2 Intracellular Signaling

Aphrothiti J. Hanrahan, Gopa Iyer, and David B. Solit

SUMMARY O F K E Y P O I N T S
Ligand binding and activation A subset of cancers are dependent develop treatment regimens that
of cell surface and internal on genomic alterations in oncogenes target the driver oncogenes and
receptors triggers the activation or tumor suppressor genes for tumor suppressors responsible for
and/or suppression of signaling their growth and survival, a tumor progression in individual
cascades that regulate diverse phenomenon known as oncogene patients with cancer. Potential
cellular processes, including addiction. challenges to the application of
cell growth, proliferation, Drugs that selectively inhibit altered this approach include the current
survival, and invasion, among proteins that are critical for the inability to directly inhibit some
others. maintenance of the transformed oncogenic proteins (i.e., KRAS),
Multiple nodes within these phenotype have shown the development of drug resistance,
intracellular signaling networks are unprecedented clinical activity in technical hurdles posed by limited
genetically and epigenetically altered genetically defined subsets of tissue availability for genomic
in human cancers, leading to cancers. studies, and intratumoral and
constitutive pathway activation or Precision medicine is the use of lesion-to-lesion genomic
suppression. genetic and epigenetic information to heterogeneity.

INTRODUCTION domain structure. Growth factors bind to the extracellular ligand-

The underlying basis of the cancer phenotype is deregulated cell
growth, which stems from two main hallmarks of cancer: uncon-
trolled proliferation and loss of programmed cell death (enhanced
survival). In normal cells, these processes are tightly controlled by the
discrete integration of signaling cascades that translate extra- and
intracellular cues into specific output responses. These signaling path-
ways are often initiated on binding of ligand to the extracellular
domain of a receptor, followed by recruitment of adaptor proteins or
kinases that activate an intracellular cascading network of protein and
lipid intermediaries that produce a cellular response. The specificity,
amplitude, and duration of signaling are critical for normal cellular
function, and these constraints are often abrogated in human cancer.
Investigation of the signal transduction pathways that regulate
normal cellular functions has revealed that key components of
these networks are commonly altered in cancer cells by mutation,
amplification/deletion, chromosomal translocation, overexpression,
or epigenetic silencing. These alterations lead to constitutive activa-
tion or suppression of signaling that underlie the various hallmarks
of the cancer phenotype. In this chapter, we will review the major
signal transduction cascades, with a focus on the ones that are com-
monly altered in human cancers. Individual sections will highlight
signaling intermediaries that have been validated as drug targets in
patients with cancer.
RECEPTOR TYROSINE KINASE SIGNALING
The receptor tyrosine kinases (RTKs) comprise a family of transmem-
brane cell surface receptors that transduce extracellular signals inter-
nally to promote growth or survival and/or regulate other cellular
phenotypes.1,2 Members of this protein family share a similar modular
binding domain of RTKs and induce dimerization of two receptor
monomers, juxtaposing the intracellular tyrosine kinase domains of
each monomer.3 This process results in transphosphorylation of tyro-
sine residues within the cytoplasmic domains of the RTK dimer. After
transphosphorylation, a variety of intracellular proteins are recruited
to the activated RTK through Src homology 2 (SH2) domains that
recognize the phosphotyrosine plus a specific amino acid sequence
motif C-terminal to the tyrosine residues.4,5
More than 117 SH2 domains have been characterized, each with
unique phosphotyrosine sequence specificities.6 Each domain is part
of a larger adaptor protein involved in transducing extracellular
signals to activate, or in some cases suppress, specific intracellular
signaling cascades. Thus the complement of signaling pathways that
a given RTK regulates is dictated by the profile of phosphorylated
tyrosine residues plus flanking amino acids within their intracellular
domains.7,8 However, more than one adaptor protein can often rec-
ognize individual context-dependent phosphotyrosine motifs within
an RTK, underscoring how this system is designed to provide both
specificity and diversity of intracellular signaling.
Recruitment of signaling intermediaries to the plasma membrane
facilitates their interaction with membrane-bound proteins respon-
sible for stimulating a diverse array of downstream pathways (Figs.
2-1 and 2-2). As an example, the lipid kinase phosphatidylinositol 3
kinase (PI3K), described in more detail in a later section, recognizes
and binds to a pattern of phosphorylated tyrosine residues found
within multiple activated RTKs through the SH2 domain located in
its p85 regulatory subunit. Binding of the p85 regulatory subunit in
turn results in activation of its kinase activity. Approximately 20
classes of RTKs have been defined based on growth factor specificity.
This section will focus on the RTK classes for which specific cancer
therapies exist or are in development.

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