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CHAPTER 88 Protein Kinase Antagonists in Therapy of Immunological and Inflammatory Diseases 1185

Protein Kinase Antagonists in Therapy of

Immunological and Inflammatory Diseases

Arian Laurence, Massimo Gadina, John J. O’Shea

Reversible phosphorylation is one of the major mechanisms kinase-independent manner but, nonetheless, signal through
controlling protein activity in all eukaryotic cells and, as such, kinase cascades to exert their effects. It is clear that many aspects
is involved in all fundamental cellular processes, including cell of protein phosphorylation are of major importance in immune
cycle and cell growth, cell shape and movement, metabolism, and inflammatory mechanisms.
differentiation, and apoptosis. This covalent modification is a The nonredundant functions of various kinases in different
major means for transmitting information from outside the cell immune cells are exemplified by both studies in knock-out mice
and between the subcellular components within the cell. Phos- and humans with mutations. On the basis of these findings,
phorylation is a major mechanism underlying normal signaling, targeting protein kinases has been proposed to be a useful strategy
as exemplified by insulin and other growth factors, but in addition, in the development of novel immunosuppressant drugs and is
the importance of protein phosphorylation is supported by one of the most active areas of pharmaceutical drug development
evidence that mutations and dysregulation of protein kinases (Table 88.3), with much of the impetus coming from oncology.
play causal roles in human disease. This is especially true in The field is so vast that it is impractical to comprehensively
cancer, in which mutant protein kinases or their upstream review all this information in one chapter; therefore we will
activators function as oncogenes. focus both on important historical precedents in the field and
From the point of view of an immunologist, protein phos- then discuss drugs and targets that are most immunologically
phorylation is also the major mechanism by which immune relevant. We will start by briefly reviewing some of the basics
receptors, including the T-cell receptor (TCR), B-cell receptor, of kinase biochemistry.
and natural killer (NK) cell receptor and Fc receptors, trigger
signaling. As discussed in Chapter 4, the first step in signaling by STRUCTURE AND FUNCTION OF PROTEIN KINASES
multichain immune recognition receptors (e.g., the aforementioned
receptors) is tyrosine phosphorylation of the receptor itself and
adapter molecules, such as linker of activated T cells (LAT), KEY CONCEPTS
mediated by Src family protein tyrosine kinases (PTKs). This Kinase Families
leads to the recruitment of PTK members spleen tyrosine kinase
(Syk) and Zap70 followed by phosphorylation of adapters, such • 518 kinases in the genome
as SH2 domain-containing leukocyte phosphoprotein of 76 kDa • 90 protein tyrosine kinases (e.g., Janus kinases [JAKs])
(SLP-76) and the activation of Tec family PTKs. These initial • 400 protein serine/ threonine kinases:
steps trigger the activation of serine-threonine kinases, including • AGC kinase family (e.g., protein kinase B/AKT)
• CAMK kinase family (e.g., calmodulin-dependent kinase)
the mitogen-activated protein kinases (MAPKs) and protein kinase • CMGC kinase family (e.g., MAP kinases: ERK, JNK, p38)
C (PKC) family (Fig. 88.1). We now know a great deal of details • STE kinase family (e.g., MAPK kinases, MAPKK kinases)
about how the cascade of protein phosphorylation links events • TKL kinase family (e.g., IRAK)
at the plasma membrane to calcium modulation, cytoskeletal • Others: casein kinase family, GYC kinase family, IKK family
rearrangement, gene transcription, and other canonical features
of lymphocyte action (Chapter 12).
Similarly, a critical first step in signaling by many cytokine Protein kinases or phosphotransferases catalyze the transfer of
receptors is the activation of phosphorylation. The receptors for the γ-phosphate from a purine nucleotide triphosphate (i.e.,
classical growth factor cytokines, including stem cell factor and adenosine triphosphate [ATP] and guanosine triphosphate [GTP])
platelet-derived growth factor (PDGF) are receptor tyrosine to the hydroxyl groups of their protein substrates. They generate
kinases (RTKs), whereas the receptors for transforming growth phosphate monoesters by using protein alcohol groups (on serine
factor family cytokines are receptor serine–threonine kinases. and threonine residues) and/or protein phenolic groups (on
Type I and II cytokine receptors signal via the activation of tyrosine residues) as phosphate acceptors. Thus protein kinases
receptor-associated Janus kinases (JAKs; see below, Table 88.1 can be classified by the amino acid substrate preference: serine/
and Table 88.2) (Chapter 9). Other cytokines like interleukin threonine kinases, tyrosine kinases, and dual kinases (i.e., both
(IL)-1 and tumor necrosis factor (TNF) initiate signaling in a serine/threonine and tyrosine residues can be phosphorylated).

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