Protein tyrosine kinase /JAK / STAT
Protein tyrosine kinase JAK / signal transducer and transcription activator STAT signaling pathway is another important kind of cytokine signaling pathways after the discovery of Ras pathway.
JAK (Januskinase) is a kind of protein tyrosine kinase, so far it has found of four family members, namely JAK1, JAK2, TYK2 and JAK3. The first three are widely distributed in various kinds of tissue cells while JAK3 can only be found in the bone marrow and lymphatic system. STATs (signal transducer and activator of transcription) are the direct substrates of JAKs, being able to transmit the signaling formulation into the nucleus to regulate the expression of specific genes.
Janus protein tyrosine kinase (JAK) a kind of non-receptor protein tyrosine kinases (protein tyrosine kinase, PTK) identified in recent years that have been found of playing an important role during the process of cell signaling transduction. It can be activated after the corresponding cytokine receptor has been bound by ligand and can activate another signaling protein molecule “signal transducer and activator of transcription" (STAT) to achieve the induction of target gene expression. JAK protein tyrosine kinase family is the third largest non-transmembrane protein tyrosine kinases (NMPTKs) family that is only behind Src and Tec, including a total of four members, namely JAK1, JAK2, JAK3 and Tyk2.
They vary on their size with the molecular weight ranging between 120 kD ~ 140 kD. The molecules of the JAK family can be structurally divided into two parts, the C-terminal is consists of two tightly connected tyrosine kinase-like domains with the one closer to the C-terminus being the catalytic region of the JAK kinase, while the other kinase-like domain located in its N-terminal has no tyrosine kinase activity. Currently it is thought that it may play a role in the conjunction between JAK kinase with other kinds of signaling protein molecules. The N-terminal of the JAK kinases contains A, B, C, D, and E 5 sub-domains, being called JAK homology domains or JH domain. It is speculated that this region may participate into the coupling between the JAK kinase with the cytokine receptor or other kinds of signaling protein molecules. Being different with most growth factor receptors with tyrosine kinase activity, cytokine receptors generally contain no tyrosine kinase active domain in the cytoplasmic part and therefore are not capable of activating other kinds of signaling molecules as what the growth factor receptor does through using the self-tyrosine kinase activity upon the binding of ligand. But the non-transmembrane protein tyrosine kinase contained in the target cell under the action of cytokines is capable of mediating the activation of the signaling protein molecules after the binding between the cytokine and its receptor [4].
STATs, as the target proteins of the JAKs, belong to a family of transcription factor presented in the cytoplasm. STAT1α, STAT2 are two transcription factors activated during the signaling transduction of interferon α / β. Moreover, the DNA binding proteins generated after the stimulation of target cells with IFN- γ are the dimmers of the STAT1α. Because these proteins can be activated under stimulation from external signals and be further directly transferred into the nucleus, triggering the transcription of the corresponding target genes, it is called STATs [5]. In addition, there is also another kind of STAT with the C-terminal containing 38 amino acids less than STAT1α, defined as STATlβ. After this, it has been cloned of IL- 6 activated STAT3, STAT3β, IL- 12 activated STAT4, prolactin activated STAT5, and IL- 4 activated STAT6 as well as the STAT proteins in the Drosophila [6, 7]. The molecule size of the mammalian STAT1 / STAT6 ranges from 734 ~ 851 amino acids.
The structure can be divided into N- terminal conserved sequence, DNA binding domain in the middle region, SH3-like domain, SH2 domain and C- terminal transcriptional activation domain. Many kinds of cytokines and non-immune biochemical media are capable of activating the JAK / STAT signaling pathway. These molecules include interferon (INF), glycoprotein 130 (GP130) the ligand of the receptor family interleukin (IL- 6), leukemia inhibitory factor (LIF), the ligand epidermis growth factor of the tyrosine kinase receptor ligands, the ligand, angiotensin (ANG) of the G-protein coupled receptor, as well as growth hormone and prolactin, etc. [8-10]. These ligands and corresponding receptors leads to JAKs activation with the activated receptor JAKs cause phosphorylation of specific tyrosine residues, and making it become the binding site of STATs and other intracellular signaling molecules. The STATs gathered in these loci are phosphorylated and activated under the action of JAKs. The activated STATs are dissociated from the receptor, have dimerization, and then penetrate through the nuclear membrane and enter into the nucleus to regulate the expression of associated genes.
JAK / STAT signaling pathway participates into a wide range of intracellular processes of cell proliferation, differentiation, apoptosis and immune regulation. Since 2005, a number of studies have found that, the mutation of Janus kinase 2 (JAK2) (JAK2V617F) are related three blood-related diseases: polycythemia Vera, thrombocythemia, and myelofibrosis. The mutation of JAK1 and JAK3 kinase is related to many inflammatory diseases of immune system such as rheumatoid arthritis. Because of these findings, there are now a total of more than a dozen JAK inhibitors, including the ruxolitinib of the Incyte Pharmaceuticals (The United States), that have entered clinical development phase (see table at right). The JAK inhibitors are mainly applied to the treatment of diseases such as bone marrow fibrosis, rheumatoid arthritis, psoriasis, polycythemia Vera, pancreatic cancer, blood cancer, and primary thrombocythemia.
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