Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have isolated cDNA clones encoding a third, widely expressed, member of the JAK family of protein tyrosine kinases (PTKs). The anticipated amino acid sequence of JAK2 predicts the presence of two kinase-related domains, a feature characteristic of this family of PTKs. The structural similarity of JAK2 to the other members of this family extends towards their N-termini, beyond the two kinase-related domains, and reveals five further domains of substantial amino acid similarity. The C-terminal portion of one of these domains, the JH4 domain, bears an intriguing, albeit tenuous, similarity to the core element of the SH2 domain, whereas the remaining JAK homology domains do not appear to be a feature of other known proteins.
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PMID:JAK2, a third member of the JAK family of protein tyrosine kinases. 162 May 48

The protein-tyrosine kinases (PTKs) are a burgeoning family of proteins, each of which bears a conserved domain of 250 to 300 amino acids capable of phosphorylating substrate proteins on tyrosine residues. We recently exploited the existence of two highly conserved sequence elements within the catalytic domain to generate PTK-specific degenerate oligonucleotide primers (A. F. Wilks, Proc. Natl. Acad. Sci. USA 86:1603-1607, 1989). By application of the polymerase chain reaction, portions of the catalytic domains of several novel PTKs were amplified. We describe here the primary sequence of one of these new PTKs, JAK1 (from Janus kinase), a member of a new class of PTK characterized by the presence of a second phosphotransferase-related domain immediately N terminal to the PTK domain. The second phosphotransferase domain bears all the hallmarks of a protein kinase, although its structure differs significantly from that of the PTK and threonine/serine kinase family members. A second member of this family (JAK2) has been partially characterized and exhibits a similar array of kinase-related domains. JAK1 is a large, widely expressed membrane-associated phosphoprotein of approximately 130,000 Da. The PTK activity of JAK1 has been located in the C-terminal PTK-like domain. The role of the second kinaselike domain is unknown.
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PMID:Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. 184 70

Interleukin-5 (IL-5) regulates the production and function of B cells, eosinophils and basophils. In particular, IL-5 plays a critical role in the development of CD5-positive B (B-1) cells. The pleiotropic activity of IL-5 on target cells is directly dependent on the initial binding to IL-5 specific cell-surface receptor (IL-5R). The IL-5 signals are mediated through the high affinity IL-5R which is composed of two different polypeptide chains, alpha and beta. The alpha chain is a membrane-penetrated glycoprotein that specifically binds IL-5 and retains features common to the cytokine receptor superfamily. The beta chain by itself does not bind IL-5, but it can convert the low affinity IL-5R into the high affinity IL-5R and in indispensable for IL-5 signal transduction. The beta chain is shared among receptors for IL-5, IL-3 and GM-CSF and is called beta c. The cytoplasmic comains of both IL-5R alpha and beta c are essential for signal transduction. The membrane proximal proline-rich sequence of the cytoplasmic domain of IL-5R alpha was found to be essential for the IL-5-induced proliferative response, expression of nuclear proto-oncogenes such as c-jun, c-fos and c-myc, and activation of Bruton's tyrosine and JAK2 kinases. Furthermore, JAK2 activation correlates with proline residues in Pro-Pro-X-Pro motif in the cytoplasmic domain of IL-5R alpha. These results indicate that activation of JAK2 and its substrate is critical to coupling IL-5-induced tyrosine phosphorylation and ultimately mitogenesis. I will discuss about molecular mechanisms of IL-5 signaling and B cell defect in X-linked immunodeficient mice in relation to IL-5 signaling.
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PMID:[Structure and function of IL-5 receptor]. 747 55

Previous studies suggested that interleukin-11 (IL-11) induces the activation of mitogen-activated protein kinase (MAPK) in mouse 3T3L1 cells. However, the mechanisms by which IL-11 activates MAPK remain elusive. Our present results show that IL-11 promotes the formation of the active GTP-bound form of Ras, suggesting that IL-11 actions may be transduced in part through the Ras/MAPK signaling pathway. By immunoblotting and immunoprecipitation, we further demonstrate the association of tyrosine phosphoproteins with Grb2, an adaptor protein serving as a key intermediate for Ras activation. These phosphotyrosine-containing proteins have been subsequently identified to be JAK2, Fyn, and Syp. JAK2 and Fyn are transiently associated with Grb2 upon stimulation with IL-11, suggesting that JAK2 and Fyn may be involved in transducing signals from the IL-11 receptor-glycoprotein 130 to the Ras system through Grb2. Taken together, these results suggest that IL-11-induced interactions of JAK2, Fyn, and Grb2 may not only provide a novel mechanism for the activation of the Ras/MAPK system but also indicate cross-talk among diverse signaling pathways.
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PMID:Interleukin-11 induces complex formation of Grb2, Fyn, and JAK2 in 3T3L1 cells. 749 80

In rat liver epithelial cell lines (WB or GN4), angiotensin II (Ang II) stimulates cytosolic tyrosine kinase activity, in part, through a calcium-dependent mechanism. In other cell types, selected hormones that activate Gi- or Gq-coupled receptors stimulate the soluble tyrosine kinase, p125FAK. Immunoprecipitation of p125FAK from Ang II-activated GN4 cells demonstrated a doubling of p125FAK kinase activity. However, an additional Ang II-activated tyrosine kinase (or kinases) representing the majority of the total activity was detected when the remaining cell lysate, immunodepleted of p125FAK, was reimmunoprecipitated with an anti-phosphotyrosine antibody. Cytochalasin D pretreatment blocks G-protein receptor-dependent tyrosine phosphorylation in Swiss 3T3 cells. While cytochalasin D decreased the Tyr(P) content of 65-75-kDa substrates in Ang II-treated GN4 cells, it did not diminish tyrosine phosphorylation of 115-130-kDa substrates, again suggesting activation of at least two tyrosine kinase pathways in GN4 cells. To search for additional Ang II-activated enzymes, we used molecular techniques to identify 20 tyrosine kinase sequences in these cell lines. None was the major cytosolic enzyme activated by Ang II. Specifically, JAK2, which had been shown by others to be stimulated by Ang II in smooth muscle cells, was not activated by Ang II in GN4 cells. Finally, we purified Tyr(P)-containing tyrosine kinases from Ang II-treated cells, using anti-Tyr(P) and ATP affinity resins; 80% of the tyrosine kinase activity migrated as a single 115-120-kDa tyrosine-phosphorylated protein immunologically distinct from p125FAK. In summary, Ang II activates at least two separate tyrosine kinases in rat liver epithelial cells; p125FAK and a presumably novel, cytosolic 115-120-kDa protein referred to as the calcium-dependent tyrosine kinase.
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PMID:Angiotensin II activates at least two tyrosine kinases in rat liver epithelial cells. Separation of the major calcium-regulated tyrosine kinase from p125FAK. 749 50

The tyrosine kinase JAK2 is an integral part of the signal transduction pathways of a number of cytokines and growth factors, including IFN-gamma. Previously, we identified a species-nonspecific binding site for the C terminus of IFN-gamma, encompassed by IFN-gamma peptide IFN-gamma(95-133), on the membrane proximal region of the cytoplasmic domain of the IFN-gamma R alpha-chain. Using both a radioligand binding assay and coimmunoprecipitation with antireceptor antiserum, we were able to demonstrate specific interaction of JAK2 with the murine IFN-gamma R(MIR) alpha-chain. Furthermore, this interaction is increased by the addition of murine IFN-gamma or its C-terminal peptide, muIFN-gamma(95-133). We also identified two regions of the cytoplasmic domain of the receptor that interact with JAK2 using synthetic peptides of the MIR alpha-chain in receptor competition studies. These regions are encompassed by receptor peptide MIR(283-309), which is adjacent to the membrane proximal region at which the C terminus of IFN-gamma binds, and receptor peptide MIR(404-432), which lies near the C terminus of the receptor, encompassing a potentially important phosphorylation site. These data show site-specific interaction between JAK2 and IFN-gamma with the IFN-gamma R and have broader implications for the role of the IFN-gamma ligand in the IFN-gamma signal transduction pathway. Furthermore, the data support previous studies that demonstrated that intracellular IFN-gamma plays a role in cell activation.
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PMID:Identification of IFN-gamma receptor binding sites for JAK2 and enhancement of binding by IFN-gamma and its C-terminal peptide IFN-gamma(95-133). 749 45

Oncostatin M (OSM) is a 28-kD glycoprotein recently identified as a growth factor for human multiple myeloma cells. It belongs to a family of distantly related cytokines that includes interleukin 6, ciliary neurotrophic factor, leukemia-inhibitory factor, and interleukin 11. These cytokines initiate signaling by inducing either homodimerization of gp130 or heterodimerization of gp130 with leukemia-inhibitory factor receptor beta components. Such dimerization in turn activates receptor-associated tyrosine kinases. In the present study using U266B1 human multiple myeloma cells, we show that OSM induces tyrosine phosphorylation and activation of JAK2, but not JAK1 or Tyk2, kinases. The results also demonstrate that OSM induces direct interaction of JAK2 kinase with Grb2, an SH2/SH3 domain containing adaptor protein. The SH2 domain of Grb2 is directly associated with tyrosine-phosphorylated JAK2. Furthermore, the presence of Sos in the JAK2-Grb2 complex suggests a role for Ras in OSM-transduced signaling.
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PMID:Oncostatin M induces association of Grb2 with Janus kinase JAK2 in multiple myeloma cells. 750 25

JAK family tyrosine kinases have recently been implicated in intracellular signal transduction by transmembrane cytokine receptors of the interferon (IFN) and hematopoietin receptor families. Using the prolactin (PRL)-dependent rat pre-T cell line Nb2, a PRL receptor-associated, candidate tyrosine kinase of 120-130 kDa was recently characterized (1). In the present work this protein is identified as JAK2, based upon reciprocal anti-JAK2 and anti-phosphotyrosine immunoprecipitation and immunoblotting. JAK2 underwent rapid and transient tyrosine phosphorylation in response to receptor activation, reaching peak levels within 5 min of exposure to 100 nM PRL at 37 degrees C. In vitro tyrosine kinase assays using either [gamma-32P]ATP and autoradiography or unlabeled ATP combined with anti-phosphotyrosine immunoblotting, demonstrated that the activity of JAK2 was stimulated by PRL. Phosphoamino acid analysis of JAK2 after in vitro tyrosine kinase assay revealed that the majority of phosphate was incorporated into tyrosine residues. Furthermore, JAK2 was associated with PRL receptors to a comparable extent before and after PRL binding, as demonstrated by anti-receptor immunoprecipitation and subsequent anti-JAK2 immunoblotting. We propose that binding of ligand to the PRL receptor activates preassociated JAK2, and that this enzyme generates the initial signal in the intracellular communication cascade.
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PMID:Activation of receptor-associated tyrosine kinase JAK2 by prolactin. 750 35

Growth hormone (GH) plays a central role in regulating growth and intermediary metabolism in vertebrates, although the mechanisms by which GH initiates these actions are largely unknown. The GH receptor, a member of the cytokine receptor superfamily, does not demonstrate homology with any known tyrosine kinases. However, addition of GH to cells in vitro has been shown to stimulate tyrosine phosphorylation of various intracellular proteins including mitogen-activated protein kinases (MAP kinases) and the newly described Janus kinase, JAK2. Subsequent steps in GH-mediated signal transduction have not been delineated. In the present study, we have examined early events in GH action in vivo. Hypophysectomized juvenile male rats were treated with GH for 15, 30, or 60 min. Rat liver whole cell and nuclear extracts were prepared and analyzed via SDS-polyacrylamide gel electrophoresis and Western blotting techniques. GH rapidly stimulated the tyrosine phosphorylation of at least 8 nuclear proteins of 205, 91, 83, 80, 65, 53, 44, and 42 kDa, and caused the dephosphorylation of a single approximately 149-kDa protein. Using specific antibodies, we have identified three of these nuclear phosphoproteins as 42- and 44-kDa MAP kinases, and as STAT91, a 91-kDa component of the interferon-stimulated gene factor-3 protein complex. One consequence of the activation of STAT91 in the nucleus is the appearance of GH-stimulated DNA binding activity, as assessed by gel-mobility shift assay using an oligonucleotide containing a c-sis-inducible element from the c-fos promoter. These results show that nuclear protein tyrosine phosphorylation is a prominent early event in GH action in vivo and demonstrate a link between GH-stimulated signal transduction and target gene expression.
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PMID:Rapid changes in nuclear protein tyrosine phosphorylation after growth hormone treatment in vivo. Identification of phosphorylated mitogen-activated protein kinase and STAT91. 751 Jun 76

Interferon-gamma (IFN-gamma) induces the expression of a set of early response genes by tyrosine phosphorylation of latent transcription factors such as p91. Although the tyrosine kinases, Jak1 and Jak2, have recently been shown to be critical for signal transduction by IFN-gamma, evidence is lacking for both tyrosine phosphorylation of the IFN-gamma receptor (IFN-gamma R) and the interaction between Jak1, Jak2, and the IFN-gamma R. In this report, we show that binding of IFN-gamma to HeLa cells initiated a series of events that resulted in the extremely rapid (15 s) tyrosine phosphorylation of not only Jak1, Jak2, and p91 but also the IFN-gamma R. Coimmunoprecipitation experiments revealed that Jak1 was associated with the IFN-gamma R prior to ligand binding, whereas Jak2 became part of the IFN-gamma R-Jak1 complex immediately after ligand binding. H2O2/vanadate treatment of cells for 15 min resulted in only the tyrosine phosphorylation of Jak1 and IFN-gamma R. Only after 60 min of this treatment did we observe tyrosine phosphorylation of Jak2 and p91 and assembly of the transcription factor complex FcRF gamma that binds to the promoter of the fcgr1 gene. These data suggest that JAK1 associates with the IFN-gamma R prior to ligand binding. IFN-gamma treatment of cells results in recruitment of JAK2 into the IFN-gamma R-Jak1 complex followed by assembly of the transcription factor FcRF gamma complex.
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PMID:Interferon-gamma induces tyrosine phosphorylation of interferon-gamma receptor and regulated association of protein tyrosine kinases, Jak1 and Jak2, with its receptor. 751 65


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