The International Journal of Biochemistry & Cell Biology
Molecules in focusJAK3: A two-faced player in hematological disorders
Introduction
Janus Kinase 3 (JAK3) also known as Leucocyte JAK (L-JAK) was cloned in 1994 from natural killer cells by the group of John O'Shea (Kawamura et al., 1994). JAK3 belongs to a family of four membrane-associated intracellular non-receptor tyrosine kinase proteins (JAK1, JAK2, JAK3, and TYK2) that mediate signals initiated by cytokine and growth factor receptors. This review highlights the recent observation that abnormal activation of JAK3 is also found in human hematologic malignancies, indicating that a tight balance in its activity is essential for normal hematopoietic development.
Section snippets
Structure
The JAK3 gene is located on human chromosome 19p13.1 and comprises 24 exons (Fig. 1). The commonly described isoform (JAK3S) encodes an 1124-amino acid (aa) protein with a predicted molecular mass of 125 kD. Alternative splicing in exon 24 also leads to the expression of JAK3B (a 1094-aa protein lacking part of the kinase domain) and JAK3 M (a 1131-aa protein).
The JAK3 protein presents seven JAK homology (JH) domains common with the other JAK proteins (Baker et al., 2007). Although the crystal
Expression and activation
In sharp contrast with the ubiquitous expression of the other JAKs, JAK3 is predominantly expressed in hematopoietic tissues (Ghoreschi et al., 2009, Thomis and Berg, 1997), but has also been detected in brain, spinal cord, heart, skeletal muscle, liver, pancreas, prostate, kidney, and lung. JAK3 expression is also found in epithelial cancer cells, including primary breast cancer and cell lines (SW480: colorectal adenocarcinoma, A549: lung carcinoma, and G361: melanoma).
In addition to its
Biological function and mutations in hematologic disorders
The function of JAK3 is linked to the function of the cytokine receptors that use the γc receptor chain. As a result, the best-characterized role of JAK3 in hematopoiesis is during lymphocyte development in which these receptors were shown to have an important role (Ghoreschi et al., 2009, Thomis and Berg, 1997). The function of JAK3 in non-hematopoietic cells remains to be determined, as is whether γc is required for its activation in these cells.
The role of JAK3 in hematopoiesis is
Therapeutic use of JAK3 inhibitors
As a kinase that can be targeted at the level of the ATP binding pocket, JAK3 has historically been a very attractive target for the development of small molecule inhibitors. Indeed, its restricted expression and function within the hematopoietic compartment should in principle result in very limited side effects on other organs. Therefore, based on the essential role of JAK3 in T and NK-cell development, the original idea was to obtain inhibitors that could serve as immunosuppressors (Pesu et
Acknowledgements
We apologize to those colleagues whose work could not be cited due to space constraints. We thank Pr. Gary Gilliland for critical discussions and support and Pr. Jon Aster, Pr. Harvey Cantor, Pr. Jean-Philippe Merlio, Dr. Scott Rodig and Dr. Olivier Bernard for helpful discussions. TJB is funded by NIAID, R01 AI075133. TM is an INSERM investigator and is funded by a European Society of Hematology (EHA) José Carreras fellowship and an Agence Nationale Recherche grant.
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