JAK3: a two-faced player in hematological disorders

Abstract

JAK3 is a non-receptor tyrosine kinase, predominantly expressed in hematopoietic cells and that has been implicated in the signal transduction of the common gamma chain subfamily of cytokine receptors. As a result, JAK3 plays an essential role in hematopoieisis during T cell development. JAK3 inactivating mutations result in immunodeficiency syndromes (SCID) in both humans and mice. Recent data indicate that abnormal activation of JAK3 due to activating mutations is also found in human hematological malignancies, including acute megakaryoblastic leukemia (AMKL) and cutaneous T cell lymphoma (CTCL). After a brief summary of the JAK3 structure and function, we will review the evidence on the emerging role of JAK3 activation in hematological malignancies that warrant further studies to test the relevance of specific inhibition of JAK3 as a therapeutic approach to these challenging clinical entities.

Fig. 1

Structure of the JAK3 gene and protein. The human JAK3 genomic structure is shown in the upper panel and the JAK3 protein structure is represented in the middle panel. JAK3 is comprised of 7 JAK homology (JH) domains. JH1 contains the C terminus kinase domain; JH2 contains a pseudokinase domain and the alanine 572 residue which mutation to valine leads to constitutive activation of the kinase in acute megakaryoblastic leukemia and cutaneous T cell lymphoma. The N terminus region (JH6 and JH7) is critical for γ_c receptor binding and signal transduction. Y100C mutation found in SCID patients abolishes the interaction between JAK3 and the common γ_c chain. A cartoon representation of the JH1 domain of Jak3 (PDB code: 1YVJ) is shown (N-lobe is in green and C-lobe in blue) in the lower panel. A small molecule staurosporine analogue is seen bound in the kinase catalytic cleft in yellow. Conserved kinase domain residues are shown in stick representation and indicated HRD, KxxN, DFG, αC-E, vaiK and are important for orientation of the substrate residue hydroxyl group (HRD), γ-phosphate neutralization (KxxN), α- and β- phosphate positioning (αC-E, vaiK), metal binding (DFG), and conformational transition between active and inactive states (DFG). Human Jak3 varies from canonical kinase domains with substitutions of the KxxN and vaiK motifs to xxRN and vavK, both commonly seen substitutions. Phosphotyrosines pTyr-980 and pTyr-981 critical for JAK3 activity are shown in stick representation. Figure was made using Pymol (www.pymol.org).

Fig. 2

Schematic representation of the signal transduction initiated by cytokine receptors through JAK3. The heterodimeric IL7 receptor is used as an example. Conformational changes resulting from the binding of the cytokine to its receptor induce autophosphorylation of JAK3 and phosphorylation of the cytokine receptor by JAK3, which lead to recruitment of STAT and adaptor proteins that are then phosphorylated by JAK3 and other JAKs. Phosphorylated STAT factors migrate to the nucleus where they act as transcription factors of genes important for survival, proliferation and differentiation of lymphoid cells.