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C H A P T E R 7

SIGNALING TRANSDUCTION AND METABOLOMICS

Pere Puigserver

Hematopoiesis is a cellular process in which self-renewing stem SIGNALING TRANSDUCTION
progenitor cells differentiate into mature blood cells, which carry
out specific biologic functions. These functions include oxygen Hematopoietic cells use general signaling transduction pathways that
delivery, clot formation, and defense of the host from infection. are common to most cell types. The specificity in these signaling
Homeostasis of the whole hematopoietic system in vivo requires a transduction pathways is often established at the beginning of the
tight control of systems and networks governing proliferation, cell pathway’s activation; for example, by specific antigen-binding or
fate, cell death, differentiation, cell–cell interaction, and migra- ligand–membrane receptor complexes (Table 7.2), and at down-
tion. Imbalance in or dysregulation of these processes results in stream targets including transcription of the specific genes that will
pathologic alterations. For example, uncontrolled cell proliferation serve to define a particular biologic response (see Fig. 7.1). Here we
is a signature of leukemias, and defective lymphocyte differentia- will review these general signaling transduction pathways, illustrating
tion can lead to immunodeficiency. A better understanding at the some of the specific components of hematopoietic cells.
molecular level of these biologic events will help to identify new
therapeutic targets for the design of better drugs to treat hematologic Receptor Tyrosine Kinases, Phosphoinosite-3-Kinase,
diseases.
Because of the diversity in cellular types and their respective, spe- and Mitogen-Activated Protein Kinase Pathways
cific biologic functions, hematopoietic cells respond to a broad array
of extrinsic and intrinsic signals transduced through signaling and Receptor Tyrosine Kinases
metabolic pathways. It is therefore important to recognize that these
pathways serve to ultimately define a specific functional response in Receptor tyrosine kinases (RTKs) are enzyme-linked receptors local-
a given cell type. These regulatory signals (Table 7.1) can be general, ized at the plasma membrane containing an extracellular ligand-
such as growth factors (e.g., insulin growth factor [IGF], fibroblast binding domain, a transmembrane domain, and an intracellular
growth factor [FGF]), or amino acids that control proliferation, or protein–tyrosine kinase domain. In general, the ligands for RTKs are
highly specific, such as the antigen signaling response in immune proteins such as IGF, epidermal growth factor (EGF), platelet-derived
cells or 2,3-diphosphoglycerate in erythrocytes. Importantly, the growth factor (PDGF), and FGF. Ephrins that bind to Eph receptors
action of these signals, as well as their integration inside the cell, also form a large subset of RTK ligands. Colony-stimulating-factor
is needed to accomplish a specific cellular task (either a physiologic 1 (CSF-1), which is important for macrophage function, is another
or cellular fate decision). Moreover, as will be discussed later in example of an RTK ligand. RTKs can function as monomers or
this chapter, these signals also serve to tightly control metabolites multimeric subunits assembled at the plasma membrane that, upon
in hematopoietic cells, defining a metabolomic profile involved in ligand binding, cause oligomerization or conformational changes
processes such as anaerobic glycolysis for energy generation in red followed by tyrosine (trans)-phosphorylation in the kinase activation
blood cells. loop. Activation of RTKs results in phosphorylation of additional
Extrinsic cellular signals, often polypeptides, are recognized by sites in the cytoplasmic part of the receptor, leading to docking of
plasma membrane receptors that trigger a phosphorylation cascade protein substrates, which initiates the intracellular signaling cascade.
(using tyrosine and/or serine/threonine residues) that propagates These substrates bind to RTK-phosphorylated tyrosines through
through the cytoplasm and cellular organelles, including the nucleus. Src Homology domain-2 (SH2) or phosphotyrosine-binding (PTB)
Thus, the sequential activation of this cascade occurs in a temporal domains. Examples of these types of proteins are insulin receptor
and spatial manner to define the specific biologic response. In general, substrates or the p85 regulatory subunit of PI3K. RTKs recruit,
there are two types of signals (Fig. 7.1): (1) signals that transduce assemble, and phosphorylate different proteins including adaptors
immediate- or short-term biologic outputs without changes in gene and enzymes.
expression, and (2) signals that transduce medium- and long-term There are mechanisms to terminate ligand-induced RTK activity
biologic outputs with changes in gene expression. In the first case, through cellular processes including receptor-mediated endocytosis
for example, chemoattractants induce the phosphatidylinositol and/or through a family of regulated protein tyrosine phosphatases
3-kinase (PI3K) and Cdc42 pathways to rapidly establish neutrophil (PTPs), some of which are transmembrane and have extracellular
polarity. One example in the second case is the signaling trans- domains, suggesting the possibility of ligand-mediated regulation.
duced through Frizzled (Fz) receptors and the transcription factor Interestingly, there is also intracellular regulation of PTPs through
T-cell–specific transcription factor (TCF)-1 necessary for T-cell negative-feedback loops to attenuate the signal or direct control
development. In both cases, the signals transduced are amplified through reactive oxygen species (ROS) (see later discussion).
through a series of physical interactions and chemical modifications
on proteins, the most common being phosphorylation, but others
such as ubiquitination, acetylation, and sumoylation also play Phosphatidylinositol-3-Kinase Pathway
important roles.
In this chapter, a general survey of the different key signaling and One of the key signaling components associated with RTKs is
changes in metabolite profiles that operate in hematopoietic cells the phosphatidylinositol-3-kinase (PI3K) signaling transduction
will be reviewed. The goal is to provide the molecular basis by which pathway. This pathway is also activated by cytokine receptors and
signals are transduced and control fundamental cellular processes in G-protein–coupled receptors (GPCRs). Among the many functions
different lineages of the hematopoietic system. of this pathway in hematopoietic cells, the IL-3–dependent survival

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