Deric L. Wheeler Yosef Yarden Editors. Receptor Tyrosine Kinases: Structure, Functions and Role in Human Disease

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2 Deric L. Wheeler Yosef Yarden Editors Receptor Tyrosine Kinases: Structure, Functions and Role in Human Disease

3 Receptor Tyrosine Kinases: Structure, Functions and Role in Human Disease

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5 Deric L. Wheeler Yosef Yarden Editors Receptor Tyrosine Kinases: Structure, Functions and Role in Human Disease

6 Editors Deric L. Wheeler Department of Human Oncology University of Wisconsin Madison, WI, USA Yosef Yarden Department of Biological Regulation Weizmann Institute of Science Rehovot, Israel ISBN ISBN (ebook) DOI / Springer New York Heidelberg Dordrecht London Library of Congress Control Number: Springer Science+Business Media New York 2015 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, 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. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Humana Press is a brand of Springer Springer is part of Springer Science+Business Media (

7 This book is dedicated to the memory of Anthony (Tony) Pawson, who passed away in August 2013 (age 60). Tony was born and educated in England and lived in Canada. His research has revolutionized our understanding of tyrosine phosphorylation networks and signal transduction in general. Many of the principles and examples discussed in these handbooks were laid down by Tony s pioneering work uncovering the phosphotyrosine-binding Src homology 2 (SH2) domain, a prototype module of phosphorylation-based protein-protein interaction domains.

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9 Preface Multicellular organisms have evolved complex cellular communication pathways that enable cells to function and communicate in specific ways. These processes are mediated through a diverse group of cell surface receptors, including a group called receptor tyrosine kinases (RTKs). Receptor tyrosine kinases have intrinsic ability to transfer the gamma phosphate group from adenosine triphosphate to a tyrosine residue on a substrate protein, serving as an important signal for maintenance of cellular homeostasis or changes in cellular function. Accordingly, RTKs regulate a diverse array of cellular functions including cellular proliferation, survival, differentiation, migration, and metabolism. The human genome encodes 58 RTKs that fall into 20 subfamilies based on the ligands they bind, their sequence homology, and structure. The architecture of all RTKs is highly conserved from the nematode Caenorhabditis elegans, with an extracellular ligand-binding domain, a single transmembrane α helix, an intracellular tyrosine kinase domain, and a tyrosine-rich C-terminal tail. Receptor tyrosine kinases are activated upon binding to cognate ligands present in the extracellular milieu, leading to receptor homo- or hetero-dimerization, kinase domain activation, and subsequent phosphorylation of tyrosine residues located within the cytoplasmic tail. Phosphorylated tyrosines serve as docking sites for a variety of intracellular adaptors and effector kinases that transmit signals to the nucleus, resulting in changes in cell function or fate. Termination of RTK activation is tightly controlled through the activation of a variety of tyrosine phosphatases, receptor-mediated endocytosis, and subsequent receptor degradation. Indeed, the importance of many RTKs in mammalian development has been displayed through the study of genetically altered mice, resulting in either severe developmental abnormalities or embryonic lethality. Collectively, RTK activation of signaling networks provides an essential mechanism by which cells communicate to regulate a multitude of different cellular responses. Since RTKs regulate both developmental and regulatory cellular processes, it is not surprising that abnormalities in RTK structure or activity can result in human diseases. Several diseases result from RTK mutation, constitutive activation, and/or overexpression such as cancer, diabetes, inflammation, arteriosclerosis, angiogenesis, autoimmune disorders, and skeletal diseases. Due to this causal relationship, vii

10 viii Preface therapeutic targeting of RTK activity is clinically approved for treatment of several human diseases. The focus of this book is to provide a comprehensive outline for the role of RTKs in mammalian cell development, with a focus on RTK evolution over time, cellsignaling networks, with a focus on RTK structure and function, and finally how RTKs play fundamental roles in human disease. In the opening chapter, Tony Hunter and Gerard Manning provide a comprehensive overview of the eukaryotic protein kinase superfamily and the emergence of RTKs. Further, they discuss the human kinome and the role it plays in pathology. In the next chapter, Manfred Schartl, Jean-Nicolas Volff, and Frederic Brunet dovetail and expand the discussion of the evolution of RTKs. This chapter provides a useful reconstruction of the evolutionary history of the mammalian RTKs and the interrelationship of RTK families and their individual members, and how the emergence of RTKs grew in parallel with the increasing complexity of cell types and their individual functions in development and disease. After a thorough discussion on the emergence and evolution of RTKs Ben-Zion Shilo describes the role of RTKs in invertebrates. Specifically, the chapter highlights lessons learned from invertebrates and primitive signal transduction pathways and how they relate to higher level signaling in vertebrate animals. Building on RTK signaling in invertebrates, Pierre De Meyts advances this discussion on classical signaling mechanisms emanating from RTKs localized to the plasma membrane. Specifically, he highlights what is known about ligand requirements and dimerization events resulting in the activation of the kinase domain and phosphorylation of C-terminal tyrosines. Further, he provides an in-depth analysis of downstream signaling cascades activated by RTKs and how these events regulate cellular homeostasis, cell cycle, and apoptosis. Extending the conversation of RTK signaling, Yi Du, Jennifer L. Hsu, Ying-Nai Wang, and Mien-Chie Hung highlight an emerging novel signaling role of RTKs localized from within the nucleus. Here they highlight families of RTKs that have been identified in the nucleus, namely the HER/ERBB, FGFR, VEGFR, insulin and insulin-like growth factor receptor, HGFR, ROR, and EPH receptor families. Further, they provide a comprehensive analysis, notably centered on the epidermal growth factor (EGFR), and the events associated with EGFR translocation from the cell membrane to the nucleus. They further discuss novel functions of nuclear RTKs, such as their ability to function as co-transcription factors and nuclear kinases, and how these functions lead to poor prognosis of cancer patients and resistance to cancer therapeutics. Yehoshua Enuka, Morris E. Feldman, and Yosef Yarden build upon these two chapters and describe in-depth computational modeling of RTK signaling networks. Specifically they discuss the complexity of signaling and how a single ligandreceptor interaction can lead to a complex layered signaling network with both positive- and negative-feedback loops controlling this signaling network, ultimately feeding the output layer. Closing this section on RTK signaling, Alexander Sorkin and Arola Fortian provide an in-depth review of the events occurring after RTK activation, highlighting the EGFR as the prototypic experimental model. Specifically, they highlight the process of receptor-mediated endocytosis, a critical cascade

11 Preface ix necessary for RTK attenuation. In conclusion they discuss other RTK systems and deviations from lessons learned from EGFR trafficking. To better understand the structural features necessary for RTK activation and signaling, Michael C. Lawrence and Colin W. Ward discuss in depth the structural features shared among the ectodomains of RTKs. In this chapter they describe the modular structure of the ectodomains of each RTK and how these structural features define the 20 phylogenetic families of the RTK superfamily. As important as the ectodomains for ligand binding, the tyrosine kinase domain is just as critical for coupling extracellular signals across the membrane resulting in a signaling output. Dániel Süveges and Natalia Jura present a thorough review of the kinase domain and the architecture of the ATP-binding site. Further, they describe shared mechanisms for the activation of the kinase domain and provide discussion on the structural basis for regulation of kinase activity, including receptor oligomerization, the intracellular juxtamembrane segment, and regulation by the C-terminal tail. In the penultimate chapter Wolfgang J. Köstler and Christoph C. Zielinski advance our knowledge of how RTKs are being identified and pursued as molecular targets in the clinical arena with a thorough discussion on how RTKs drive tumor progression, approaches to target RTKs in the clinic, and the development of resistance to advanced therapeutics targeting RTKs. Further, this chapter elaborates on the approaches taken in the clinic to inhibit RTK activation, highlighting the next generation of RTK inhibitors. In the closing chapter of this book, Maria Sibilia and colleagues systematically review the contribution of genetic mouse models, including transgenic, knockout, and knock-in mice for several RTKs, used to elucidate the functions of individual receptors and their roles in mammalian development, embryogenesis, immune function, and pathophysiological processes. This chapter represents the most comprehensive summary of mouse models leading to the advancement of our understating of RTKs. Collectively, the chapters presented in this book provide the reader with a cumulative summary of how RTKs function and behave in mammalian systems, with hopes of fostering new endeavors by the next generation of RTK researchers. Madison, WI, USA Rehovot, Israel Deric L. Wheeler Yosef Yarden

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13 About the Editors Born in Washington State, Deric Wheeler received his Bachelor of Science degrees in Botany and Zoology from the University of Idaho (Moscow, ID), followed by a Masters in Pathology from the University of Iowa (Iowa City, IA) and a Ph.D. in Cancer Biology from the University of Wisconsin (Madison, WI). After his graduate training Deric Wheeler started his postdoctoral training at the Fred Hutchinson Cancer Research Center in Seattle, WA (c/o Larry R. Rohrschneider), and at the University of Wisconsin School of Medicine and Public Health in Madison (c/o Paul M. Harari). He completed his postdoctoral training and transitioned to faculty, at the level of Assistant Professor, at the University of Wisconsin School of Medicine and Public Health in the Department of Human Oncology. Dr. Wheeler s lab research centers on the role of subcellular localization of receptor tyrosine kinases and their roles in oncogenesis and therapeutic resistance. Currently, Dr. Wheeler s research is supported by the American Cancer Society, Mary Kay Foundation, the Department of Defense Lung Cancer Research Program, and the Clinical and Translational Science Award (CTSA) program through the NIH National Center for Advancing Translational Sciences (NCATS). xi

14 xii About the Editors Born in Israel, Yosef Yarden received his B.Sc. in Biological and Geological Sciences from the Hebrew University of Jerusalem, and a Ph.D. in Molecular Biology from the Weizmann Institute of Science. His postdoctoral training was undertaken at Genentech, Inc. (c/o Axel Ullrich) in San Francisco, and at the Massachusetts Institute of Technology (c/o Robert A. Weinberg). He returned to the Weizmann Institute of Science as an Assistant Professor, eventually becoming a Full Professor there. His past administrative responsibilities at the Weizmann Institute include Dean of the Faculty of Biology, Vice President for Academic Affairs, Director of the M.D. Moross Institute for Cancer Research, and Dean of the Feinberg Graduate School. Dr. Yarden s lab research centers on the roles played by growth factors and receptor tyrosine kinases in tumor progression. Currently, Yarden s research is supported by the US National Cancer Institute (MERIT Award), a grant from the European Research Council (ERC- AdG), the German Research Foundation (DIP), and a professorship from the Israel Cancer Research Fund (ICRF).

15 Contents 1 The Eukaryotic Protein Kinase Superfamily and the Emergence of Receptor Tyrosine Kinases... 1 Tony Hunter and Gerard Manning 2 Evolution of Receptor Tyrosine Kinases Manfred Schartl, Jean-Nicolas Volff, and Frederic Brunet 3 RTKs in Invertebrates: Lessons in Signal Transduction Ben-Zion Shilo 4 Receptor Tyrosine Kinase Signal Transduction and the Molecular Basis of Signalling Specificity Pierre De Meyts 5 Nuclear Functions of Receptor Tyrosine Kinases Yi Du, Jennifer L. Hsu, Ying-Nai Wang, and Mien-Chie Hung 6 Computational and Modeling Aspects of RTK Networks Yehoshua Enuka, Morris E. Feldman, and Yosef Yarden 7 Endocytosis and Endosomal Sorting of Receptor Tyrosine Kinases Alexander Sorkin and Arola Fortian 8 Structural Features of the Receptor Tyrosine Kinase Ectodomains Michael C. Lawrence and Colin W. Ward 9 Structural Features of the Kinase Domain Dániel Süveges and Natalia Jura 10 Targeting Receptor Tyrosine Kinases in Cancer Wolfgang J. Köstler and Christoph C. Zielinski xiii