Disease relevance of JAK3

• In XSCID and SCID resulting from mutations in JAK3, which encodes a Janus family tyrosine kinase that couples to gamma(c) and is required for gamma(c)-dependent signalling, T- and natural killer (NK)-cells are decreased but B-cell numbers are normal (T(-)B(+)NK(-)SCID) [1].
• Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins [2].
• Additionally, JAK3 was detected in lysates from bone marrow lymphoblasts of patients with B cell precursor acute lymphocytic leukemia and cell lines derived from human B cell lymphomas [3].
• IL-4 also stimulated all three kinases and substrates, but unlike in immune cells, IL-4 did not involve JAK3 activation for its signaling in colon cancer cell lines [4].
• In B cells isolated from PBMC of AD patients with high serum IgE levels, JAK3 was constitutively phosphorylated at the tyrosine residue, and its phosphorylation was enhanced by the treatment with CD40L and/or IL-4 as was that in splenic B cells of NC/Nga mice with dermatitis and high IgE levels [5].

High impact information on JAK3

• Interaction of JAB with Jak1, Jak2 or Jak3 markedly reduces their tyrosine-kinase activity and suppresses the tyrosine-phosphorylation and activation of STATs [6].
• An Epstein-Barr virus (EBV)-transformed cell line derived from her lymphocytes had normal gamma c expression but lacked Jak3 protein and had greatly diminished Jak3 messenger RNA [7].
• The Janus family tyrosine kinase Jak3 is the only signaling molecule known to be associated with gamma c, so it was hypothesized that defects in Jak3 might cause an XSCID-like phenotype [7].
• Jak1 and Jak3 were found to be selectively associated with the "serine-rich" region of IL-2R beta and the carboxyl-terminal region of IL-2R gamma, respectively [8].
• Furthermore, Jak3-negative fibroblasts expressing reconstituted IL-2R became responsive to IL-2 after the additional expression of Jak3 complementary DNA [8].

Chemical compound and disease context of JAK3

• Here, we show that the inhibition of IL-2R expression and proliferation induced by ligation of CD4 by HIV envelope glycoprotein, gp120, is correlated with inhibition of expression and activation of JAK3 [9].
• While Jak3 SCID patients possess mature peripheral B cells, we demonstrate that the Jak3 tyrosine kinase is also expressed in human pre-B cells and can be activated by the pre-B cell growth factor IL-7 [10].

Biological context of JAK3

• Regulation of JAK3 expression in human monocytes: phosphorylation in response to interleukins 2, 4, and 7 [11].
• The absence of JAK3, but not IL-2R in T cells correlated with impaired IL-2-dependent signal transduction and proliferation [12].
• Downregulation of JAK3 protein levels in T lymphocytes by prostaglandin E2 and other cyclic adenosine monophosphate-elevating agents: impact on interleukin-2 receptor signaling pathway [12].
• Our findings show that prostaglandin E2 (PGE2) can inhibit upregulation of JAK3 protein in naive T cells and can downregulate its expression in primed cells [12].
• Inhibition of JAK3 induces apoptosis and decreases anaplastic lymphoma kinase activity in anaplastic large cell lymphoma [13].

Anatomical context of JAK3

• Recently, we have cloned a novel JAK family member, JAK3, that is expressed in natural killer and activated T cells and is coupled functionally and physically to the interleukin 2 (IL-2) receptor in these cells [11].
• Here we report that JAK3 was expressed at low but detectable levels in human monocytes [11].
• Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation [14].
• The characterization of the genetic defects and biochemical abnormalities in these JAK3-deficient patients will help define the role of JAK3 in the ontogeny of a competent immune system and may lead to a better understanding of the JAK3 functional domains [15].
• The discovery of these signaling pathways has led to important new insights into their role in lymphocyte maturation, as it has emerged that mutations in the genes encoding both gamma c and JAK3 result in similar forms of severe combined immunodeficiency (SCID) [16].

Associations of JAK3 with chemical compounds

• In contrast, JAK3 expression was strongly induced during activation by interferon gamma (IFN-gamma) or lipopolysaccharide [11].
• A single cysteine to arginine substitution (Cys759Arg) in this region resulted in high basal levels of constitutive JAK3 tyrosine phosphorylation unresponsive to either downregulation by serum starvation or cytokine-mediated upregulation [15].
• Moreover, 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of cAMP phosphodiesterase, potentiated PGE2-induced suppression of JAK3 [12].
• Inhibition of JAK3 may be controlled by intracellular cyclic adenosine monophosphate (cAMP) levels, as forskolin, a direct activator of adenylate cyclase and dibutyryl cAMP (dbcAMP), a membrane permeable analogue of cAMP suppressed JAK3 expression [12].
• Interestingly, JSI-124 also dramatically decreased the protein levels of JAK3 and nucleophosmin (NPM)-ALK, and these effects were reversible by MG132 [17].

Physical interactions of JAK3

• Both IL-2 and IL-4 bind to receptors containing the common gamma chain and JAK3 [18].
• As a result of this interaction, p12(I) increases signal transducers and activators of transcription 5 (STAT5) DNA binding and transcriptional activity and this effect depends on the presence of both IL-2R beta and gamma(c) chains and Jak3 [19].

Enzymatic interactions of JAK3

• JAK1 was also phosphorylated in one of two cell lines while JAK3 was present but not phosphorylated in any of the cell lines studied [20].
• Notably a polypeptide representing the kinase domain of Jak3 (Jak3-JH1) gained the ability to tyrosine phosphorylate STAT1, suggesting that the changes in substrate recognition may be influenced by domains outside the kinase domain [21].
• Furthermore, Jak3 protein was phosphorylated upon treatment of these cells with interleukin-4 [22].
• Neither Jak1 nor Jak3 was phosphorylated after IL-2 stimulation of an Epstein-Barr virus-transformed cell line (LCL) from an X-SCID patient with a gamma-c null mutation [23].
• In order to study whether there was any correlation between SHP-1 protein expression and tyrosine phosphorylated state of JAK3, the state of phosphorylation of JAK3 was studied in the T cell line HUT-78, and found to be highly phosphorylated [24].

Regulatory relationships of JAK3

• In these B cells, IL-4 failed to induce tyrosine phosphorylation of Jak3 and activation of STAT6, or activation of these molecules was significantly decreased compared with Epstein-Barr virus-transformed normal B cells [25].
• We demonstrate that IL4R triggering induced the tyrosine phosphorylation of JAK3 and of a p170 protein [26].
• On the other hand, IL-4 further augmented phosphorylation of JAK3 and induced the phosphorylation of JAK1 kinases [27].
• Expression of MMP-1 and MMP-3 was significantly inhibited by inhibition of JAK3 activity [28].
• Dendritic cells triggering through CD40 induced JAK3 activity, the expression of costimulatory molecules, production of IL-12, and potent allogeneic stimulatory capacity [29].

Other interactions of JAK3

• However, no detectable tyrosine phosphorylation of JAK1, JAK3, or TYK2 was observed [30].
• Recently, CD40 has been shown to associate with JAK3, a member of the family of Janus Kinases, which are nonreceptor protein kinases involved in intracellular signaling mediated by cytokines and growth factors [31].
• JAK3 mRNA was neither detected in colon cancer cells nor did IL-4 treatment cause phosphorylation of JAK3 [32].
• However, Jak3 was not activated by IL-13, even in normal B cells [25].
• Treatment with AG490, a JAK inhibitor, decreased but did not completely abrogate tyrosine phosphorylation of JAK3 and STAT3 in a concentration-dependent manner [13].

Analytical, diagnostic and therapeutic context of JAK3

• Interleukin (IL)-4 signaling proceeds via cytoplasmic activation of the Janus kinases JAK1 and JAK3 and the signal transducer and activator of transcription STAT6 [33].
• Analyses of expression of the JAK3 splice isoforms by reverse transcriptase-polymerase chain reaction on a panel of cell lines show splice preferences in different cell lines: the S-form is more commonly seen in hematopoietic lines, whereas the B- and M-forms are detected in cells both of hematopoietic and epithelial origins [34].
• At the steady state, JAK3 showed detectable tyrosine phosphorylation by immunoprecipitation [13].
• Ligation of RARgamma inhibits proliferation of phytohaemagglutinin-stimulated T-cells via down-regulating JAK3 protein levels [35].
• Western blot analysis showed that tumor supernatants suppressed expression of JAK3 and tyrosine phosphorylation of STAT5 [36].

References