Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application

JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway is one of the critical intracellular signaling cascades in transduction of extracellular signals to the nucleus to control gene expression. A variety of cytokines and growth factors complete their physiological tasks through JAK-STAT pathway, including hematopoiesis, immune-regulation, fertility, lactation, growth and embryogenesis [1-6].JAK family contains four cytoplasmic tyrosine kinases, JAK1-3 and Tyk2 [7]. These kinases bind to the juxta-membrane region of cytokine receptors [8]. Each molecule contains seven JAK homology domains (JH1-7). The carboxyl JH1 domain contains the catalytic activity, whereas N-terminal JH7 domain is responsible for receptor binding. JH2 domain has significant homology to JH1 but lacks enzymatic activity and therefore is a pseudo-kinase domain. Binding of a ligand to its receptor results in receptor dimerization, leading to activation of the JAK kinase activity. Subsequently activated JAKs phosphorylate cytoplasmic domain of the receptor [9]. Activated JAK-cytokine receptor complex recruits and phosphorylates specific cytoplasmic transcription factors called STAT proteins [10]. Seven STAT proteins have been identified in human cells, STAT1-6, including STAT5a and STAT5b [7]. Phosphorylation of specific STAT proteins results in their dimerization and subsequent translocation into the nucleus to interact with various regulatory elements for gene expression (Figure 1) [11,12].Three major mechanisms have been implicated to negatively regulate the JAK-STAT pathway [11]. Figure 1 depicts the positive and negative regulation of the JAK-STAT pathway.Src homology-2 (SH2) containing tyrosine phosphatase and CD45 tyrosine phosphatase play a major role in modulating JAK-STAT pathway. SH2 containing tyrosine phosphatases include SHP1 and SHP2 (shatterproof 1 & 2). Their SH2 domains allow attachment to the phospho-tyrosine residues present on activated recep