Table Of ContentDeric L. Wheeler
Yosef Yarden Editors
Receptor Tyrosine
Kinases: Structure,
Functions and
Role in Human
Disease
Receptor Tyrosine Kinases: Structure, Functions
and Role in Human Disease
Deric L. Wheeler (cid:129) Yosef Yarden
Editors
Receptor Tyrosine Kinases:
Structure, Functions and
Role in Human Disease
Editors
Deric L. Wheeler Yosef Yarden
Department of Human Oncology Department of Biological Regulation
University of Wisconsin Weizmann Institute of Science
Madison , WI , USA Rehovot , Israel
ISBN 978-1-4939-2052-5 ISBN 978-1-4939-2053-2 (eBook)
DOI 10.1007/978-1-4939-2053-2
Springer New York Heidelberg Dordrecht London
Library of Congress Control Number: 2014954081
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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.
Pref ace
M ulticellular organisms have evolved complex cellular communication pathways
that enable cells to function and communicate in specifi c 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 resi-
due on a substrate protein, serving as an important signal for maintenance of cellu-
lar homeostasis or changes in cellular function. Accordingly, RTKs regulate a
diverse array of cellular functions including cellular proliferation, survival, differ-
entiation, 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 extra-
cellular 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 sub-
sequent 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 mamma-
lian 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, infl ammation, arteriosclerosis, angiogene-
sis, autoimmune disorders, and skeletal diseases. Due to this causal relationship,
vii
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, cell-
signaling networks, with a focus on RTK structure and function, and fi nally how
RTKs play fundamental roles in human disease. In the opening chapter, T ony
Hunter and Gerard Manning provide a comprehensive overview of the eukary-
otic 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 , a nd 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 emer-
gence 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 B en-Zion Shilo describes the role of
RTKs in invertebrates. Specifi cally, 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 dis-
cussion on classical signaling mechanisms emanating from RTKs localized to the
plasma membrane. Specifi cally, he highlights what is known about ligand require-
ments 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 high-
light an emerging novel signaling role of RTKs localized from within the nucleus.
Here they highlight families of RTKs that have been identifi ed 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 compre-
hensive 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 func-
tion 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.
Specifi cally they discuss the complexity of signaling and how a single ligand-
receptor interaction can lead to a complex layered signaling network with both posi-
tive- and negative-feedback loops controlling this signaling network, ultimately
feeding the output layer. Closing this section on RTK signaling, A lexander Sorkin
and Arola Fortian provide an in-depth review of the events occurring after RTK
activation, highlighting the EGFR as the prototypic experimental model. Specifi cally,
they highlight the process of receptor-mediated endocytosis, a critical cascade
Preface ix
necessary for RTK attenuation. In conclusion they discuss other RTK systems and
deviations from lessons learned from EGFR traffi cking.
To better understand the structural features necessary for RTK activation and
signaling, M ichael C. Lawrence and Colin W. Ward discuss in depth the struc-
tural 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 defi ne 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 out-
put. D ániel 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.
I n the penultimate chapter W olfgang J . Köstler and Christoph C. Zielinski
advance our knowledge of how RTKs are being identifi ed 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 resis-
tance 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, includ-
ing 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 Deric L. Wheeler
Rehovot, Israel Yosef Yarden
