Chapter 27. The Role of JAKs and STATs in Transcriptional Regulation by Cytokines

Publisher Summary Cytokines exert their effects on the target cells by binding to specific cell surface receptors, triggering various intracellular events, including rapid changes in gene expression. The binding of a cytokine to its receptor activate the particular members of a family of tyrosine kinases that are known as just another kinases (JAKs). JAKs associate noncovalently with the cytoplasmic domain of the receptor. Activated JAKs then phosphorylate several substrates, including the receptor itself and members of a family of latent cytoplasmic transcription factors known as signal transducers and activators of transcriptions (STATs). Upon phosphorylation of a specific tyrosyl residue, STAT proteins become activated, and form homo- or heterodimeric complexes that translocate to the nucleus and bind to specific DNA sequences termed STAT binding elements (SBEs). The members of the JAK family interact noncovalently with cytoplasmic domains of cytokine receptor subunits. Like the JAKs, STAT proteins also form a complex with the receptor, but only after binding of the cytokine. The STAT1 and STAT2 proteins have been first identified as constituents of a heterotrimeric protein complex termed ISGF3 that bound to specific promoter sequences called IFN α/β-stimulated response elements (ISREs). Recent studies show that STAT1 is phosphorylated on a serine located near the C-terminus of the protein, within a mitogen-activated protein (MAP) kinase consensus sequence that is also present in a similar location in several other STAT proteins. Many cytokines that signal via the JAK/STAT pathway, including IFN α, IFN β IFN γ, IL-2, growth hormone, and the hematopoietic growth factors, Epo, G-CSF, and GMCSF, have proven clinical utility and other cytokines have high potential. The JAK–STAT signal transduction cascade is also amenble to the development of biochemical assays. Thus, the ordered series of steps mediated by JAKs and STATs has presented excellent opportunities for the discovery of novel drugs that modulate cytokine action.