Janus kinases (JAK) are a family of non-receptor tyrosine kinases consisting of four members, JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). These highly related protein tyrosine kinases are 120-140 kDa, characterized by an amino-terminal portion of approximately 600 amino acids and two kinase domains, each of about 250 residues, separated by a short hinge region. They play a role in cell growth, survival, development and differentiation of a variety of cells. JAKs are involved in signal transduction of Type I and Type II cytokine receptors. Hormone-like cytokines bind to and activate Type I receptors which are characterized by a single transmembrane domain and a cytoplasmic tail lacking a kinase domain. Erythropoietin (EPO), prolactin (PRL) and growth hormone (GH) are hormone-like cytokines that bind to receptor homodimers EPOR, PRLR and GHR, respectively. JAK2 binds each of these receptors and plays a key role in signal transduction. Interestingly, JAK2 catalytic activity is also required for the degradation of EPOR, GHR and PRLR.
In EPO signaling, activation of JAK2 leads to phosphorylation of key tyrosine residues in EPOR thereby providing docking sites for SH2 domain-containing downstream signaling molecules. An unusual feature of JAK2 in EPOR signaling is that JAK2 autophosphorylation at Tyr913 results in negative regulation of the kinase. JAK2 also phosphorylates STAT5 resulting in its dimerization and nuclear translocation where it mediates EPO function in the production of red cells. SHP-1 and LNK negatively regulate EPOR signal transduction by inhibiting JAK2.
GH binding to GHR increases the affinity of JAK2 for GHR, potently activates JAK2, and stimulates the phosphorylation of tyrosines within JAK2 and the cytoplasmic domain of GHR. This allows the binding of adaptor molecules such as SHC1, which activates the ERK signaling pathway, and IRS, which activates the PI3K/AKT signaling pathway. SH2-B and SIRP are other JAK2 binding proteins that modulate the actions of growth hormone. JAK2 also phosphorylates STAT1,STAT3 and STAT5 thus allowing the formation of homo/heterodimers which translocate to the nucleus and regulate gene expression.
PRL binding to PRLR leads to receptor dimerization and activation of JAK2. JAK2 phosphorylates STAT1 and STAT5 on tyrosine residues. Homodimers of each of these STAT molecules can translocate to the nucleus and induce the expression of various genes involved in PRL function. Recent studies have shown that PRL induces JAK2 phosphorylation of the transcription regulator RUSH, creating the possibility of PRL-induced JAK/RUSH signaling.