Table Of ContentSignal Transduction
in Mast Cells
and Basophils
Springer
New York
Berlin
Heidelberg
Barcelona
Hong Kong
London
Milan
Paris
Singapore
Tokyo
Ehud Razin
Juan Rivera
Editors
Signal Transduction
in Mast Cells
and Basophils
With 65 Illustrations
Springer
Preface
The recent advances in the field of receptor-mediated molecular
signaling were a major impetus in the compilation of this book. In
particular, we believed the time was appropriate to compile the
current knowledge in signal transduction in mast cells and baso
phils, not necessarily because of a major therapeutic breakthrough
in the treatment of allergies, but mostly because a summary of
recent work may provide new perspectives that may serve to ad
vance the field and delineate new areas of research. Hope for the
development of new areas with therapeutic potential has driven
much of the ongoing effort, but to date success based on the target
ing of particular molecular events has been limited. However, a
clearer picture is evolving from the study of signal transduction in
various systems. The redundancy in many signaling pathways
makes the effort to find a cell-specific target molecule akin to the
search for a "needle in a haystack." Furthermore, the daunting task
of cell-specific delivery of therapeutic agents is an issue that per
vades the fields of molecular and genetic therapies.
Regardless of the limited success in the area of therapeutics, the
study of molecular signals has allowed major advances in our un
derstanding of the biochemical events that govern cell responses
and has driven the rapid growth of technology for study of protein
structure and function. Our knowledge of the fundamental mecha
nisms that govern protein-protein interactions, enzyme-substrate
reactions, cellular ontogeny and differentiation, and other areas
has been greatly enhanced by the study of molecular signaling
events. It is in this context that we have set out to compile the
current information in the area of molecular signals in mast cells
and basophils. We believe this monograph reflects the advances
made in this field and may serve as a resource tool for the expert
and novice alike.
We have arbitrarily divided the book into four sections to pro
vide the reader with a framework of the areas we wish to cover. The
first section discusses the molecular events that govern the ontog
eny, growth, differentiation, and physiological function of mast
cells. The second section focuses on the early events mediated
v
VI Preface
primarily through the activation of the high-affinity receptor for
IgE on mast cells and basophils. As a major route of mast cell and
basophil activation, this topic has been the most extensively studied
and is therefore emphasized. The third section reviews what is
known about events that link the receptor activation to the effector
function of mast cells and basophils. Finally, the last section consid
ers the molecular events that govern the secretion of preformed
and newly formed allergic mediators. Each topic area has been
introduced by a perspective chapter from one of the leaders in the
particular area of research. We hope the perspective chapters serve
to provide the reader with a useful framework for evaluating the
following chapters and stimulating thought and discussion. It will
be evident to the reader that the four topic areas have much in
common as well as distinct identities. We wish to leave the reader
with the task of merging the useful information in each of these
areas that may benefit the reader's purpose in perusing this
book.
This book represents the wide-ranging effort of many individual
scientists who pursue studies in various aspects of mast cell and
basophil biology with a concentration on molecular signaling
events. We are extremely grateful to the contributing authors with
out whom this comprehensive effort would not be possible. We
hope you, the reader, will gain an up-to-date perspective on ad
vances relevant to allergic disease and inflammation and that you
will find your time has been well spent.
Ehud Razin
Jerusalem, Israel
Juan Rivera
Bethesda, Maryland
Contents
Preface. . ... . .. ... . .. . .... ... . .. ... ... . .... . ..... . . . v
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv
Section I
1 Signals in the Regulation of Mast Cell Growth and
Development: A Perspective ..................... 3
Stephen 1. Galli
Mast Cells: Versatile Effector Cells in Health and
Disease 3
Mast Cell Development: A Brief Overview 4
In Vivo Veritas: In Vitro Versus In Vivo Models of
Mast Cell Development 5
Mice or Humans? Species Differences in Mast Cell
Development and Phenotype 6
Conclusions 7
2 The Regulation of Mast Cell and Basophil
Development by the Kit Ligand, SCF,
and IL-3 ....................................... 11
Stephen 1. Galli, Mindy Tsai, and Chris S. Lantz
Discovery of SCF, a Ligand for the
Receptor Encoded at c-kit 11
Effects of SCF in Mast Cell Biology 12
Recombinant Human SCF Promotes Human Mast
Cell Hyperplasia In Vivo 13
SCF/Kit Signaling and the Regulation of the
Survival and Size of Mast Cell Populations
In Vivo 13
SCF Can Regulate Mast Cell Secretory
Function 14
vii
Vlll Contents
Interleukin-3 16
Assessing the Role of IL-3 in Mouse Mast Cell and
Basophil Development Using IL-3 -/-Mice 17
Kitw/Kitw,v, IL-3 -/-Mice Exhibit a Profound
Impairment of Mucosal Mast Cell Development
and Immunity, During Infection with
Strongyloides venezuelensis 18
SCF and IL-3 Have Distinct Roles in the Regulation
of Physiological Mast Cell and Basophil
Development and Immunologically Induced Mast
Cell and Basophil Hyperplasia 21
Conclusions 23
3 The c-kit Receptor and the mi Transcription
Factor: Two Important Molecules for Mast
Cell Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Yukihiko Kitamura, Eiichi Morii, and Tomoko fippo
Kit 31
MITF 34
Conclusions 36
4 Mouse and Rat Models of
Mast Cell Development ......................... 39
Guang W. Wong, Daniel S. Friend, and
Richard L. Stevens
Identification of the Major Granule Constituents
of Mouse MC 39
Granule Characterization of Varied Populations of
MC in Normal Mice 41
Helminth-Induced Mastocytosis in the Jejunum 41
mBMMC 43
Transformed MC Lines 46
Future Directions 47
5 Factors That Affect Human Mast Cell and
Basophil Growth ............................... 54
Lixin Li, Xiao-Tong Zhang, and Steven A. Krilis
Ontogeny of Mast Cells and Basophils 54
General Characteristics of Mast Cells and
Basophils 55
Mast Cell Phenotypes In Vivo 55
Development In Vitro of Human Basophils and
Mast Cells 56
In Vitro Studies on Mast Cells and Basophils
Utilizing Cell Lines 59
Development of Human Mast Cells and Basophils
In Vivo 60
Conclusions 60
Contents ix
6 Signal Transduction by Cytokines 66
John VV. Schrader
Mast Cells and Cytokines 66
The Four-Helix Bundle Cytokine Family 67
Interferons and IL-lO 68
Tyrosine Phosphorylation Events 70
Activation of Ras Proteins 70
Tyrosine Phosphorylation of Shc and Its Function
as an Adaptor 72
MAP Family Kinases 72
Functions of MAP Family Kinases in Mast
Cells 74
The IL-4 and IL-13 Receptors 76
Similarities and Differences in Signal Transduction by
Different Cytokines 78
Conclusions 78
7 Mast Cell Apoptosis and Its Regulation 85
Yoseph A. Mekori, Karin Hartmann, and
Dean D. Metcalfe
Physical Triggers of Mast Cell Apoptosis 87
Cytokines Regulating Mast Cell Apoptosis 87
Genetic Control of Mast Cell Apoptosis 90
Mast Cell Apoptosis In Vivo: Clinical
Correlates 91
Conclusions 91
Section II
8 Early Signals in Mast Cell Activation:
A Perspective .................................. 97
Henry Metzger
Role of Aggregation: Two Models 97
Ligand Affinity and Signaling 98
Conclusions 100
9 FCERI Signaling in Specialized
Membrane Domains ............................. 102
Kenneth A. Field, David Holowka, and
Barbara Baird
Background 102
FCERI Activation in Membrane Domains 104
Future Directions 109
Conclusions 111
x Contents
10 Regulation and Function of Protein Tyrosine
Kinase Syk in FCERI-Mediated Signaling ........... 115
Reuben P. Siraganian, Juan Zhang, and
Teruaki Kimura
Protein Tyrosine Phosphorylation 115
Importance of Syk in Cellular Signaling 116
Present Model for Early Events in FCERI Signaling 116
Structure of Syk 117
Regulation of the Function of Syk 121
Association of Syk with Other Proteins 123
Downstream Molecules: Substrates 124
Conclusions 126
11 The Role of Protein Phosphatases in Cell
Signaling by the High-Affinity Receptor for
Immunoglobulin E .............................. 134
Matthew J. Peirce
Protein Tyrosine Phosphatases 134
Phosphatase-Dependent Inhibitory Receptors 140
Protein SerinefThreonine Phosphatases 142
General Considerations 143
12 Protein Kinase C and Early Mast Cell Signals 152
Patrick G. Swann, Sandra Odom, and Juan Rivera
Molecular Structure of PKC Family Members 153
Translocation and Activation of PKC Isozymes 153
Regulation of PKC Activity 154
PKC, the Mast Cell, and the Basophil 156
Activation of PKC in the Mast Cell: Is Activation an
Early Event? 157
PKC and Receptor Phosphorylation 158
Molecular Associations of PKC In Vivo 162
Protein Kinase C: A Suitable Target for Therapeutic
Intervention? 165
Conclusions 165
13 Mast Cell Inhibitory Receptors of the
Immunoglobulin Superfamily ..................... 171
Howard R. Katz
Mast Cell FcyRIIb 172
Mouse gp49BlIHuman HL9 173
Mast Cell p91 and PIR-B1 174
Functional Implications of Multiple ITIM-Bearing
Inhibitory Receptors in Mast Cells 175
