Tyrosine protein kinase/signal transducer and transcriptional activator inhibitor (JAK/STAT)

The protein tyrosine kinase JAK/signal and transcriptional activator STAT signaling pathway is another important cytokine signaling pathway that follows the Ras pathway. JAK (Januskinase) is a protein tyrosine kinase, and four family members have been discovered so far, namely JAK1, JAK2, TYK2 and JAK3. The first three are widely distributed in a variety of tissue cells, while JAK3 is only found in the bone marrow and lymphatic system. STATs (signal transducer and activator of transcription) are direct substrates of JAKs that deliver signaling agents into the nucleus and regulate the expression of specific genes. The JAK protein tyrosine kinase (JAK) is a non-receptor protein tyrosine kinase (PTK) that has been identified in recent years and plays an important role in cell signaling. It activates the cytokine receptor after binding to the corresponding ligand and activates another signaling protein molecule, the "signal transducer and activator of transcription" (STAT), to induce expression of the target gene. The JAK protein tyrosine kinase family is the third largest nontransmembrane protein tyrosine kinase (NMPTKs) family, second only to Src and Tec. It consists of four members, JAK1, JAK2, and JAK3. And Tyk2. They vary in size and have a molecular weight between 120 kD and 140 kD. The JAK family of molecules can be divided into two major structures. The C-terminus is two tightly linked tyrosine kinase activity-like domains, one of which is closest to the C-terminus is the catalytically active region of JAK kinase, and the other is located at its N-terminus. A kinase-like domain does not have tyrosine kinase activity and is currently thought to play a role in the binding of JAK kinase to other signaling protein molecules. The N-terminus of JAK kinase includes five subdomains of A, B, C, D, and E, which are called JAK homology or JH domain. It is speculated that this site may be involved in the coupling of JAK kinase to cytokine receptors or other signaling protein molecules. Unlike most growth factor receptors with tyrosine kinase activity, cytokine receptors usually have no tyrosine kinase activity domain in the cytoplasmic domain and therefore cannot be utilized under the action of the corresponding ligands like growth factor receptors. The tyrosine kinase activity of the body itself activates other signaling protein molecules. However, non-transmembrane protein tyrosine kinases present in target cells acting as cytokines can mediate activation of signaling protein molecules after binding of cytokines to their receptors [4]. As a target protein of JAKs, STATS is a family of transcription factors present in the cytoplasm. STAT1α and STAT2 are two transcription factors that are activated in the signaling of interferon α/β (Interferon, IFNα/β). The DNA-binding protein produced by IFN-γ stimulation of target cells is a dimer of STAT1α. These protein molecules are called STATs because they can be activated by external signals and directly transferred into the nucleus to trigger transcription of the corresponding target genes [5]. In addition, a STAT with a C-terminal 38 amino acids less than STAT1α is defined as STAT1β. Following this, IL-6-activated STAT3, STAT3β, IL-12-activated STAT4, prolactin-activated STAT5, IL-4-activated STAT6, and STAT proteins in Drosophila were cloned successively [6,7]. Mammalian STAT1/STAT6 molecules range in size from 734 to 851 amino acids. The structure can be divided into a N-terminal conserved sequence, a central DNA binding region, an SH3-like domain, an SH2 domain, and a C-terminal transcriptional activation region. Many cytokines and non-immunological biochemical mediators activate JAK/STAT signaling pathways, such as interferon (INF), glycoprotein 130 (glycoprotein 130, GP130) receptor family of interleukins (interleukin, IL- 6), leukemia inhibitory factor (LIF), tyrosine kinase receptor ligand epidermal growth factor, G-protein coupled receptor ligand angiotensin (ANG), and growth hormone and Prolactin and other [8~10]. Binding of these ligands to the corresponding receptors leads to activation of JAKs, which activate phosphorylation of specific tyrosine residues on the receptor and make them a binding site for STATs and other intracellular signaling molecules. The STATs at the site are activated by phosphorylation under the action of JAKs, and the activated STATs are separated from the receptor, dimerized, and then passed through the nuclear membrane to enter the nucleus to regulate the expression of related genes. JAK/STAT signal transduction pathway is widely involved in cell proliferation, differentiation, apoptosis and immune regulation. Some studies since 2005 have found that the variation of Janus kinase 2 (JAK2) (JAK2V617F) is associated with three blood system diseases of polycythemia vera, thrombocytosis and myelofibrosis. Mutations in JAK1 and JAK3 kinases are associated with inflammatory diseases of the immune system such as rheumatoid arthritis. As a result of these findings, including the ruxolitinib of Incyte Pharmaceuticals Inc., there are currently more than a dozen JAK inhibitors entering the clinical development phase (see table to the right). JAK inhibitors are mainly used for the treatment of diseases such as myelofibrosis, rheumatoid arthritis, psoriasis, true red blood cell polycytosis, pancreatic cancer, blood cancer and essential thrombocytosis.