JAK3

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JAKs are a family of nonreceptor protein tyrosine kinases that are critical for cytokine-receptor-binding-triggered signal transduction through Signal Transducer and Activator of Transcription (STAT) to the nuclei of cells. Structurally, JAK kinases are characterized by the presence of a pseudokinase domain directly adjacent to the kinase domain, and supposed to prevent inappropriate catalytic activity of the kinase domain in the absence of stimulus. The major substrates of activated JAKs are the cytoplasmic STAT molecules. STAT factors play an active role not only in physiologic hematopoiesis, but also in uncontrolled tumor transformation. STAT activation leads to growth signal self-sufficiency. In hematological malignancies, a common mechanism for constitutive STAT activation is the deregulation of tyrosine kinase activity of the cytokine-receptor complex by gain-of-function alterations affecting the JAK itself or its associated receptor chain.

The JAK family consists of four members: JAK1, JAK2, JAK3 and TYK2. In mammals JAK1, JAK2 and TYK2 are commonly expressed. In contrast, the expression of Janus tyrosine kinase 3 (JAK3) is more restricted. It is predominantly expressed in haematopoietic cells and is highly regulated with cell development and activation. JAK3 is solely activated by type I cytokine receptors featuring a common γ-chain (γc) subunit that are activated by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Mutations in either the γ-chain or JAK3 have been identified in humans as a cause of severe combined immunodeficiency disease (SCID), which manifests as a depletion of T, B, and natural killer (NK) cells with no other defects.

Several reports show that JAK is directly involved in human malignancies. The evidence is the identification of the TEL–JAK2 fusion gene in rare cases of leukemia. More and more reports show that JAK1 and JAK3 play an important part in activating mutations in human lymphoid leukemia. In contrast, TYK2 mutations are extremely rare in malignancies. Besides, the JAK family is also involved in the regulation of T-cell prolymphocytic leukemia (T-PLL), T-PLL is a rare hematological disease in elderly people characterized by a mature T-cell phenotype, a large tumor burden and a dismal prognosis.

In fact, JAK3 mutations have been identified in acute megakaryoblastic leukemia, T-cell prolymphocytic leukemia, and more recently in juvenile myelomonocytic leukemia and natural killer T-cell lymphoma (NK/T-lymphoma). The transformative potential of these JAK3 mutations has been confirmed in cell-based assays in vitro, and the JAK3 A572V mutation identified in acute megakaryoblastic leukemia was also shown to confer features of megakaryoblastic leukemia and transform murine lymphoid cells in vivo. Moreover, some reports show that expression of JAK3 mutants in hematopoietic stem/progenitor cells leads to the development of a T-ALL–like disease in a mouse bone marrow transplant model.

The aberrant activation of the Jak3/STAT pathway and interleukin-independent proliferation of malignant T cells appears to be in part a result of deficient expression and/or function of negative regulators such as Suppressors of Cytokine Signaling-3 (SOCS3) and the protein tyrosine phosphatases (e.g. SHP1). Importantly, the Jak3/ STAT pathway regulates the production of angiogenetic factors, and confers resistance to treatment with. In addition, it has been shown that a close relationship exists between JAK1 and JAK3 at the normal IL7 receptor (and other type I cytokine receptors), JAK1 is essential for the transforming properties of JAK3 pseudokinase domain mutants, and that transformation by JAK3 mutants was lost upon knock-down of JAK1.