems can distinguish between
Recombination of domains occurs through evolution 262 transient and sustained input 292
Combinations of interaction domains or motifs
can be used as a scaffold for the assembly of MODIFYING THE STRENGTH OR DURATION OF
signaling complexes 263 OUTPUT 294
Scaffold proteins containing PDZ domains organize Signaling pathways often amplify signals as they
cell–cell signaling complexes such as the are transmitted 294
postsynaptic density 264 Negative feedback allows fine-tuning of output 294
Proteins with multiple phosphotyrosine motifs Adaptation allows cells to control output duration 296
function as dynamically regulated scaffolds 265 Feedback can cause output levels to oscillate
between two stable states 299
RECOMBINING INTERACTION AND CATALYTIC
DOMAINS TO BUILD COMPLEX ALLOSTERIC Bistable responses also underlie more permanent
outputs 301
SWITCH PROTEINS 266
Many signaling enzymes are allosteric switches 266 Summary 303
14-3-3 Protein regulates the Raf kinase by Questions 303
coordinately binding two phosphorylation sites 267 References 303

CellSig_FM.indd xv 12/05/14 7:18 PM

 xvi Detailed Contents

Chapter 12 Chapter 13
How Cells Make Decisions 305 Methods for Studying Signaling Proteins
VERTEBRATE VISION 307 and Networks 345
Organ: vertebrate eye 308 BIOCHEMICAL AND BIOPHYSICAL ANALYSIS
Cell: photoreceptor cell 308 OF PROTEINS 345
Molecular Network: visual transduction cascade 309 Analytical methods can determine quantitative
How does the photoreceptor cell detect light binding parameters 345
and convert it to a biochemical signal? 310 Michaelis–Menten analysis provides a way to
How is the photoreceptor cell able to detect low measure the catalytic power of enzymes 347
light, even a single photon? 311 Methods to determine and analyze protein
How can the response be so rapid? 312 conformation are central to the study
of signaling 349
How does the photoreceptor cell reset itself to
enable detection of further changes in light? 312 X-ray crystallography provides high-resolution
protein structures 352
Summary 314
Nuclear magnetic resonance (NMR) can reveal
References 314 the dynamic structure of small proteins 353
PDGF SIGNALING 315 Electron microscopy can map the shape of very
Tissue: process of wound healing 316 large protein complexes 353
Cell: fibroblast response to wounding Specialized spectroscopic methods can be used to
& platelet activation 316 study protein dynamics 354
Molecular Network: control of fibroblast proliferation 317 MAPPING PROTEIN INTERACTIONS
How do fibroblasts detect the local occurrence AND LOCALIZATION 355
of a wound? 318 Interacting proteins can be identified by
How are PDGF signals propagated within the cell isolating protein complexes from cell extracts 355
to generate outputs such as cell proliferation? 319 Binding partners can be identified by screening
How is misactivation of the proliferation large libraries of genes 356
response prevented? 320 Direct protein–protein interactions can be detected
How is the proliferative response terminated? 321 by solid-phase screening 357
Summary 322 Fluorescent protein tags are used to locate and
track proteins in living cells 357
References 322
Protein–protein interactions can be visualized
THE CELL CYCLE 323 directly in living cells 359
Cell: distinct phases of the cell cycle 324
METHODS TO PERTURB CELL SIGNALING
Molecular Network: cyclin-dependent kinase (Cdk) NETWORKS AND MONITOR CELLULAR
is a central switch whose activity is modulated
RESPONSES 360
by the different cyclins 325
Genetic and pharmacological methods can be used
How are sharp and commited transitions between
to perturb networks 361
cell cycle phases achieved? 326
Chemical dimerizers and optogenetic proteins provide a
How does the cell cycle ensure that each transition
dynamic way to artificially activate pathways 362
proceeds only under appropriate conditions? 329
cDNA microarrays and high-throughput
Summary 331 sequencing are used to monitor the transcriptional
References 331 state of a cell 363
T CELL SIGNALING 333 Modification-specific antibodies provide a method
Organism: launching the adaptive immune response 334 to track post-translational changes 364
Cell: engagement of T cell and antigen presenting cell 335 Mass spectrometry is the workhorse for identification
of proteins and their modifications 366
Molecular Network: T cell receptor (TCR)
signaling network 336 Live-cell time-lapse microscopy provides a way to
track the dynamics of single-cell responses 368
How does the T cell receptor transmit signals
after peptide/MHC recognition? 338 Biosensors allow signaling activity to be monitored
in living cells 369
How does the T cell prevent misactivation? 339
Flow cytometry provides a method to analyze rapidly
How does the T cell launch a robust response
single-cell responses 371
when stimulated by as few as ten antigenic
peptide complexes? 340 Questions 372
How might the T cell discriminate between References 373
antigenic and non-antigenic peptides? 342
Glossary 375
Summary 344
References 344 Index 385

CellSig_FM.indd xvi 12/05/14 7:18 PM

 1

Introduction to
Cell Signaling

All living cells perceive signals from the outside environment and adjust
1
their behavior accordingly. If you think back to the earliest living cells, it
is easy to imagine the incredible pressure they were under to evolve the
ability to sense features of the environment and to change in response to
these signals. The ability to sense and move toward nutrients, or to sense
and avoid stresses and toxins, would give a unicellular organism a huge
competitive advantage. This ability to respond to environmental cues is
important for single cells, but it is also absolutely essential for the normal
development and functioning of multicellular organisms, which depend
on a continuous and extensive exchange of information to coordinate the
activities of many individual cells. Furthermore, when this cellular com-
munication goes awry, it can result in diseases such as cancer. In this
chapter, we will introduce the basic principles of cell signaling and the
molecular mechanisms that underlie it.

What Is Cell Signaling?

Cells are the smallest fundamental units of life. Part of what makes
them so distinctly “living” is their remarkable ability to sense stimuli
and to respond to them in a dynamic manner. This ability of cells to
detect or receive information and process it to make decisions can also
be considered from the broader perspective of information processing.
Here we can draw analogies to the engineering and design principles
of other, more familiar information-processing systems, such as human-
made electronic devices. It is this interface between the unique proper-
ties of living systems and the more universal properties of any system
that processes information that makes the study of cellular signaling
mechanisms so compelling.

CellSig ch01.indd 1 5/20/14 4:15 PM

 2 Chapter 1 Introduction to Cell Signaling

All cells have the ability to respond to their environment

While biologists and philosophers may not all agree on the precise defini-
tion of life, most definitions include a number of common properties, such
as autonomy, the ability to generate energy, and the ability to reproduce.
One of these common properties is adaptability—the ability to respond
to changes in the environment. We all understand that one way to test
whether a thing is animate or inanimate, or living or dead, is to poke it
and see if it responds.

Single-celled organisms display the ability to detect diverse molecular

species and stresses in their environment, and are able to change aspects
of their gene expression, growth, structure, and metabolism in response,
usually to improve their ability to survive under changing conditions.
With the emergence of multicellular organisms, individual cells within
the organism evolved the highly specialized ability to sense specific sig-
nals transmitted from other cells in the organism, allowing for extraor-
dinary levels of communication within the organism. The coordinated
regulation of growth, death, morphology, and metabolism is absolutely
essential for many individual cells to function in concert as an integrated
organism. Moreover, cells have the ability to monitor aspects of their own
internal state, and to respond in a self-correcting way—the foundation of
cellular homeostasis and repair. Thus, cell signaling, which encompasses
the study of this wide range of stimulus–­response behaviors observed in
cells, is central to all of biology.

Today, as our knowledge of biological systems increases rapidly, we have

begun to view cell signaling from the perspective of a more general
question: how do cells process information? How a cell receives diverse
signaling inputs, processes and integrates these signals, and converts
them into responses is in many ways analogous to how other systems, at
widely varying scales, process information. We can think about informa-
Figure 1.1 tion processing and storage in the cell, just as we focus on these concepts
Cell signaling systems process when we consider a brain or a computer (Figure 1.1a). At the level of the
information. (a) The role of cell signaling organism, for example, we can marvel at the ability of an athlete to detect
systems is to receive input from the the movement of a ball, calculate its trajectory, and mount an effective
environment and, on the basis of that response to intercept it that involves the coordinated action of hundreds
input, generate an appropriate output of different muscles, all within a fraction of a second. Individual cells per-
response. Information processing performed form similarly remarkable feats, such as detecting the presence of just a
by the cell is conceptually similar to that few specific molecules in the outside environment, and responding by set-
of other, familiar information-processing
ting in motion elaborate cellular programs that culminate in behaviors
systems, such as the brain or a computer.
such as proliferation, directed migration, or cell death. At each of these
(b) Cellular information processing must
be accomplished by a densely packed scales, a common series of challenges must be overcome. Just a few exam-
and diverse collection of biomolecules. ples include detecting, amplifying, and robustly responding to a faint
(b, Adapted from D. S. Goodsell, Trends incoming signal; integrating and responding coherently to diverse and
Biochem. Sci. 16: 203–206, 1991. With contradictory signals; and adapting to the strength or duration of a sig-
permission from Elsevier.) nal and shutting down the response when appropriate. These represent

(b)
(a)
INPUTS

decision-making system

OUTPUTS

Cell Signaling | chapter 01 | figure 01

CellSig ch01.indd 2 5/20/14 4:15 PM

 What Is Cell Signaling? 3

universal information-processing tasks that a cell or an organism must

be able to perform.

In this book, we will focus on information processing by the smallest

unit of life, the cell. It is particularly interesting to consider how such
tasks are accomplished by the molecules that make up a cell. Unlike the
tidy systems of wires, transistors, and other components that make up
human-made signaling devices like mobile phones or computers, the cel-
lular signal-processing machinery consists of a densely packed mixture of
rapidly diffusing proteins, lipids, nucleic acids, and other biomolecules, all
surrounded by a water-impermeable membrane (Figure 1.1b). How this
genetically encoded set of molecules can perform complex information-
processing behaviors is one of the most exciting and fundamental ques-
tions in modern biology.

Cells must perceive and respond to a wide range of signals

To get a better sense of the scope of the challenges faced by cellular sig-
naling systems, we will briefly consider the types of inputs to which they
must react. Some of these inputs, along with the types of responses that
can be evoked, are illustrated in Figure 1.2.

The most basic inputs, those common both to free-living unicellular organ-
isms and the cells of multicellular organisms, are nutrients and other raw
materials useful to the cell, along with various environmental stresses. In
the case of nutrients, the cell is likely either to take advantage of a hospi-
table environment by staying in place, or to move to where resources are
more plentiful. On the other hand, noxious physical or chemical stimuli
may cause the cell to migrate away, or otherwise adapt to endure the hard
times until conditions improve. A yeast cell that is starved for phosphate,
for example, mounts a complex response in which phosphate utilization
is minimized, phosphate transport is increased, and enzymes (known as
phosphatases) are secreted by the cell to release phosphate from environ-
mental sources.

In multicellular organisms, a whole new set of signals needs to be detected

by each of the many cells that make up the various tissues and organs. For
example, cells signal to nearby or adjacent cells to regulate the develop-
ment and function of organs and tissues. This permits the cells to work

INPUTS

extracellular
matrix
signals from nutrient
other cells signals

environmental
stresses internal states
FEEDBACK

- homeostasis
- cell cycle
Figure 1.2
Cell signaling involves a diversity
gene senescence/ of inputs and outputs. Cells must read
expression death diverse external and intracellular signals,
and use this information to generate many
morphological growth/ output responses. Some common inputs
changes division
production/ (green arrows) and outputs (orange arrows)
secretion are indicated. In many cases, the output
of the system will change the response to
OUTPUTS future inputs (feedback).
Cell Signaling | chapter 01 | figure 02

CellSig ch01.indd 3 5/20/14 4:15 PM

Random documents with unrelated
content Scribd suggests to you:
 KING HAROLD SHOWN IN A MÊLÉE OF FIGHTING-MEN
Vit. MS., A. xiii.

William, for his part, did well to consider before attacking London.
Thirty years before, as he knew perfectly well, another king had
ridden to London like himself, only to find the gates shut. Cnut laid
siege to London: he was beaten off: he had to divide the kingdom
with Edmund Ironside. Not till London admitted him was he truly
King of England. William certainly knew this episode in history very
well, and understood what it meant. In the north there were Saxon
lords who needed nothing more than the support and
encouragement of London to raise an army equal to that of Harold’s,
and to march south upon him. William, who had many friends in
London, therefore waited.
In London there was much running to and fro; much excitement,
with angry debates, in those days. The funeral procession, simple
and plain, carrying the body of Harold from the field of battle to the
Abbey of Waltham, had passed through the City. It must have
passed through the City, because there was no other way. The King
was dead; who was to succeed him? And some said Edgar Atheling;
and some said nay, but William himself—strong as Cnut; just as
Cnut; loyal to his people as Cnut.
First they chose the Atheling, but when the great bell of St. Paul’s
rang for the Folkmote, to Paul’s Cross all flocked—the craftsmen in
their leathern doublets, the merchants in their cloth. All assembled
together; all the citizens and freemen of the City, according to a
right extending beyond the memory of man, and a custom as old as
the City itself, claiming for every man the right of a voice in the
management of the City.
Standing above the rest was the Bishop; silent at first amid the
uproar, silent and watchful, beside him the Atheling himself, a
stripling unable to wield the battle-axe of Harold; beside him, also,
the Portreeve, the chief civil officer of the City; behind the Bishop
stood his clergy and the canons of St. Paul’s. Outside the throng
stood the “men of Rouen” and the “men of Cologne,” who had no
voice or vote, but looked on in the deepest anxiety to learn the will
of the people.

Augustin Rischgitz.
CHARTER OF THE CITY OF LONDON GIVEN BY WILLIAM THE CONQUEROR
To larger image.

Then arose an aged craftsman, and after him another, and yet a
third, and the burden of their words was the same: “I remember
how King Cnut besieged us, and behind our walls we laughed at
him.”
And all the people cried, “Yea! yea!”
“And he drew his ships by the trench that he cut in the mud round
the bridge, and we fought the ships and beat him off.”
 And all the people cried, “Yea! yea!”
“And we would have none but our own king, Edmund Ironside.”
And all the people cried, “Yea! yea!”
Meantime the Bishop listened and bowed his head as if in assent.
And when all had spoken, he said, “Fair citizens, it is true that King
Cnut besieged you and that you beat him off, like valiant citizens.
Remember, however, that in the end you made Cnut your king. Was
he a just king—strong in battle and in peace merciful—was he, I say,
a good king?”
And all the people lifted up their voices, “Yea, yea.” For the
memory of King Cnut was more precious with them than that of any
other king since the great King Alfred.
Much more the Bishop said. In the end, by order, as he said, of
the Folkmote—whom he had persuaded to their good, he set off
with the Portreeve and Edgar Atheling. He was ready to offer the
submission of the City on conditions. What were those conditions?
They were almost certainly similar to those which the city of Exeter
afterwards proposed: viz. that William should promise to be a law-
abiding king. He made that promise. He entered the City, whose
gates were thrown open to him.
 A NORMAN KNIGHT
MS. 2, A. xxii.

London made William king. What did William do for London in

return? He gave her, probably soon after his coronation, his famous
Charter. It could not have been before his coronation, because he
describes himself as king, and from the nature of the contents it
must have been given very shortly after his reign began. This
document is written on a slip of parchment no more than six inches
in length and one in breadth. It contains four lines and a quarter.
There are slight variations in the translation. The following is that
of Bishop Stubbs:—
“William, King, greets William, Bishop, and Gosfrith, Portreeve,
and all the burghers within London, French and English, friendly;
and I do you to wit that I will that ye be all law worthy that were in
King Edward’s day. And I will that every child be his father’s heir
after his father’s day. And I will not endure that any man offer any
wrong to you. God keep you.”
It is the first charter of the City.
This charter conveys in the fewest possible words the largest
possible rights and privileges. It is so clear and distinct that it was
certainly drawn up by the citizens themselves, who knew then—they
have always known ever since—what they wanted. We can read
between the lines. The citizens are saying: “Promise to grant us
three points, these three points, and we will be your loyal subjects.
Refuse them, and we will close our gates.” Had the points been put
into words by the keenest of modern lawyers, by the most far-seeing
lawyer of any time, they could not have been clearer or plainer. They
leave no room at all for evasion or misconception, and they have the
strength and capability of a young oak sapling.
The points were these: Every man was to have the rights of a
freeman, as those rights were then understood, and according to the
Saxon customs.
Secondly, every man was to inherit his father’s estate.
Thirdly, the King would suffer no man to do them wrong.

Consider what has grown out of these three clauses. From the
first we have derived the right, among other things, for which every
man of our race would fight to the death—the right of trial by our
fellow-citizens, i.e. by jury. I do not say that the citizens understood
what we call Trial by Jury, but I do say that without this clause, trial
by jury could not have grown up. London did not invent the popular
method of getting justice; but she did preserve the rights of the
freeman, as understood by Angle, Saxon, and Jute alike, and by that
act preserved for all her children developments yet to come; among
others, this method of trial, which has always impressed our people
with the belief that it is the best way of getting justice that has yet
been invented.
As for the second, the right of inheritance. This right, which
includes the right of bequest, carries with it the chief spring of
enterprise, industry, invention, and courage. Who would work if the
fruits of his work were to be taken from his children at his death by
a feudal lord? The freeman works with all his heart for himself and
his family; the slave works as little as he can for his master. The
bestowal of this right was actually equivalent to a grant—a grant by
charter—to the City—of the spirit of enterprise and courage. Who
would venture into hostile seas, and run the gauntlet of pirates, and
risk storm and shipwreck, if his gains were to be swept into the
treasury of a feudal lord?
As for the third point, the promise of personal protection, London
was left with no one to stand between the City and the King. There
never has been any one between the King and the City. In other
cities there were actually three over-lords—king, bishop, earl,—and
the rights of each one had to be separately considered. The citizens
of London have always claimed, and have always enjoyed, the
privilege of direct communication with the sovereign. No one,
neither earl nor bishop, has stood between them and their King, or
claimed any rights over the City.

NORMAN HORSEMEN
 HAROLD TRYING TO PULL THE ARROW FROM HIS EYE

NORMAN ARCHERS
From the Bayeux Tapestry.

Now these liberties, and others that have sprung from them, we
have enjoyed so long that they have become part of ourselves. They
are like the air we breathe. When an Australian or an American
builds a new town, he brings with him, without thinking of it, the
rights of the freeman, the right of inheritance, the right of owning no
master but the State. We cannot understand a condition of society in
which these rights could be withheld. Picture to yourself, if you can,
a country in which the king imposed his own judges upon the
people; a king who could order them as he pleased; could sentence,
fine, banish, imprison or hang without any power of appeal; who
could make in his own interest his own laws without consulting any
one; who could seize estates at their owner’s death and could give
the heirs what he pleased, as much or as little; who could hand
these heirs over to be the prey of a feudal lord, who only suffered
them to live in order that he might rob them. That was the position
of a city under a feudal lord, but it was never the position of London.
 It must be added that William’s Charter conferred no new liberties
or privileges upon the City. London asked for none: the City was
content with what it had. William surrendered none of the power or
authority of the sovereign. London asked for no such surrender. We
shall see, in the charters which followed, how jealously the royal
authority was guarded.
From a modern point of view it would seem an unpatriotic thing
for the City to throw over the Saxon heir; but we must remember
that Cnut, the best and strongest king they had had since Alfred,
was a Dane, that the City was full of Normans, and that the memory
of the Saxon Ethelred was still rankling among them. What better
argument could the Bishop advance than the fact that William was
known everywhere to be a just man, faithful to his word, and strong
—the strongest man in western Europe? Above all things the country
desired in a king, then and always, so long as kings ruled and after
kings began to reign, was that he should be strong and faithful to
his word.

The principal citizens24—among them Edgar Atheling himself—

rode forth, met William, and giving hostages, made their submission,
and he “concluded a treaty with them,” that is, he promised to
respect their laws. According to the A.S. Chronicle, William “vowed
that he would be a loving lord” to the City.
William was crowned at Westminster. It is uncertain whether the
rival whom he had slain had been crowned at Westminster or at St.
Paul’s—probably the latter, as the cathedral church of London.
William, in that case, was the first of our kings to be crowned at
Westminster. The place was chosen because it contained the tomb of
the Confessor, to whom William claimed to succeed by right.
Dean Stanley has told the story of this memorable coronation with
graphic hand. It was on Christmas Day. The vast Cathedral, which,
newly built, was filled with the burgesses of London—sturdy
craftsmen for the most part—“lithsmen” or sailors, merchants—
anxious to know whether the old custom would be observed of
recognising the voice of the people. It would: every old custom
would be jealously observed. But there was suspicion: outside, the
Cathedral was guarded by companies of Norman horse. Two prelates
performed the ceremony: for the Normans, Godfrey, Bishop of
Coutances; for the English, Aldred, Archbishop of York. Stigand,
Archbishop of Canterbury, had fled into Scotland. When the time
came for the popular acclamation, both Bishops addressed the
people. Then came the old Saxon shout of election, “Yea—yea.” The
Norman soldiers, thinking this to be an outbreak of rebellion, set fire
to the Abbey Gates—why did they fire the Gates?—upon which the
whole multitude, Saxon and Norman together, poured out in terror,
leaving William alone in the church with the two Bishops and the
Benedictine monks of St. Peter’s. A stranger coronation was never
seen!
Stanley points out the connection, which was kept up, of the
Regalia with King Edward the Confessor.

WILLIAM THE CONQUEROR AND HIS KNIGHTS (FROM THE BAYEUX TAPESTRY)

“The Regalia were strictly Anglo-Saxon, by their traditional names:

the crown of Alfred, or of St. Edward, for the King; the crown of
Edith, wife of the Confessor, for the Queen. The sceptre with the
dove was the reminiscence of Edward’s peaceful days after the
expulsion of the Danes. The gloves were a perpetual reminder of his
abolition of the Danegelt—a token that the King’s hands should be
moderate in taking taxes. The ring with which, as the Doge to the
Adriatic, so the King to his people was wedded, was the ring of the
pilgrim. The coronation robe of Edward was solemnly exhibited in
the Abbey twice a year, at Christmas and on the festival of its patron
saints, St. Peter and St. Paul. The ‘great stone chalice,’ which was
borne by the Chancellor to the altar, out of which the Abbot of
Westminster administered the sacramental wine, was believed to
have been prized at a high sum ‘in Saint Edward’s days.’ If after the
anointing the King’s hair was not smooth, there was King Edward’s
‘ivory comb for that end.’ The form of the oath, retained till the time
of James II., was to observe ‘the laws of the glorious Confessor.’ A
copy of the Gospels, purporting to have belonged to Athelstane, was
the book which was handed down as that on which, for centuries,
the coronation oath had been taken. On the arras hung round the
choir, at least from the thirteenth century, was the representation of
the ceremony, with words which remind us of the analogous
inscription in St. John Lateran, expressive of the peculiar privileges
of the place:—
‘Hanc regum sedem, ubi Petrus consecrat aedem,
Quam tu, Papa, regis; inungit et unctio regis.’
The Church of Westminster was called, in consequence, ‘the head,
crown, and diadem of the kingdom.’
 BISHOPS
Royal MS. 2, B. vi.

The Abbot of Westminster was the authorised instructor to

prepare each new king for the solemnities of the coronation, as if for
confirmation; visiting him two days before, to inform him of the
observances, and to warn him to shrive and cleanse his conscience
before the holy anointing. If he was ill, the Prior (as now the
Subdean) took his place. He was also charged with the singular
office of administering the chalice to the King and Queen, as a sign
of their conjugal unity, after their reception of the sacrament from
the Archbishop. The Convent on that day was to be provided, at the
royal expense, with 100 simnels (that is, cakes) of the best bread, a
gallon of wine, and as many fish as became the royal dignity.”
The coronation happily over, William began to build his Tower. The
City should be fortified against an enemy by its strong wall—the
stronger the better—but he was not going to allow it to be fortified
against himself. Therefore he would build one Tower on the east and
another on the west of the City wall, so that he could command
ingress or egress, and also the river above or below the bridge. The
Tower on the east became the great White Tower, that in the west
was the Castle Montfichet. He was, however, in no hurry to build the
greater fortress: the City was loyal and well disposed, he would wait:
besides, he had already one foot in the City in Montfichet Tower. So
it was not until eleven years after Hastings that he commanded
Gundulf, Bishop of Rochester, to undertake the work. The history of
the Tower will be found in its place. It took more than thirty years to
build.

THE SEAL OF ODO, BISHOP OF BAYEUX, HALF-BROTHER OF WILLIAM I.

Archæologia, vol. i.

One of the many great fires which have from time to time ravaged
London occurred in 1077, and another in 1087 or 1088; this burned
St. Paul’s. Maurice, Bishop of London, began at once to rebuild it.
Matthew of Westminster, writing at the beginning of the fourteenth
century, says “necdum perfectum est.”
It is a great pity that William’s Domesday Book does not include
London. Had it done so, we should have had a Directory, a Survey,
of the Norman City. We should have known the extent of the
population, the actual trades, the wealth, the civic offices, the
markets, motes, hustings, all. What we know, it is true, amounts to
a good deal; it seems as if we know all; only those who try to
restore the life of early London can understand the gaps in our
knowledge, and the many dark places into which we vainly try to
peer.
 A second Charter granted by William the Conqueror is also
preserved at the Guildhall. It is translated as follows:—
“William the King friendly, salutes William the Bishop and Sweyn
the Sheriff, and all my Thanes in East Saxony, whom I hereby
acquaint that I have granted to Deorman my man, the hide of land
at Geddesdune, of which he was deprived. And I will not suffer
either the French or the English to hurt them in anything.”
Of this Deorman or Derman, Round (Commune of London, p. 106)
makes mention. Among the witnesses to a Charter by Geoffrey de
Mandeville, occurs the name of “Thierri son of Deorman.” It is
impossible not to suppose that this “Deorman” is the same as
William’s “man” of the Charter. Thierri belonged to a rich and
prosperous family; his son Bertram held his grandfather’s property at
Navington Barrow in Islington, and was a benefactor to the nuns of
Clerkenwell. Bertram’s son Thomas bestowed a serf upon St. Paul’s
about the beginning of the thirteenth century.
It has always been stated that William the Conqueror brought
Jews over with him. But Mr. Joseph Jacobs (Jews of Angevin
England), investigating this tradition, inclines to believe that there
were no Jews in England before the year 1073 or thereabouts, when
there is evidence of their residence in London, Oxford, and
Cambridge. Their appointed residence in London was Old Jewry,
north of Cheapside.
Stanley recalls the memory of one of those mediæval miracles
which seem invented in a spirit of allegory in order to teach or to
illustrate some great truth. It was a miracle performed at the tomb
of Edward the Confessor:—
“When, after the revolution of the Norman Conquest, a French
and foreign hierarchy was substituted for the native prelates, one
Saxon bishop alone remained—Wulfstan, Bishop of Worcester. A
Council was summoned to Westminster, over which the Norman king
and the Norman primate presided, and Wulfstan was declared
incapable of holding his office because he could not speak French.
The old man, down to this moment compliant even to excess, was
inspired with unusual energy. He walked from St. Catherine’s Chapel,
where the Council was held, straight into the Abbey. The King and
the prelates followed. He laid his pastoral staff on the Confessor’s
tomb before the high altar. First he spoke in Saxon to the dead king:
‘Edward, thou gavest me the staff: to thee I return it.’ Then, with the
best Norman words that he could command, he turned to the living
king: ‘A better than thou gave it to me—take it if thou canst.’ It
remained fixed in the solid stone, and Wulfstan was left at peace in
his see. Long afterwards King John, in arguing for the supremacy of
the Crown of England in matters ecclesiastical, urged this story at
length in answer to the claims of the Papal Legate. Pandulf
answered, with a sneer, that John was more like the Conqueror than
the Confessor. But, in fact, John had rightly discerned the principle at
stake, and the legend expressed the deep-seated feeling of the
English people, that in the English Crown and Law lies the true
safeguard of the rights of the English clergy. Edward the Confessor’s
tomb thus, like the Abbey which incases it, contains an aspect of the
complex union of Church and State, of which all English history is a
practical fulfilment.” (Westminster Abbey, p. 35.)
The City already contained a mixed population of Saxons, Danes,
Normans—“men of Rouen,” and Germans—“men of the Emperor.”
There were also Norwegians, Flemings, Gascons, and others of
foreign descent in the City when William succeeded. Without
insisting too strongly on the actual magnitude of the trade, small
indeed compared with that which was to follow, we may point to this
gathering of various peoples as a proof that the trade of London was
already considered by the whole of western Europe as considerable,
and, indeed, of the highest importance. Many more Normans came
over after the Conquest. It is said that they chose London in
preference to Rouen, because it was “fitter for their trade, and better
stored with the merchandise in which they were wont to traffic.”
There was also a large settlement of craftsmen in London and in
other towns; among them, especially, were weavers and builders. Of
these the weavers became, and remained for many generations,
extremely unpopular. Cunningham (Growth of English Industry and
Commerce, p. 179) suggests an explanation for the otherwise
unintelligible hostility of the people towards the weavers. He thinks
that before the Conquest weaving was not a national industry; that
weavers were brought over by William and remained foreigners, not
as taking “scot and lot” with the people.
William appears to have been true to his word as regards the City:
he neither oppressed the people himself, nor did he suffer others to
do them any harm.
 CHAPTER II
DOMESDAY BOOK
The following are the returns of Domesday Book for the villages
round London which are included in this Survey. The translations are
those of the Rev. William Bawdwen, 1812:—
Stepney.—“In Osuluestan (Ossulston) hundred, the Bishop of
London holds Stibenhede (Stepney) for thirty-two hides. There is
land to twenty-five ploughs. Fourteen hides belong to the demesne,
and there are three ploughs there; and twenty-two ploughs of the
villanes. There are forty-four villanes of one virgate each; and seven
villanes of half a hide each; and nine villanes of half a virgate each;
and forty-six cottagers of one hide; they pay thirty shillings a year.
There are four mills of four pounds and sixteen shillings save
fourpence. Meadow sufficient for twenty-five ploughs. Pasture for
the cattle of the village, and fifteen shillings. Pannage for five
hundred hogs, and forty shillings. Its whole value is forty-eight
pounds; and it was worth the same when received; in King Edward’s
time fifty pounds. This manor was and is part of the see.
In the same village Hugh de Berneres holds five hides and one
virgate of land under the bishop. There is land to four ploughs.
There is one plough in the demesne; and the villanes have three
ploughs. There is one villane of half a hide; and six villanes of three
virgates; and two bordars of half a virgate; and three cottagers of
two acres and a half; and one mill of sixty-six shillings and
eightpence. Meadow sufficient for four ploughs. Pannage for one
hundred and fifty hogs, and three shillings and a half. The whole is
worth six pounds; the same when received; in King Edward’s time
seven pounds. Sired held two hides and a half of this manor, he was
a canon of St. Paul’s, he might give and sell it to whom he would
without leave of the bishop. In King Edward’s time the canons of St.
Paul held two hides and a half for their Sabbath day’s support (de
dominico victu suo); and Doding held one virgate, and one mill of
the proper manor of the bishop; he could not give or sell it without
his leave.
In the same village the wife of Brien holds five hides of the
bishop. There is land to two ploughs and a half. There is one plough
in the demesne, and the villane might make one plough. There is
one villane of half a hide; he pays four shillings a year for his house;
and another villane of half a hide, pays eight shillings. Roger the
sheriff holds a half a hide, and fifteen bordars of ten acres, pay nine
shillings. Pannage for sixty hogs. Pasture for the cattle of the village,
and five shillings. It is altogether worth sixty shillings; when received
the like; in King Edward’s time one hundred shillings. William, the
bishop, held this land in demesne, in the manor of Stibenhede
(Stepney), on the very day on which King Edward died.
In the same village Rannulf Flambard holds three hides and a half
of the bishop. There is land to five ploughs. There are two ploughs
in the demesne; and three ploughs belonging to the villanes. There
are fourteen bordars of one hide and a half. Meadow for two ploughs
and two shillings. There is no pasture. Wood (nemus) to make
hedges. It is altogether worth four pounds. Goduin held this land
under Bishop William. In King Edward’s time he could not give nor
sell it without leave of the bishop. [Orig. 127, b. 1.]
 PART OF A PAGE OF DOMESDAY BOOK
From the original in the Public Record Office.

In the same village William de Ver holds one hide of the bishop.
There is land to one plough, and it is there in the demesne. This
land is worth sixteen shillings; the like when received; in King
Edward’s time twenty shillings. In King Edward’s time, William, the
bishop, held this land in demesne with his manor of Stibenhede
(Stepney).
In the same village Engelbric, a canon, holds of the bishop one
hide and one virgate. There is land to one plough, and it is there in
the demesne. There is one villane of one virgate; and four bordars
of seven acres each; and one cottager. It is worth altogether forty
shillings; the like when received; in King Edward’s time forty
shillings. The same canon held it of Bishop William. In King Edward’s
time he could not sell it.
In the same village the Bishop of Lisieux holds one hide and a half
of the Bishop of London. There is land to one plough; and there is a
half a plough there; and a half may be made. There are two bordars
of five acres each; and two cottagers of four acres; and one
cottager. In the whole it is worth forty shillings; the like when
received; in King Edward’s time fifty shillings. Bishop William held
this land in demesne on the very day King Edward died.
 WILLIAM I. AND II.
HENRY I. AND STEPHEN
Royal MS. 14 C vii.

In the same village, William, the chamberlain, holds one hide and
a half, and one virgate, of the bishop. There is land to one plough
and a half. There is one plough in the demesne; and a half may be
made. There is one villane of one virgate; and six bordars of five
acres. It is in the whole worth thirty shillings; when received the like;
in King Edward’s time forty shillings. Bishop William held this land in
demesne on the day on which King Edward died.
In the same village Aluric Chacepul holds one hide of the bishop.
There is land to one plough, but the plough is wanting. This land is
worth ten shillings; the like when received; in King Edward’s time
thirteen shillings and fourpence. Bishop William held this land in
demesne in King Edward’s time.
In the same village Edmund, son of Algot, holds one mill of the
bishop, which is worth thirty-two shillings and sixpence; the like
when received; but it was not there in King Edward’s time.
In the same village Aluuin, son of Britmar, holds one mill which is
worth twenty shillings; the like when received; in King Edward’s time
the like. He himself held it of Bishop William.”
Fulham.—“In Fvleham (Fulham) the Bishop of London holds forty
hides. There is land to forty ploughs. Thirteen hides belong to the
demesne, and there are four ploughs there. Among the freemen
(franc) and the villanes are twenty-six ploughs; and ten more might
be made. There are five villanes of one hide each; and thirteen
villanes of one virgate each; and thirty-four villanes of half a virgate
each; and twenty-two cottagers of half a hide; and eight cottagers
with their own gardens. Foreigners and certain burgesses of London
hold amongst them twenty-three hides of the land of the villanes.
Thirty-one villanes and bordars dwell under them. Meadow for forty
ploughs. Pasture for the cattle of the village. For half the stream ten
shillings. Pannage for one thousand hogs, and seventeen pence. Its
whole value is forty pounds; the like when received; in King
Edward’s time fifty pounds. This manor was and is part of the see.
In the same village Fulchered holds five hides of the Bishop of
London. There is land to three ploughs. There is one plough in the
demesne; and one plough of the villanes, and a third may be made.
There are six villanes of half a hide; and four cottagers of eight
acres; and three cottagers. Meadow for one ox. Pasture for the
cattle of the village. Pannage for three hundred hogs. Its whole
value is sixty shillings; the like when received; in King Edward’s time
one hundred shillings. Two sokemen held this land; they were
vassals of the Bishop of London; they could not give or sell without
leave of the bishop in King Edward’s time. [Orig. 127, b. 2.]
Manor.—In the same village the canons of St. Paul hold of the
King five hides for one manor. There is land to five ploughs. Three
hides belong to the demesne, and there are two ploughs there. The
villanes have two ploughs, and a third may be made. There are eight
villanes of one virgate each; and seven villanes of half a virgate
each; and seven bordars of five acres each; and sixteen cottagers;
and two bondmen. Meadow for five ploughs. Pasture for the cattle of
the village. Pannage for one hundred and fifty hogs. It is worth, in
the whole, eight pounds; the same when received; in King Edward’s
time ten pounds. The same canons of St. Paul held this manor in
demesne in King Edward’s time, and it is for their support (de victu
eorum).”
Rugmere.—“Ralph, a canon, holds Rugemere (Rugmere). It
answered for two hides. There is land to one plough and a half.
There is one plough in the demesne, and half a plough may be
made. Wood (nemus) for the hedges, and four shillings. This land is
worth thirty-five shillings; the same when received; in King Edward’s
time forty shillings. It was, in King Edward’s time, and is now in the
demesne of the canons.”
St. Pancras.—“The canons of St. Paul hold four hides to Scm
Pancratium (St. Pancras). There is land to two ploughs. The villanes
have one plough, and another plough may be made. Wood for the
hedges. Pasture for the cattle, and twentypence. There are four
villanes who hold this land under the canons; and seven cottagers.
Its whole value is forty shillings; the same when received; in King
Edward’s time sixty shillings. This manor was and is in the demesne
of St. Paul.”
 Islington.—“In Isendone (Islington) the canons of St. Paul have
two hides. Land to one plough and a half. There is one plough there,
and a half may be made. There are three villanes of one virgate.
Pasture for the cattle of the village. This land is and was worth forty
shillings. This laid and lies in the demesne of the church of St. Paul.
In the same village the canons themselves have two hides of land.
There is land there to two ploughs and a half, and they are there
now. There are four villanes who hold this land under the canons;
and four bordars and thirteen cottagers. This land is worth thirty
shillings; the same when received; in King Edward’s time forty
shillings. This laid and lies in the demesne of the church of St. Paul.”
Hoxton.—“In Hochestone (Hoxton) the canons of St. Paul have
one hide. Land to one plough, and it is now there; and three villanes
hold this land under the canons. Pasture for the cattle. This land was
and is worth twenty shillings. This laid and lies in the demesne of
the church of St. Paul.
Manor.—The canons hold Hochestone (Hoxton) for three hides.
There is land to three ploughs, and they are there; and seven
villanes who hold this land; and sixteen cottagers. It is worth in the
whole fifty-five shillings; the same when received; in King Edward’s
time sixty shillings. This manor belonged and belongs to the church
of St. Paul.
The canons of St. Paul have, at the bishop’s gate, ten cottagers of
nine acres, who pay eighteen shillings and sixpence a year. In King
Edward’s time they likewise held them, and they had the same.”
Westminster.—“In the village where the church of St. Peter is
situate, the abbot of the same place holds thirteen hides and a half.
There is land to eleven ploughs. Nine hides and one virgate belong
to the demesne, and there are four ploughs therein. The villanes
have six ploughs, and one plough more may be made. There are
nine villanes of one virgate each; one villane of one hide; and nine
villanes of half a virgate each; and one cottager of five acres; and
forty-one cottagers who pay forty shillings a year for their gardens.
Meadow for eleven ploughs. Pasture for the cattle of the village.
Pannage for one hundred hogs. And twenty-five houses of the
knights of the abbot and of other vassals, who pay eight shillings a
year. Its whole value is ten pounds; the same when received; in King
Edward’s time twelve pounds. This manor was and is in the demesne
of the church of St. Peter, of Westminster.
In the same village Bainiard holds three hides of the abbot. There
is land to two ploughs, and they are there in the demesne, and one
cottager. Pannage for one hundred hogs. Pasture for the cattle.
There are four arpents of vineyard, newly planted. Its whole value is
sixty shillings; when received twenty shillings; in King Edward’s time
six pounds. This land belonged and belongs to the church of St.
Peter.”
Hampstead.—“The Abbot of St. Peter holds Hamestede
(Hampstead) for four hides. Land to three ploughs. Three hides and
a half belong to the demesne, and there is one plough therein. The
villanes have one plough, and another may be made. There is one
villane of one virgate; and five bordars of one virgate; and one
bondman. Pannage for one hundred hogs. In the whole it is worth
fifty shillings; the same when received; in King Edward’s time one
hundred shillings.
In the same village Rannulf Pevrel holds under the abbot, one hide
of the land of the villanes. Land to half a plough, and it is there. This
land was and is worth five shillings. This manor altogether laid and
lies in the demesne of the church of St. Peter.”
Tyburn.—“The abbess of Berking holds Tiburne (Tyburn) of the
King; it answered for five hides. Land to three ploughs. There are
two hides in the demesne, and there is one plough therein. The
villanes have two ploughs. There are two villanes of half a hide; and
one villane of half a virgate; and two bordars of ten acres; and three
cottagers. Pasture for the cattle of the village. Pannage for fifty
hogs. For herbage fortypence. It is worth in the whole fifty-two
shillings; the same when received; in King Edward’s time one
hundred shillings. This manor always belonged and belongs to the
church of Berking.”

NORMAN SOLDIERS
Harl. MS., Roll Y. 6.

Eia.—“Geoffry de Mandeville holds Eia (qu. Ealing). It answered

for ten hides. There is land to eight ploughs. In the demesne are five
hides, and there are two ploughs therein. The villanes have five
ploughs, and a sixth may be made. There is one villane of half a
hide; and four villanes of one virgate each; and fourteen others of
half a virgate each; and four bordars of one virgate; and one
cottager. Meadow for eight ploughs, and for hay sixty shillings. For
pasture seven shillings. Its whole value is eight pounds; when
received six pounds; in King Edward’s time twelve pounds. Harold,
son of Earl Ralph, held this manor, whom Queen Eddid protected
(custodiebat) with the manor on that very day on which King Edward
died. Afterwards William, the chamberlain, held it of the Queen in
fee for three pounds a year rent; and after the death of the Queen
he held it in the same manner of the King. There are now four years
since William relinquished the manor, and the rent (that is twelve
pounds) is not paid to the King from it.
In the same hundred Ralph holds of Geoffry one hide and a half.
There is land to one plough, and it is there; and four bordars of
fourteen acres; and one bondman. Meadow for one plough. Pasture
for the cattle, and thirteen pence. Wood (nemus) for the hedges.
This land is worth twenty shillings; when received, and in King
Edward’s time, thirty shillings. Two of King Edward’s sokemen held
this land; they might sell it to whom they would.”
Stepney.—“Robert Fafiton holds four hides of the King in
Stibenhed (Stepney). There is land to three ploughs, and they are
now there. There is one villane of fourteen acres; and another of
twelve acres; and Roger, the sheriff, has one hide; and a bordar of
half a hide and half a virgate. Pannage for sixty hogs, and four
shillings. It is worth in the whole twenty shillings; the same when
received; in King Edward’s time eight pounds. Sired, a canon of St.
Paul’s, held this manor; he might sell it to whom he would. In King
Edward’s time the Bishop of London disputed his right to it (reclam
se habe debere). Besides these four hides there are now fifty-three
acres of land, which were not there in King Edward’s time, which
Hugh de Berneres usurped on the canons of St. Paul, and added it to
this manor, as the hundred testifies.
Robert, son of Rozelin, holds of the King three hides and a half in
Stibenhed (Stepney). Land to two ploughs. Two hides are in the
demesne, and there is one plough therein. The villanes have one
plough. There is one villane of one virgate; and eight bordars of half
a virgate each; and four cottagers of nineteen acres. Meadow for
two ploughs; and wood for the hedges (nemus ad sepes). The whole
is worth fifty-three shillings; when received ten shillings; in King
Edward’s time four pounds. Aluuin Stichehare held this land for one
manor; he was a vassal of King Edward’s; he might sell it to whom
he would. The Bishop of London claims it.”
 Chelsea.—“Edward de Sarisberie holds Chelched or Cercehede
(Chelsea) for two hides. There is land to five ploughs. One hide is in
the demesne, and there are now two ploughs there. The villanes
have one plough, and two ploughs might yet be made. There are
two villanes of two virgates; and four villanes of half a virgate each;
and three bordars of five acres each; and three bondmen. Meadow
for two ploughs. Pasture for the cattle of the village. Pannage for
sixty hogs, and fifty-two pence. Its whole value is nine pounds; the
same when received, and always. Wluuene, a vassal of King
Edward’s, held this manor; he might sell it to whom he would.”
Kensington.—“Aubrey de Ver holds Chenesit (Kensington) of the
Bishop of Constance. It answered for ten hides. There is land to ten
ploughs. There are four ploughs in the demesne there, and the
villanes have five ploughs, and a sixth might be made. There are
twelve villanes of one virgate each; and six villanes of three virgates.
A priest has half a virgate; and there are seven bondmen. Meadow
for two ploughs. Pasture for the cattle of the village. Pannage for
two hundred hogs. And three arpents of vineyard. Its whole value is
ten pounds; when received six pounds; in King Edward’s time ten
pounds. Eduuin, a thane of King Edward’s, held this manor, and
might sell it.”
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