Table Of ContentCurrent Topics in
Microbiology
228 and Immunology
Editors
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M. Cooper, Birmingham/Alabama
l.H. Hogle, Boston/Massachusetts' Y. Ito, Kyoto
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Protein Modules
in Signal Transduction
Edited by A. 1. Pawson
With 42 Figures and 14 Tables
Springer
Professor ANTHONY J. PAWSON, FRS
Samuel Lunenfeld Research Institute
Mount Sinai Hospital
600 University Avenue
Toronto, Ontario
Canada M5G lX5
Cover illustration: The figure illustrates a series of modular inter
actions through which PTB, SH2 and SH3 domains collaborate
to activate the Ras guanine nucleotide exchange factor Sos.
Cover design: design & production GmbH, Heidelberg
ISBN-13: 978-3-642-80483-0 e-ISBN-13: 978-3-642-80481-6
DOl: 10.1007/978-3-642-80481-6
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Preface
The behavior of eukaryotic cells, particularly those of multicel
lular organisms, depends on the transmission of signals from one
cell to another. Such extracellular signals can take the form of
hormones, antigens, cells surface molecules, or components of the
extracellular matrix and exert their effects by binding to specific
receptors, usually exposed on the surface of the target cell. These
transmembrane receptors possess a cytoplasmic domain that al
lows communication with intracellular signaling pathways, pro
viding access to the regulation of gene expression, cytoskeletal
architecture, cell metabolism, survival, and the cell cycle. Defining
the process through which a signal emanating from an individual
receptor can influence so many aspects of cellular function is of
central importance for our understanding of signal transduction.
Many polypeptide factors that regulate cellular growth and
differentiation bind to receptors with cytoplasmic tyrosine kinase
domains. Recent evidence has indicated that intracellular sig
naling from receptor tyrosine kinases proceeds through a series of
modular protein-protein interactions, typified by the interaction
of autophosphorylated growth factor receptors with the Src ho
mology 2 (SH2) domains of cytoplasmic target proteins. Thus, a
crucial role of tyrosine phosphorylation is to promote the for
mation of protein complexes through the creation of specific SH2
domain-binding sites, thereby regulating the activation of bio
chemical pathways within the cell. The interactions of SH2 do
mains with their ligands have two interesting features: first,
phosphorylation of a tyrosine residue within the ligand is ab
solutely required for high-affinity binding and serves as a switch
for recognition of the phosphorylated site by an SH2 domain;
second, SH2 domains recognize specific phosphopeptide se
quences in a fashion that is dictated by the ligand residues im
mediately C-terminal to the phosphotyrosine, providing an
element of specificity. SH2-mediated interactions are important
not only in signaling by transmembrane receptors, but also for
the functions of cytoplasmic tyrosine kinases that act down
stream of cytokine- and antigen-receptors.
VI Preface
SH2 domains can be viewed as the prototype for a growing
number of protein modules that control protein-protein and
protein-phospholipid interactions in a wide range of cellular
processes. These include phospho tyrosine-binding (PTB) do
mains that, in some cases, also recognize phosphotyrosine-con
taining motifs on activated receptors, although in a quite different
manner from SH2 domains, and SH3 and WW domains that bind
proline-rich peptide sequences. PDZ domains recognize short
peptide motifs at the C-terminal ends of receptors and ion
channels and are involved in receptor clustering and subcellular
organization as well as engaging in direct PDZ-PDZ interactions.
The pleckstrin homology (PH) domain, although it has a fold
very much like that of a PTB domain, apparently associates with
specific phosphoinositides and probably functions to target pro
teins to the plasma membrane.
An important feature of these modules is that they are fre
quently found covalently linked within the same polypeptide
chain and thereby allow the formation of a network of protein
protein and protein-phospholipid complexes that can, in princi
ple, disseminate signaling information to a wide range of cellular
processes. It is also apparent that these modular interactions are
employed by a variety of cell-surface receptors and internal sig
naling pathways and are certainly not confined to the targets of
tyrosine kinases.
The articles in this volume address the various mechanisms
through which protein modules control signal transduction. At
tention is focussed on the genetic, biochemical, and structural
analysis of domains that act downstream of tyrosine kinases and
their role in specific biological events during embryonic devel
opment, the response to insulin, and in organization of the
cytoskeleton. However, the subjects of protein modules that
control the functions of ion channels, as well as signaling by
serine kinase receptors, and transmembrane proteins such as
Notch, have also been addressed. Taken together, these chapters
provide an over view of the molecular process by which signals
emanating at the plasma membrane are transmitted to targets in
the cytoplasm and within the nucleus.
Canada T. PAWSON
List of Contents
B.J. MAYER and R. GUPTA
Functions of SH2 and SH3 Domains
J-P. BORG and B. MARGOLIS
Function of PTB Domains . . . . . . . . . . . . . . . . . . . . . . 23
M.A. LEMMON and K.M. FERGUSON
Pleckstrin Homology Domains . . . . . . . . . . . . . . . . . . . 39
L.W. JURATA and G.N. GILL
Structure and Function of LIM Domains 75
D.ROTIN
WW (WWP) Domains: From Structure to Function. . .. 115
J.M. TAYLOR, A. RICHARDSON, and J.T. PARSONS
Modular Domains of Focal Adhesion-Associated
Proteins ................................... 135
C. PONZETTO
Physiological Function of Receptor-SH2 Interactions 165
M.F. WHITE and L. YENUSH
The IRS-Signaling System: A Network
of Docking Proteins That Mediate Insulin
and Cytokine Action . . . . . . . . . . . . . . . . . . . . . . . . .. 179
A.S. FANNING and J.M. ANDERSON
PDZ Domains and the Formation of Protein Networks
at the Plasma Membrane . . . . . . . . . . . . . . . . . . . . . .. 209
P.A. HOOD LESS and J.L. WRANA
Mechanism and Function of Signaling by the TGF~
Superfamily ................................ 235
S.E. EGAN, B. ST-PIERRE and c.c. LEOW
Notch Receptors, Partners and Regulators:
From Conserved Domains to Powerful Functions 273
VIII List of Contents
T. TAKENAWA, H. MIKI and K. MATUOKA
Signaling Through Grb2/Ash-Control of the Ras
Pathway and Cytoskeleton. . . . . . . . . . . . . . . . . . . . .. 325
T. RAABE
Genetic Analysis of Sevenless Tyrosine Kinase
Signaling in Drosophila ........................ 343
Subject Index ............................... 363
List of Contributors
(Their addresses can be found at the beginning of their respective
chapters.)
ANDERSON,l.M. 209 MAYER, B.l.
BORG.I-P 23 MIKI, H. 325
EGAN, S.E. 273 PARSONS, 1.T. 135
FANNING, A.S. 209 PONZETIO, C. 165
FERGUSON, K.M. 39 RAABE, T. 343
GILL, G.N. 75 RICHARDSON, A. 135
GUPTA, R. 1 ROTIN, D. 115
HOODLES, P.A. 235 ST-PIERRE, B. 273
lURATA, L.W. 75 T AKENA W A, T. 325
LEMMON, M.A. 39 TYLOR,l.M. 135
LEOW, c.c. 273 WHITE, M.F. 179
MARGOLIS, B. 23 WRANA,l.L. 235
MATUOKA, K. 325 YENUSH, L. 179
Functions of SH2 and SH3 Domains
B.1. MAYER and R. GUPTA
I Introduction.............. ........ . I
1.1 SH2 Domains Bind Tyrosine-Phosphorylated Ligands . 2
1.2 SH3 Domains Bind Proline-Rich Peptides. 3
2 Domain-Ligand Interactions
2.1 SH2 Domains . . . . 4
2.2 SH3 Domains . . . . . . 4
3 The Grb2 Paradigm . 5
3.1 Advantages of Networks 6
4 Unconventional Ligands for SH2 and SH3 Domains. 7
4.1 Phospho tyrosine-Independent SH2 Binding. 7
4.2 SH2-lnositol Lipid Interactions ........ . 8
4.3 Unusual SH3 Interactions .... 9
5 Complex and Dynamic Networks of Interactions. 10
5.1 Cbl-Adaptor Complexes . . . . . . . . .. II
5.2 Dynamics of Adaptor-Cbl Interactions ..... . 12
6 Complex Networks of SH3-Mediated Interactions 14
6.1 Assembly of the Neutrophil Oxidase. . . . . 14
6.2 Revising the Model for Oxidase Assembly .... IS
6.3 Other Complex SH3-Mediated Assembly Processes. 17
7 Conclusion. 18
References . . . 18
1 Introduction
Cells have a remarkable ability to extract information from the extracellular en
vironment and to respond by altering their transcriptional and replication pro
grams, metabolism, shape, and many other aspects of their behavior. The
transduction of extracellular signals is particularly crucial in multicellular organ
isms, where development and adult life requires that each cell precisely adjust its
activities to conform to the needs of the whole organism. From an engineering
standpoint the mechanisms used to transduce signals must be combinatorial in
nature, because the limited number of total gene products implies that the trans-
Howard Hughes Medical Institute, Children's Hospital and Department of Microbiology and Molecular
Genetics, Harvard Medical School, 320 Longwood Avenue, Boston, MA 02115, USA
