Current Topics in Microbiology 228 and Immunology Editors R.W. Compans, Atlanta/Georgia M. Cooper, Birmingham/Alabama l.H. Hogle, Boston/Massachusetts' Y. Ito, Kyoto H. Koprowski, Philadelphia/Pennsylvania' F. Melchers, Basel M. Oldstone, La lolla/California . S. Olsnes, Olso M. Potter, Bethesda/Maryland' H. Saedler, Cologne P.K. Vogt, La lolla/California . H. Wagner, Munich Springer Berlin Heidelberg New York Barcelona Budapest Hong Kong London Milan Paris Santa Clara Singapore Tokyo 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 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. (1) Springer-Verlag Berlin Heidelberg 1998 Library of Congress Catalog Card Number 15-12910 Softcover reprint of the hardcover I st edition 1998 The use. of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting other relevant literature. Typesetting: Scientific Publishing Services (P) Ltd, Madras SPIN: 10630881 27/3020 - 5 4 3 2 I 0 - Printed on acid-free paper 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