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30-702: 5AEP , 2B7A , 2W1I , 2XA4 , 3E62 , 3E63 , 3E64 , 3FUP , 3IO7 , 3IOK , 3JY9 , 3KCK , 3KRR , 3LPB , 3Q32 , 3RVG , 3TJC , 3TJD , 3UGC , 3ZMM , 4AQC , 4BBE , 4BBF , 4C61 , 4C62 , 4D0W , 4D0X , 4D1S , 4E4M , 4E6D , 4E6Q , 4F08 , 4F09 , 4FVP , 4FVQ , 4FVR , 4GFM , 4GMY , 4HGE , 4IVA , 4JI9 , 4JIA , 4P7E , 4ZIM , 4YTC , 4YTF , 4YTH , 4YTI , 5CF4 , 5CF5 , 5CF6 , 5CF8 , 5I4N , 4Z32 , 5L3A 3717 16452 ENSG00000096968 ENSMUSG00000024789 O60674 Q62120 NM_001322199 NM_001322204 NM_001048177 NM_008413 NP_001309133 NP_004963 NP_001041642 NP_032439 Janus kinase 2 (commonly called JAK2 )

60-452: A pleckstrin homology (PH) domain . These PH domains bind to phosphatidylinositol lipids that have been phosphorylated at particular positions on the head group. These enzymes can bind to activated signaling complexes at the membrane through PH domain interactions with phosphorylated phosphatidylinositol lipids. The most common theme in nRTKs and RTK regulation is tyrosine phosphorylation. With few exceptions, phosphorylation of tyrosines in

90-535: A pseudokinase domain , has since been found to be catalytically active, albeit at only 10% that of the JH1 domain. Loss of JAK2 is lethal by embryonic day 12 in mice. JAK2 orthologs have been identified in all mammals for which complete genome data are available. JAK2 gene fusions with the TEL ( ETV6 ) ( TEL-JAK2 ) and PCM1 genes have been found in patients suffering leukemia , particularly clonal eosinophilia forms of

120-433: A transmembrane -spanning region. Most of the nRTKs are localized in the cytoplasm, but some nRTKs are anchored to the cell membrane through amino-terminal modification. These enzymes commonly have a modular construction and individual domains are joined together by flexible linker sequences. One of the important domain of nRTKs is the tyrosine kinase catalytic domain, which is about 275 residues in length. The structure of

150-528: A pseudo-substrate sequence thought to interfere with Jak substrate binding and phosphoryl transfer. In addition to a pseudo-substrate sequence, SOCS proteins possess an SH2 domain that binds to a phosphotyrosine in the Jak activation loop, which may facilitate interaction between the pseudosubstrate sequence and the kinase domain. Binding of the SH2 domain to the activation loop could also block substrate access directly or alter

180-399: A treatment of these tumors. Some of nRTKs inhibitors are already tested as an anti-cancer agents. This targeted therapy blocks intracellular processes involved in the tumor transformation of cells and / or maintenance of malignant phenotype of tumor cells. Usually monoclonal antibodies are used for the targeted blockade of RTK, which block the extracellular domain of the receptor and prevent

210-448: Is Ile/Val–Tyr–Gly–Val–Leu/Val. Different preferred sequences around Tyr in Src and Abl suggest that these two types of nRTKs phosphorylates different targets. Non-receptor tyrosine kinases do not contain only a tyrosine kinase domain, nRTKs also possess domains that mediate protein-protein, protein-lipid, and protein- DNA interactions. One of the protein-protein interaction domains in nRTKs are

240-501: Is 40 kilobases long and has 12 exons . The receptor, found on pluripotent progenitor cells, induces tyrosine phosphorylation within the cell and promotes proliferation and differentiation within the hematopoietic cell lines. It can be found on basophils and pDCs as well as some cDCs among peripheral blood mononuclear cells. CD123 is expressed across acute myeloid leukemia (AML) subtypes, including leukemic stem cells . Tagraxofusp, human IL-3 fused to diphtheria toxin,

270-498: Is Tyr-416. This is an autophosphorylation site in the activation loop. It was found that a phosphorylation of Tyr-416 and Tyr-416 can suppressing the transforming ability of the activating Tyr-527→Phe mutation by Tyr-416→Phe mutation leads to maximal stimulation of kinase activity. Both the SH2 and SH3 domains are important for a negative regulation of Src activity. Mutations in the SH2 and SH3 domains that disrupt binding of phosphotyrosine lead to activation of kinase activity. Although

300-552: Is a non-receptor tyrosine kinase . It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors), the GM-CSF receptor family ( IL-3R , IL-5R and GM-CSF-R ), the gp130 receptor family (e.g., IL-6R ), and the single chain receptors (e.g. Epo-R , Tpo-R , GH-R , PRL-R ). The distinguishing feature between janus kinase 2 and other JAK kinases

330-564: Is activated by stimulation of B-cell receptor, which leads to the recruitment and phosphorylation of Zap70-related nRTK, Syk . Another nRTK, Btk , is also involved in signaling mediated by the B-cell receptor. Mutations in the Btk gene are responsible for X-linked agammaglobulinemia , a disease characterized by the lack of mature B-cells. Unlike receptor tyrosine kinases, nRTKs lack receptor-like features such as an extracellular ligand -binding domain and

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360-424: Is enzymatically nonfunctional, but maybe it plays a role in the regulation of Jak activity. The experiments with a mutant of the Jak family member Tyk2 , in which the pseudo-kinase domain is deleted, showed that these mutant enzyme lacks catalytic activity in vitro and is not capable of interferon-mediated signal transduction. In contrast, another mutant of the Jak family Jak2 , also lacking the pseudo-kinase domain,

390-695: Is one of the methods of diagnosing polycythemia vera . Janus kinase 2 has been shown to interact with: Prolactin signals through JAK2 are dependent on STAT5 , and on the RUSH transcription factors . Non-receptor tyrosine kinase Unlike the receptor tyrosine kinases (RTKs), the second subgroup of tyrosine kinases, the non-receptor tyrosine kinases are cytosolic enzymes. Thirty-two non-receptor tyrosine kinases have been identified in human cells ( EC 2.7.10.2 ). Non-receptor tyrosine kinases regulate cell growth, proliferation, differentiation, adhesion, migration and apoptosis , and they are critical components in

420-426: Is the lack of Src homology binding domains ( SH2 / SH3 ) and the presence of up to seven JAK homology domains (JH1-JH7). Nonetheless the terminal JH domains retain a high level of homology to tyrosine kinase domains. An interesting note is that only one of these carboxy-terminal JH domains retains full kinase function (JH1) while the other (JH2), previously thought to have no kinase functionality and accordingly termed

450-524: The Src family member Lck . When antigen binds to T-cell receptor, Lck becomes autophosphorylated and phosphorylates the zeta chain of the T-cell receptor , subsequently another nRTK, Zap70 , binds to this T-cell receptor and then participates in downstream signaling events that mediate transcriptional activation of cytokine genes. Another Src family member Lyn is involved in signaling mediated by B-cell receptor. Lyn

480-490: The activation loop of nRTKs leads to an increase in enzymatic activity. Activation loop phosphorylation occurs via trans-autophosphorylation or phosphorylation by different nRTKs. It is possible to negatively regulate kinase activity by the phosphorylation of tyrosines outside of the activation loop. Protein tyrosine phosphatases (PTPs) restore nRTKs to their basal state of activity. In some cases PTPs positively regulate nRTKs activity. Tyrosine kinases of Src family contain

510-552: The Src homology 2 ( SH2 ) and 3 ( SH3 ) domains. The longer SH2 domain (~100 residues) binds phosphotyrosine (P-Tyr) residues in a sequence-specific manner. The P-Tyr interacts with SH domain in a deep cleft, which cannot bind unphosphorylated Tyr. The SH3 domain is smaller (~60 residues) and binds proline-containing sequences capable of forming a polyproline type II helix . Some nRTKs without SH2 and SH3 domains possess some subfamily-specific domains used for protein-protein interactions. For example, specific domains that target enzymes to

540-418: The binding of a ligand. For the specific blockade of nRTKs, however, low molecular weight substances called Tyrosine-kinase inhibitor (TKIs) are used, that block the transduction cascade either at the intracytosplasmatic level, or directly block the nRTKs. Examples of non-receptor tyrosine kinases include: IL-3R The interleukin-3 receptor ( CD123 ) is a molecule found on cells which helps transmit

570-457: The catalytic domain can be divided into a small and a large lobe, where ATP binds to the small lobe and the protein substrate binds to the large lobe. Upon the binding of ATP and substrate to nRTKs, catalysis of phosphate transfer occurs in a cleft between these two lobes. It was found that nRTKs have some sequence preference around the target Tyr. For example, the Src preferred sequence is Glu–Glu/Asp–Ile–Tyr–Gly/Glu–Glu–Phe and Abl preferred sequence

600-417: The conformation of the activation loop to repress catalytic activity. The mutation in a gene for non-receptor tyrosine kinase can results an aberrant activity of this enzyme. This pathologically increased activity of nRTK may be responsible for growth and progression of cancer cells, the induction of drug-resistance, formation of metastasis and tumor neovascularization . The inhibition of nRTKs could help to

630-489: The cytoplasmic part of cytokine receptors ( Jak family ) or two domains: an integrin -binding domain and a focal adhesion -binding domain (Fak family). The nRTK Abl possess the SH2 and SH3 domains, but also possesses other domains for interactions: F actin–binding domain and a DNA-binding domain contains a nuclear localization signal and is found in both the nucleus and the cytoplasm. In addition to SH2 and SH3 domains, Btk/Tec subfamily of nRTKs possess another modular domain,

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660-546: The disease. Mutations in JAK2 have been implicated in polycythemia vera , essential thrombocythemia , and myelofibrosis as well as other myeloproliferative disorders . This mutation (V617F), a change of valine to phenylalanine at the 617 position, appears to render hematopoietic cells more sensitive to growth factors such as erythropoietin and thrombopoietin , because the receptors for these growth factors require JAK2 for signal transduction. JAK2 mutation, when demonstrable,

690-626: The kinase domain, leading to stimulation of catalytic activity. Kinase activity of Zap70 can be increased by phosphorylation of Tyr-493 in the activation loop by Src family member Lck. Conversely the phosphorylation of Tyr-492 inhibit the kinase activity of Zap70; the mutation of Tyr-492 to phenylalanine results in Zap70 hyperactivity. Jak family members possess a fully functional tyrosine kinase domain and additionally pseudo-kinase domain in which substitution of several key catalytic residues leads to inactivation of kinase activity. This pseudo-kinase domain

720-451: The nRTK Abl contains SH3, SH2, and kinase domains in the same linear order as in Src, regulation of Abl is different. Abl lacks the negative regulatory phosphorylation site that is present in the carboxy terminus of Src, so the carboxy terminus of Abl does not have a functional role in the control of kinase activity. In a contrast to Src, mutations in the SH2 domain of Abl that abrogates phosphotyrosine binding do not activate Abl in vivo. For

750-588: The nRTK Csk . By the experiment of v-Src, an oncogenic variant of Src, the importance of this phosphorylation site was confirmed. This oncogenic v-Src is a product of the Rous sarcoma virus and as a result of an carboxy-terminal truncation, v-Src lacks the negative regulatory site Tyr-527 leading this enzyme to be constitutively active that in turn causes uncontrolled growth of infected cells. Moreover, substitution of this tyrosine with phenylalanine in c-Src results in activation. A second regulatory phosphorylation site in Src

780-444: The regulation of the immune system . The main function of nRTKs is their involvement in signal transduction in activated T- and B-cells in the immune system. Signaling by many receptors is dependent on nRTKs including T-cell receptors ( TCR ), B-cell receptors ( BCR ), IL-2 receptors ( IL-2R ), Ig receptors, erythropoietin ( EpoR ) and prolactin receptors . CD4 and CD8 receptors on T lymphocytes require for their signaling

810-481: The repression of kinase activity of Abl is important the SH3 domain; mutations in the SH3 domain result in activation of Abl and cellular transformation. The kinase activity of Syk is regulated by the SH2 domains. Binding of the two SH2 domains to the tyrosine-phosphorylated ITAM (immunoreceptor tyrosine-based activation motif) sequences in the zeta chain of the T-cell receptor is thought to relieve an inhibitory restraint on

840-399: The same typical structure: myristoylated terminus, a region of positively charged residues, a short region with low sequence homology, SH3 and SH2 domains, a tyrosine kinase domain, and a short carboxy-terminal tail. There are two important regulatory tyrosine phosphorylation sites. To repress kinase activity it is possible by phosphorylation of Tyr-527 in the carboxy-terminal tail of Src by

870-400: The signal of interleukin-3 , a soluble cytokine important in the immune system . The gene coding for the receptor is located in the pseudoautosomal region of the X and Y chromosomes . The receptor belongs to the type I cytokine receptor family and is a heterodimer with a unique alpha chain paired with the common beta (beta c or CD131) subunit . The gene for the alpha subunit

900-514: Was able to mediate growth hormone signaling. The role of the pseudo-kinase domain in Jak regulation is still not fully understood. There are two tyrosine phosphorylation sites within the activation loop. It is known that the autophosphorylation of the first of these tyrosines is important for stimulation of tyrosine kinase activity and biological function, but the role of the second tyrosine is not clear. JAKs are also regulated by SOCS (suppressor of cytokine signaling) proteins. These proteins contain

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