ReviewSignaling through the JAK/STAT pathway, recent advances and future challenges
Introduction
Cytokines regulate numerous aspects of hematopoiesis and immune response. They mediate their responses through activation of the JAK/STAT signaling pathway. STATs (signal transducers and activators of transcription) comprise a family of seven structurally and functionally related proteins: Stat1, Stat2, Stat3, Stat4, Stat5a and Stat5b, Stat6. JAKs (janus kinases) represent a family of four non-receptor tyrosine kinases, Jak1, Jak2, Jak3 and Tyk2. These kinases selectively phosphorylate STATs, leading to their activation. Once activated, STAT then play a critical role in regulating innate and acquired host immune responses. Dysregulation of at least two STAT signaling cascades (i.e. Stat3 and Stat5) is associated with cellular transformation.
STATs transduce signals for the large hematopoietin subfamily of cytokines, and the conserved family of the receptors they bind. This includes the interferon (IFN) family (IFN-α/β, IFN-γ; interleukin (IL)-10, IL-19, IL-20, IL-22), the gp 130 family (IL-6, IL-11, OSM, LIF, CT-1, G-CSF, IL-12, IL-23, Leptin, CTNF, NNT-1/BSF-3), the γC family, (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21) and the single chain family (Epo, GH, PRL, Tpo) of the receptors (reviewed in Schindler and Strehlow, 2000). STATs can also be activated by receptor tyrosine kinases, such as epidermal growth factor receptor (EGF-R), colony stimulating factor-1 receptor (CSF-1R), and platelet derived growth factor receptor (PDGF-R). Several members of the G-protein-coupled receptors, a primitive family, have also been shown to signal through STATs (Leonard and O'Shea, 1998, Schindler and Strehlow, 2000).
Signaling through the JAK/STAT pathway is initiated when a cytokine binds to its corresponding receptor (Fig. 1). This leads to conformational changes in the cytoplasmic portion of the receptor, initiating activation of receptor associated members of the JAK family of kinases. The JAKs, in turn, mediate phosphorylation at the specific receptor tyrosine residues, which then serve as docking sites for STATs and other signaling molecules. Once recruited to the receptor, STATs also become phosphorylated by JAKs, on a single tyrosine residue. Activated STATs dissociate from the receptor, dimerize, translocate to the nucleus and bind to members of the GAS (gamma activated site) family of enhancers. This review will focus on more recent developments in STAT signaling, highlighting structural studies, nuclear translocation, gene targeting, as well as newly identified regulatory molecules.
Section snippets
JAKs in cytokine signaling
When ligands bind to their receptors they initiate a cascade of intracellular phosphorylation events. However, members of the hematopoietin receptor family, which bind to type I and type II cytokines, possess no catalytic kinase activity. Rather, they rely on members of the JAK family of tyrosine kinases to provide this activity. JAKs are constitutively associated with a proline-rich, membrane proximal domain of these receptors, often referred to as box1/box2 region (Ihle, 2001). Upon ligand
STATs
The seven STAT proteins identified in mammals range in size from 750 and 850 amino acids. Both, the chromosomal distribution of these STATs, as well as the identification of STATs in more primitive eukaryotes, suggest that this family arose from a single primordial gene. Duplications of this locus appear to reflect an increasing need for cell-to-cell communication as eukaryotes became more complex. Consistent with this evolutionary pattern, STATs share structurally and functionally conserved
Regulation of the JAK/STAT signaling pathway
The JAK/STAT pathway is important for many host responses including defense, differentiation, proliferation, and oncogenesis. It is, therefore, not surprising that numerous regulatory layers exist to modulate this signaling pathway. This includes both negative and positive regulation. The effect of these regulatory processes determines the rate at which STAT signals are transduced.
Concluding comments
STATs were first identified as IFN dependent transcription factors. However, now seven members of the mammalian STAT family are known to transduce vital signals for all ∼50 hematopoietin ligands (see Table 1), as well as a limited number of additional ligands. Characterization of STAT homologs in Drosophila and Dictyostelium suggest that this family evolved with the need for increased cell-to-cell communication. STATs continued to co-evolve with mammals, increasing both in number and diversity
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