Structure and Function
Mutations of Jak3 and Related Disorders
Jak3 Related Treatments for Immunodeficiency Disorders
Alterations of Jak3 Signaling
Jak3 is a member of the Janus kinase family of proteins which is comprised of Jak1, Jak2, Jak3, and Tyk2. These proteins bind to cytokine receptors and play an essential role in cytokine signaling (Chen and others 1997). Of these, Jak3 is unique in its expression and association. Jak3 is highly expressed in hematopoetic cells (Witthuhn and others 1994). Furthermore, it binds specifically to the common gamma chain (gc), which is a shared component of the Interleukin 2 (IL-2), IL-4, IL-7, IL-9, IL-15 receptors . These receptors are known to cause proliferation and differentiation of lymphocytes (Miyazaki and others 1994). The Jak3-gc interaction has proven to be of great interest due to its role in the causation of several different types immunodeficiency disorders (Candotti and others 1997, Russell and others 1994, Thomis and Berg 1997). The intense research in this area has important implications including treatment of Severe Combined Immunodeficiency (SCID) and production of novel immunosuppressant drugs.
Function (No PDB file currently available)
Jak3 functions as a key element in the signaling of cytokines. Jak3 is known to associate with the gc chain of receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, and is activated by these cytokines. In order to elucidate the role of Jak3 in the cytokine signaling pathway, the IL-2 pathway will be used as an example. IL-2 causes the heterodimerization or oligomerization of IL-2R chains a, b, and gc. Of relevance to Jak3 is the dimerization of the IL-2Rb and gc chains to both of which Jak3 binds. When dimerized these chains bind Jak3 and another member of the Janus kinase family, Jak1 (See Fig. 1). After binding Jak1 and Jak3 are activated presumably through auto- and trans-phosphorylation of the associated Jaks (Zhu and others 1998). These activated Jaks induce rapid tyrosine phosphorylation of signal transducers and activators of transcription 5 (STAT5) which then dimerizes through reciprocal phosphotyrosine-SH2 domain interactions. Upon dimerization STAT5 translocates into the nucleus and regulates transcription of target genes (Liu and others 1997).
Fig. 1: Schematic model demonstrating
binding of Jak3 to both IL-2Rb and gc.
A) (in order from left) Wildtype gc asscociates with Jak3 and is activated fully. Truncated gc cannot bind Jak3 and is partially
activated. Truncated gc cannot bind to Jak3 and no functional Jak3 is present, thus there is no activation
B) The formation of the IL-2Rb and gc heterodimer, stabilization of the complex by Jak3 and ensuing to signal cascade.
(Zhu and others 1998) Source: http://www.jbc.org/cgi/content/full/273/17/10719/F9
Permission requested, Figure will be removed if denied
Jak proteins are between 1100 and 1200 amino acids and are divided
into seven structural domains known as Jak homology (JH) domains (see Fig.
2). Liu (1997) demonstrates that the carboxyl JH1 region of the protein
contains the activation loop, a region that contains the tyrosine kinase
catalytic domain. JH1 has also been shown to be regulatory region.
Multiple sites of autophosphorylation have been identified. Furthermore
two tyrosine residues, Y980 and Y981, positively and negatively regulate
the Jak3 kinase activity, respectively (Zhu and others 1998). The
JH7-6 domains have also been shown to be important to the function of Jak3.
The amino terminal JH7-6 domains (aa 1-192) are the minimal region necessary
for gc association with Jak3. A model
has been proposed which explains binding. The JH7-6 domains of Jaks
contain loosely conserved region as well as highly variable regions.
The loosely conserved regions can bind to conserved membrane proximal regions
termed Box1 and Box2 in cytokine receptors. The highly variable regions
thus determine ligand specificity, gc as in
the case of Jak3 (Chen and others 1997).
Fig. 2: The organization of the Jak homology (JH) domains of the Jak3 protein (Notarangelo and Vihinen 1999).
See Copywrite Notice: http://www.uta.fi/imt/bioinfo/JAK3base/copyr.html
Another important function of Jak3 is its role in negative selection. Jak3-deficient mice when seeded with precursor cells were found to possess autoreactive T cells in the thymus and in the periphery. However, no autoimmune disease developed, indicating that the autoreactive T cells were anergic. The exact mechanism of this phenomenon is unknown, but several have been proposed. A Jak3-mediated growth signal may cause the deletion of autoreactive thymocytes in conjunction with the signals from the TCR. Other evidence supports the possibility that Jak3 is directly involved in T cell activation, but no conclusive evidence exists (Saijo and others 1997).
Mutations of Jak3 and Related Disorders
The cause for the immense amount of research on Jak3 is its role in several forms of immunodeficiency diseases. Approximately 50% of all SCID cases are caused by mutations in the gc chain resulting in an X-linked SCID phenotype. Jak3 mutations result in an autosomal recessive SCID that accounts for about 10% of all cases. The phenotypes of these two forms of SCID are indistinguishable as are the defects in the signaling pathways. An interesting note is that while humans with these mutations have B+ T- NK- SCID, mice with the same condition suffer from profound B lymphopenia as well (Brown and others 1999). The Jak3 -/- SCID mouse was found to have a diminished thymus and a lack of peripheral lymph nodes and Peyer’s patches. However, the thymocyte development and splenic T cells appeared normal. The T cell defects occurred in the proliferative response and in secretion of IL-2 in the presence of mitogen. Jak3 -/- mice also had B cell development arrested at the pre-B stage, presumably indicative of a defect in the IL-7 signaling pathway (Thomis and others 1995). Thomis and Berg (1997) further elucidate the defect in the T cells of Jak3 -/- mice. A transgenic reconstitution of the T cell function was performed with one transgenic line expressing Jak3 in the thymus and in the periphery and another transgenic line just expressing Jak3 in the thymus. Peripheral T cells in Jak3 -/- mice were found to resemble activated or memory T cells as were the peripheral T cells from the transgenic line expressing Jak3 only in the thymus. Conversely, the transgenic line that expressed Jak3 ubiquitously was found to have normal peripheral T cells. Thus, the cause of the phenotypic and functional defects in peripheral Jak3 -/- T cells were found to be a result of acquired defects in the periphery and not due to aberrant development within the thymus (Thomis and Berg 1997).
The membrane proximal regions of cytokine receptors contain the Box1 and Box2 motif that is essential to Jak activation and signal transduction. Jaks associate directly with these regions; moreover, a single point mutation has been shown to be able to disrupt this association sufficiently to cause SCID when the mutation occurs in the JH7 domain of Jak3. Point mutations gc can also result in SCID as well as XCID, an immunodeficiency disorder that still retains some function. A chimeric kinase was created using the JH7-6 domains of Jak3 with JH5-1 of Jak1. The resulting kinase was able to functionally substitute for Jak3 in the IL-2 receptor, indicating that the N-terminal JH7-6 domains determine binding with the cognate receptor in Jaks (Cacalano and others 1999).
Jak3 Related Treatments for
As a result of the intense research into the Jak3 -/- SCID, some novel approaches to treatment have been developed. The typical treatment of SCID is irradiation and bone marrow transplant (BMT). This is a cure if successful, but BMT is potentially dangerous and requires an HLA-matching donor, of which there are few (Bunting and others 1999). Brown (1998) demonstrates that the IL-3 pathway reconstitutes early lymphoid proliferation and function in Jak3 -/- mice. This alternative pathway could provide a means by which XSCID and Jak3 -/- SCID patients could receive treatment. Gene therapy is also becoming a viable approach. Retroviral-mediated gene transfer of murine Jak3 into the bone marrow of a Jak3 -/- mouse has been shown to reconstitute the T and B lymphocytes to sufficient levels to withstand a viral infection that had 100% mortality in Jak3 -/- mice without the gene therapy. This result has clear implications in human SCID and is entering human preclinical experimentation (Bunting and others 1999).
Alterations of Jak3 Signaling
No drugs are currently known to affect the Jak3 protein, although such a drug could have tremendous potential as a powerful immunosuppressant. However, staphylococcal enterotoxins disrupt the Jak/Stat pathway sufficiently to render T cells unresponsive to IL-2, leading to anergy and apoptosis (Nielsen and others 1995). Conversely, the Epstein-Barr virus latent membrane protein 1 (LMP1) inhibits apoptosis resulting in immortalized B cells. The purpose of this response is not entirely clear, but likely has to do with cell transformation and induction of growth in the context of an EBV infection (Gires and others 1999).
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