JAKs are ubiquitously expressed, cytoplasmic proteins that are associated with tyrosine kinase receptors; they are required for the biological effects of most cytokines. They can couple cytokine receptors to a variety of downstream signal transduction pathways, but are specific for activation of a unique family of transcription factors, known as STATs.
The JAK family consists of four members, each with a molecular weight in the range of 120 to 130 kDa. These proteins have a kinase domain in the C-terminus, which is preceded by a pseudokinase domain, the function of which is uncertain. The association of JAKs with the receptor depend upon the receptor structure (1). Single-chain receptors (such as those for GM-CSF colony stimulating factor or growth hormone) interact with JAK through a JAK-binding domain in the juxtamembrane region. Receptor aggregation is then thought to bring the kinases into proximity, causing their phosphorylation of each other and activation. Receptors for ligands such as the interleukins IL-3 and IL-6 contain two subunits. In this case, the b chain, which may be shared among different ligand-binding achains, interacts with JAK in a similar juxtamembrane region, undergoing activation upon aggregation. Some receptors (such as those for interferons) contain three independent subunits, in which b and g chains are required for signaling through JAK.
1. Downstream Substrates
Like tyrosine kinase receptors, the JAK-associated cytokine receptors activate a variety of signaling pathways in cells, depending on the combinatorial diversity of the SH2 domain-containing proteins that are involved (1). A number of the signaling subunits for the cytokine receptor have consensus binding sites for proteins such as g, SHP2, phosphoinositide 3′-kinase, Shc, and others. Additionally, the JAK proteins can phosphorylate a variety of intracellular substrates, including IRS proteins, Shc, and others, that lead to activation of the MAP kinase and phosphoinositide 3′-kinase-initiated cascades. However, the one family of intracellular substrates that is more or less specific for this family of receptors are the STAT proteins.
2. STATs
STATS are SH2-containing substrates of the JAK kinases that act as transcription factors, directly linking the receptor to the regulation of gene expression. All of these proteins contain a C-terminal SH2 domain, an SH3 domain, and several additional domains at the amino terminus. The SH2 domains of the different STAT family members recognize discrete docking sites on the receptor complex. STATs are recruited to the receptor upon cytokine binding, when they undergo phosphorylation of tyrosine residues by JAK. Phosphorylation then triggers formation of another complex with other cellular proteins, or in some cases dimerization. This dimerization is mediated by intermolecular SH2 interactions. These phosphorylation-induced protein-protein interactions are accompanied by nuclear localization of the protein, where it can bind to specialized upstream activating sequences in the promoters of responsive genes.
