Immunotherapy for Infectious Diseases

122 Matthews
The Jak-Stat Model of Signal Transduction
Several cytokine receptors lack intrinsic tyrosine kinase activity in their cytoplasmic
domains but can activate a family of cytoplasmic protein tyrosine kinases, Jaks (Janus
kinases). The model for the signaling mechanism that utilizes Jaks was characterized by
activation studies in mutants of the IFN-�� and IFN-� receptors (15). In this model, binding
of cytokine ligand to the IFN-�� or IFN-� receptors results in the dimerization of
the receptor subunits. This dimerization (or oligomerization in cytokine receptors with
more than two chains) increases the affinity of the dimers’ cytoplasmic domain that is
proximal to the membrane to bind two Jaks. In the case of IFN-� the two chains bind
Jak 1 and Tyk 2; the chains of the IFN-� receptor bind Jak 1 and Jak 2. Both the Jaks
and the cytoplasmic region of the receptor chain become phosphorylated simultaneously.
This phosphorylation subsequently becomes a catalyst for the binding and phosphorylation
of two latent cytoplasmic transcription factors called Stats, i.e., Signal transducers
and activators of transcription. Following the phosphorylation of Stats by Jaks, the Stats
dimerize, and this activated Stat-Stat complex enters the nucleus, where it initiates gene
transcription by binding to specific promoter sequences in cytokine response genes,
resulting in the ultimate step of gene transcription.
Four Jaks have been identified: Jak 1, Jak 2, Jak 3, and Tyk 2. In addition to the
IFN-� receptor, Jak 2 is involved with signaling by granulocyte/macrophage (GM)-
CSF, granulocyte (G)-CSF, IL-6, and IL-3. Both Jak 1 and Jak 3 are involved with signaling
of the � chain subfamily of the cytokine receptor superfamily such as IL-2, IL-4,
and IL-9. IL-12 activates Jak 2 and Tyk 2. The actual number of Stats is uncertain, but
at least six have been characterized. The Stats have structurally conserved binding sites
to phosphotyrosine and conserved sequences of their nuclear DNA binding regions.
Given the number of Jaks and Stats, it is understandable that different cytokine receptors
associate with different Jaks, which then catalyze the binding and phosphorylation
of different Stats (16). The network of interaction between the Jaks and Stats can be
quite extensive. For example, the Jak 1 and Jak 3 activated by IL-2 receptor binding
activates Stat 3 and Stat 5, and the same Jaks activated by IL-4 binding activates Stat
6. To add to the complexity, Stats can be phosphorylated by kinases other than Jaks,
e.g., protein tyrosine kinases of the src family. Although many receptors related to the
cytokine receptor superfamily as well as receptors in some of the other families use the
Jak-Stat model of signal transduction, other cytokines such as TNF-� and IL-1-� activate
members of the mitogen-activated protein (MAP) kinases, with resultant transcription
of nuclear protooncogenes.
CHEMOKINES
Chemokines are low-molecular-weight peptides that have evolved relatively recently.
They share a high basic nature and can bind heparin through heparin binding domains.
Chemokines are produced by nearly every cell type in response to inflammatory signals,
particularly signals that activate interactions between leukocytes and endothelial
cells. The first chemokine purified was platelet factor 4 (PF-4) in 1977 (17), and IL-8
was purified ten years later (18). Chemokines range between 68 to 100 amino acids in
length and are defined by conserved motifs containing either two or four cysteine
residues that form disulfide bonds in the protein tertiary structure.